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Precision Medicine in Practice: Timely Use of Tumor NGS Remains Suboptimal in Common Cancers

July 24, 2025July 24, 2025 RR

SUMMARY: Next-generation sequencing (NGS) has revolutionized the management of advanced cancers by enabling identification of tumor-specific genomic alterations for which targeted therapies are now available. National guidelines recommend early and routine NGS testing for patients with advanced or metastatic solid tumors to inform treatment decisions. In the United States, the five most prevalent advanced or metastatic solid tumors include advanced Non-Small Cell Lung Cancer (aNSCLC), metastatic Breast Cancer (mBC), metastatic Prostate Cancer (mPC), advanced Colorectal Cancer (aCRC), and metastatic Pancreatic Cancer (mPanC). For these malignancies, the integration of NGS has become increasingly critical in guiding targeted therapy selection and improving survival outcomes. Despite the approval of multiple targeted therapies for these malignancies, real-world utilization of NGS remains inconsistent.

In this study presented at the 2025 ASCO Annual Meeting, Chehade and colleagues, evaluated patterns in NGS testing and its timing, relative to patient mortality.

Study Overview: This retrospective analysis leveraged the Flatiron Health EHR-derived de-identified database across 280 cancer clinics, spanning data from 2011 onward. The study included patients with a diagnosis of aNSCLC, mBC, mPC, aCRC, or mPanC, all of whom had records of NGS testing and a documented date of death. The researchers identified 86,536 patients with advanced non-small cell lung cancer, 36,000 with metastatic breast cancer, 35,702 with advanced colorectal cancer, 24,105 with metastatic prostate cancer and 14,964 with metastatic pancreatic cancer. About a third of patients from each cancer group received NGS testing (NSCLC, 36.3%; breast cancer, 32.1%; colorectal cancer, 41%; prostate cancer, 30.9%; and pancreatic cancer, 35.4%).

Patients were categorized based on the interval between receipt of NGS results and death:

More than 3 months before death
Within 3 months of death
After death

Key Findings Across cancer types, only 30% to 40% of patients received NGS testing. Among those who were tested and had a recorded date of death, the timing of NGS was as follows:

Timing of First NGS	aNSCLC (N=19,958)	mBC (N=5,689)	mPC (N=3,397)	aCRC (N=8,553)	mPanC (N=3,957)
>3 mo before death	72.3%	81.6%	85.4%	85.0%	71.1%
Within 3 mo of death	25.6%	16.9%	13.5%	13.7%	26.5%
After death	2.1%	1.5%	1.1%	1.3%	2.4%

Notably, up to one in four patients with NSCLC or pancreatic cancer received their first NGS results within 3 months of death, a timeframe often too late for actionable therapeutic intervention.

Interpretation and Implications Despite advances in molecularly targeted therapies and growing guideline support for comprehensive genomic profiling, real-world testing patterns remain suboptimal:

Low uptake: Only about a third of eligible patients undergo NGS testing.
Late testing: A substantial proportion of tested patients receive results within 3 months of death.
Missed opportunities: Many patients are never tested—or are tested too late to benefit from life-extending therapies.

These findings highlight ongoing gaps in precision oncology implementation, especially in community-based settings.

Next Steps & Recommendations To improve the utility of NGS in oncology, efforts should focus on:

Earlier testing: At diagnosis or at first progression of advanced disease.
Workflow integration: Embedding NGS into routine clinical pathways.
Education: Raising awareness among clinicians and patients about the benefits of timely testing.
Health system support: Addressing barriers such as reimbursement, turnaround times, and tissue availability.

Conclusion: Real-World Data from this large retrospective analysis reveal late-stage testing and underutilization of life-prolonging genomic profiling. This study underscores an urgent need to optimize the timing and uptake of NGS testing in patients with advanced solid tumors. Earlier and broader testing is essential to ensure patients have access to the most effective, personalized treatment strategies, and to avoid the missed potential of life-extending therapies.

Utilization and timing of first tumor next-generation sequencing testing (NGS) in patients (pts) with five most common cancers in the USA. Chehade CH, Jo Y, Ozay ZI, et al. Doi: 10.1200/JCO.2025.43.16_suppl.11014. Abstract # 11014. Presented at: ASCO Annual Meeting; May 30-June 3, 2025; Chicago.

Practice-Changing Insights in Myeloma Prevention: DARZALEX® Shows Landmark Results in High-Risk Smoldering Myeloma (AQUILA Trial)

July 24, 2025July 24, 2025 RR

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Multiple Myeloma evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM.

Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. Smoldering Multiple Myeloma or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years.

The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3 g/dL, IgA M-spike of at least 2 g/dL or a urinary Bence Jones protein level of more than 1 g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values. Immunoparesis describes the reduction of normal/polyclonal immunoglobulin levels and is commonly seen in conditions such as MM, SMM, and MGUS. This phenomenon involves a decline in immunoglobulins not associated with the malignant clone-for instance, in IgG-type myeloma, levels of IgA and IgM are typically decreased. The severity of immunoparesis at diagnosis serves as an independent prognostic indicator in newly diagnosed multiple myeloma. Patients presenting with lower levels of uninvolved immunoglobulins tend to experience shorter Progression-Free Survival (PFS) and Overall Survival (OS).

High-risk SMM has long posed a therapeutic dilemma—patients face a substantial risk of progression to symptomatic disease, yet no standard treatment has been approved. Traditionally, observation has remained the mainstay approach, despite the documented risk of end-organ damage. Daratumumab (DARZALEX®), a CD38-targeting monoclonal antibody already approved for multiple myeloma, has now been evaluated in this pre-malignant population through the pivotal Phase 3 AQUILA trial.

Study Design: The AQUILA Trial
AQUILA was a global, multicenter, open-label, randomized Phase 3 study, evaluating the efficacy of subcutaneous Daratumumab monotherapy versus active monitoring in patients with high-risk SMM. Conducted across 124 sites in 23 countries, the trial enrolled 390 patients, randomized 1:1 to receive either subcutaneous Daratumumab 1800 mg with recombinant Hyaluronidase PH20 weekly during cycles 1–2, biweekly during cycles 3–6, and monthly thereafter for 39 cycles for 36 months, or until disease progression (N=194), or active monitoring (N=196).

Eligibility criteria included:

10% or more clonal plasma cells in bone marrow
At least one high-risk feature, such as:
- Serum M-protein 30 g/L or more
- IgA subtype
- Immunoparesis (2 or more uninvolved Ig isotypes)
- FLC ratio between 8 and 100
- Clonal plasma cells more than 50% but less than 60%

The Primary end point was Progression-Free Survival (PFS) defined as progression to active multiple myeloma as assessed by an Independent Review Committee in accordance with International Myeloma Working Group (IMWG) diagnostic criteria.

Efficacy Outcomes
After a median follow-up of 65.2 months, results demonstrated a clear and significant benefit for Daratumumab over observation:

Progression-Free Survival (PFS):
- 5-year PFS: 63.1% with Daratumumab vs 40.8% with active monitoring
- Hazard ratio (HR): 0.49 (95% CI: 0.36–0.67; P<0.001)
Overall Survival (OS):
- 5-year OS: 93.0% with Daratumumab vs 86.9% with active monitoring
- HR for death: 0.52 (95% CI: 0.27–0.98)

These results support a 51% reduction in risk of progression to active multiple myeloma or death with early Daratumumab intervention.

Safety Profile
Daratumumab was well tolerated:

Grade 3–4 hypertension was the most frequent serious AE (5.7%)
Treatment discontinuation due to AEs occurred in only 5.7%
No new safety signals were observed
Quality of life was maintained throughout treatment and comparable to active monitoring

Clinical Interpretation
The AQUILA trial provides the strongest evidence to date supporting early therapeutic intervention in high-risk SMM. Unlike prior trials (e.g., QuiRedex, ECOG E3A06), which demonstrated benefit with Lenalidomide-based regimens but did not lead to regulatory approval, AQUILA offers compelling long-term survival and disease control data using a well-tolerated, single-agent regimen. Importantly, patient-reported outcomes indicated no decline in quality of life, reinforcing the feasibility of early intervention.

Context & Historical Comparison

In QuiRedex (Rd vs monitoring), median time to progression was prolonged (9.5 vs 2.1 years), but approval was not pursued
ECOG E3A06 (Lenalidomide vs monitoring) showed improved PFS but no OS benefit
AQUILA uniquely demonstrates both PFS and OS advantages with a favorable safety profile, positioning Daratumumab as a potential new standard for early treatment of high-risk SMM

Conclusion
The AQUILA study marks a paradigm shift in the management of high-risk Smoldering Multiple Myeloma. Subcutaneous Daratumumab monotherapy not only halved the risk of progression or death but also preserved quality of life, supporting its consideration as the first active treatment option for this high-risk population. Oncologists should engage in shared decision-making with high-risk SMM patients regarding early therapeutic intervention, particularly in the context of these compelling new data.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. for the AQUILA Investigators. N Engl J Med 2025;392:1777-1788

OPDIVO Qvantig^TM (nivolumab + hyaluronidase-nvhy) is delivered via subcutaneous injection, streamlining administration for eligible patients^{1^*}

July 21, 2025July 21, 2025 RR

*3-5–minute vs 30-minute infusion of IV nivolumab. This does not account for all aspects of treatment. Actual clinic time may vary.^1,2

Expert opinion: Saby George, MD, FACP^†^†Dr Saby George, MD, is a paid consultant of Bristol Myers Squibb (BMS) who was compensated by BMS for his contributions to this article.

Content sponsored by Bristol Myers Squibb

Subcutaneous administration overview

While immune checkpoint inhibitors have emerged as key treatment options for certain types of cancer, they are primarily delivered through intravenous (IV) administration,³ creating a need for alternative routes of administration.^4-5 A subcutaneous (SC) injection may reduce the time preparing and administering treatment compared to IV delivery, offer practice flexibility that may free up infusion chairs, and deliver treatment faster.^3,5 “Infusion centers are overwhelmed. Infusion chairs may open up if we transition to approved SC options,” remarked Dr George.

Evaluation of comparable PK, efficacy, and safety of SC OPDIVO Qvantig with IV nivolumab

OPDIVO Qvantig is formulated with hyaluronidase to increase the dispersion and absorption of SC nivolumab.¹ CheckMate 67T, a randomized, open-label, phase 3 noninferiority trial, was designed to compare the PK, efficacy, and safety of OPDIVO Qvantig (delivered as a SC injection) with IV nivolumab.^1,4

OPDIVO QVANTIG, as monotherapy, is indicated for the first-line treatment of adult patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), following treatment with intravenous nivolumab and ipilimumab combination therapy. OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma. Please see additional 16 indications below.

OPDIVO QVANTIG is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO QVANTIG is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

Please see Important Safety Information for OPDIVO QVANTIG below and US Full Prescribing Information for OPDIVO QVANTIG.

CheckMate 67T was a phase 3, randomized (1:1), open-label, noninferiority trial evaluating OPDIVO Qvantig (1,200 mg of nivolumab and 20,000 units of hyaluronidase) compared to intravenous nivolumab, in adult patients with advanced or metastatic clear-cell renal cell carcinoma (ccRCC) who received prior systemic therapy.^1,4 Patients were stratiﬁed by weight (<80 kg versus ≥80 kg) and International Metastatic RCC Database Consortium (IMDC) risk score (favorable vs intermediate vs poor risk).¹ A total of 495 patients were randomized to receive either OPDIVO Qvantig every 4 weeks subcutaneously (n=248) or nivolumab 3 mg/kg every 2 weeks intravenously (n=247).^1,4 The co-primary endpoints were time-averaged serum concentration over 28 days (C_avgd28) and minimum serum concentration at steady state (C_minss).⁴ The key powered secondary endpoint was overall response rate, as assessed by blinded independent central review. The minimum follow-up time was 8 months.⁴

Pharmacokinetic, efficacy, and safety results

CheckMate 67T demonstrated that the PK of OPDIVO Qvantig was noninferior to that of intravenously administered nivolumab.^1,4*

OPDIVO Qvantig resulted in a safety profile comparable with IV nivolumab.¹ Dr George noted, “Safety was similar between administration methods. Rates of adverse reactions were similar for IV and SC nivolumab administration.”⁶ Please see safety table below for more information.

Summary and conclusions

OPDIVO Qvantig resulted in comparable PK, efficacy, and safety to IV nivolumab and may be the right option for your eligible patients.¹ This 3-5 minute SC injection option may reduce the steps required for preparation and time needed for administration compared to IV nivolumab.^1,2* There is no need for IV preparation, dilution, weight-based dose calculations, or port access with OPDIVO Qvantig.¹ According to Dr George, “For my appropriate patients, it gives me flexibility. It may save administration time.* For eligible patients, it’s great to have this subcutaneous treatment option.”

*3-5–minute vs 30-minute infusion of IV nivolumab. This does not account for all aspects of treatment. Actual clinic time may vary.^1,2

INDICATIONS

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the first-line treatment of adult patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), following treatment with intravenous nivolumab and ipilimumab combination therapy.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma following treatment with intravenous nivolumab and ipilimumab combination therapy.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for treatment of unresectable or metastatic melanoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of adult patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting after surgical resection.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma (UC).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant
chemoradiotherapy (CRT).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1%).
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine-and platinum-based chemotherapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1%).

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO QVANTIG. Early identification and management are essential to ensure safe use of OPDIVO QVANTIG. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity (please see Section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO QVANTIG interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over for at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO QVANTIG can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.
Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions.

Immune-Mediated Colitis

OPDIVO QVANTIG can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions.

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO QVANTIG can cause immune-mediated
Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions. Intravenous nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to intravenous nivolumab alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. With the combination of intravenous nivolumab and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% (35/320) of patients.

Immune-Mediated Endocrinopathies

OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO QVANTIG depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (1.2%) adverse Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions. Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade 1 (0.4%) adverse reaction.
Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (0.4%) adverse reactions. Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (5.7%) adverse reactions.
Grade 3 diabetes occurred in 4% (1/247) of patients receiving OPDIVO QVANTIG.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO QVANTIG can cause immune-mediated
Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving OPDIVO QVANTIG.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO QVANTIG can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (drug rash with eosinophilia and systemic symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative Withhold or permanently discontinue OPDIVO QVANTIG depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
Immune-mediated rash occurred in 7% (17/247) of patients, including Grade 3 (0.8%) and Grade 2 (2.8%) adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous nivolumab as single agent or in combination with chemotherapy or immunotherapy, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.
Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO QVANTIG. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO QVANTIG and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO QVANTIG prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when Nivolumab Is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including intravenous nivolumab, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO Qvantig.

Serious Adverse Reactions

In Checkmate 67T, serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG (n=247). Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications. In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving intravenous The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, the most frequent (≥10%) serious adverse reactions in the intravenous nivolumab arm (n=313) were diarrhea (2.2%), colitis (1.9%), and pyrexia (1.0%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the intravenous nivolumab plus intravenous ipilimumab arm (n=313) relative to the intravenous nivolumab arm (n=313). The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab plus intravenous ipilimumab arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).
In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with intravenous nivolumab in combination with platinum-doublet Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy. In Checkmate 77T, serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment (n=228). The most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). In the adjuvant phase of Checkmate 77T, 22% of patients experienced serious adverse reactions (n=142). The most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab plus intravenous ipilimumab (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.
In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving intravenous nivolumab (n=270). The most frequent serious adverse reactions reported in ≥ 2% of patients receiving intravenous nivolumab were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving intravenous nivolumab (n=351). The most frequent serious adverse reaction reported in ≥ 2% of patients receiving intravenous nivolumab was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). In Checkmate 901, serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in combination with chemotherapy; these included sepsis (1%). In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving intravenous nivolumab (n=452). Grade 3 or 4 adverse reactions occurred in 25% of intravenous nivolumab-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab (n=209). Serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab (n=532). A serious adverse reaction reported in ≥2% of patients who received intravenous nivolumab was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received intravenous nivolumab. In Checkmate 648, serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in combination with chemotherapy (n=310). The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury. In Checkmate 648, serious adverse reactions occurred in 69% of patients receiving intravenous nivolumab in combination with intravenous ipilimumab (n=322). The most frequent serious adverse reactions reported in ≥2% who received intravenous nivolumab in combination with intravenous ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in combination with intravenous ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with intravenous nivolumab in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia, (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. In Checkmate 76K, serious adverse reactions occurred in 18% of patients receiving intravenous nivolumab (n=524). Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1% of patients included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury).
The most frequent Grade 3-4 lab abnormalities reported in ≥1% of intravenous nivolumab-treated patients were increased lipase (2.9%), increased AST (2.2%), increased ALT (2.1%), lymphopenia (1.1%), and decreased potassium (1.0%).

Common Adverse Reactions

In Checkmate 67T, the most common adverse reactions (≥10%) in patients treated with OPDIVO QVANTIG (n=247) were musculoskeletal pain (31%), fatigue (20%), pruritus (16%), rash (15%), hypothyroidism (12%), diarrhea (11%), cough (11%), and abdominal pain (10%). In Checkmate 037, the most common adverse reaction (≥20%) reported with intravenous nivolumab (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with intravenous nivolumab (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the intravenous nivolumab arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 067, the most common (≥20%) adverse reactions in the intravenous nivolumab plus intravenous ipilimumab arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%).
In Checkmate 816, the most common (>20%) adverse reactions in the intravenous nivolumab plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). In Checkmate 77T, the most common adverse reactions (reported in ≥20%) in patients receiving intravenous nivolumab in combination with chemotherapy (n= 228) were anemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with intravenous nivolumab plus intravenous ipilimumab (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving intravenous nivolumab (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving intravenous nivolumab (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigator’s In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving intravenous nivolumab (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 274, the most common adverse reactions (20%) reported in patients receiving intravenous nivolumab (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%). In Checkmate 901, the most common adverse reactions (reported in ≥20% of patients) were nausea (52%), fatigue (48%), musculoskeletal pain (33%), constipation (30%), decreased appetite (30%), rash (25%), vomiting (23%), and peripheral neuropathy (20%). In Checkmate 238, the most common adverse reactions (≥20%) reported in intravenous nivolumab-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (≥20%) in intravenous nivolumab-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%). In Checkmate 648, the most common adverse reactions (≥20%) in patients treated with intravenous nivolumab in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with intravenous ipilimumab were rash (31%), fatigue (28 %), pyrexia (23%), nausea (22%), diarrhea (22%), and constipation (20%). In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with intravenous nivolumab in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%). In Checkmate 76K, the most common adverse reactions (≥20%) reported with intravenous nivolumab (n=524) were fatigue (36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and pruritus (20%).

Surgery Related Adverse Reactions

In Checkmate 77T, 5.3% (n=12) of the intravenous nivolumab-treated patients who received neoadjuvant treatment, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each).

Please see US Full Prescribing Information for OPDIVO QVANTIG.

References:

OPDIVO Qvantig [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
Bittner B et al. BioDrugs. 2018;32:425-440.
Albiges L et al. Ann Oncol. 2025;36(1):99-107.
Bittner B, Schmidt J. BioDrugs. 2024;38(1):23-46.
George S et al. Oral presentation at ASCO GU 2024. Abstract LBA360.

1992-US-2500197 05/25

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights

July 17, 2025July 17, 2025 RR

SUMMARY: The American Cancer Society estimates that 46,950 new cases of rectal cancer will be diagnosed in the US in 2025. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer all SEER stages combined is 67%.

The American Society of Clinical Oncology (ASCO) in 2024 published a guideline on treatment of locally advanced rectal cancer following a systematic review of research from 2013 to 2023. The systematic review included data from 12 randomized controlled trials, 2 systematic reviews, and 1 nonrandomized study.

The ASCO recommendations encouraged patients with MicroSatellite Stable (MSS) or proficient MisMatch Repair (MMR) locally advanced rectal cancer who have undergone assessment with dedicated rectal sequence pelvic MRI to consider Total Neoadjuvant Therapy (TNT) as initial treatment, for tumors in the lower rectum. They also encouraged those who are at a higher risk of local or distant metastases (T4, extramural vascular invasion and/or tumor deposits, threatened mesorectal fascia or intersphinteric plane and/or not eligible for sphincter sparing surgery, to consider TNT. For patients receiving TNT, long course chemoradiation is preferred, followed by chemotherapy consolidation prior to surgery.

Patients who do not present with high-risk factors (upper and middle rectal cancer and more than 5 mm of extramural invasion) are eligible to receive neoadjuvant FOLFOX chemotherapy, with selective ChemoRadiation Therapy (CRT) when extent of tumor response to chemotherapy is deemed insufficient.

Nonoperative management may be offered instead of total mesorectal excision for patients who demonstrate a clinical Complete Response to neoadjuvant therapy.

Immunotherapy is the recommended treatment for patients with tumors presenting with MicroSatellite Instability-High (MSI-H) or MisMatch Repair (MMR)-deficient disease.

The additional information provided below by ASCO is meant to addresses some of the questions that clinicians may face as they implement the recommendations into clinical practice.

Which Patients Are Included in the ASCO Guideline for Locally Advanced Rectal Cancer?
The ASCO guideline for locally advanced rectal cancer includes patients with T3 or T4 and/or node-positive disease. While T3 tumors with MRI-assessed extramural invasion ≤5 mm generally have better outcomes, the guideline classifies all low T3 rectal tumors, regardless of depth of invasion, as higher risk and includes them due to their increased recurrence risk. Patients with favorable T3 features may be addressed in a future guideline for early-stage rectal cancer.

What Is the Extent of Tumor Response Required for Omission of Radiation, That Is, Delivery of FOLFOX (Fluorouracil, Leucovorin, and Oxaliplatin) Chemotherapy Alone, for Patients with Locally Advanced Rectal Cancer?
This question applies to patients similar to those enrolled in the PROSPECT trial—specifically, individuals with T2 or T3 rectal tumors situated at least 3 mm from the circumferential resection margin, with no more than three involved pelvic lymph nodes, and eligible for sphincter-sparing surgery. In the trial, a tumor area reduction of at least 20% was considered an adequate response to potentially omit radiation therapy. However, it’s important to note that some lower-risk patients from the study fall outside the scope of the current ASCO guidelines for locally advanced rectal cancer.

What Is the Balance of Benefits and Harms in the PROSPECT Trial of FOLFOX with Selective Chemoradiation Versus Chemoradiation Alone?
Neoadjuvant chemoradiation (CRT) for rectal cancer has historically been associated with long-term bowel, bladder, and sexual dysfunction in approximately 14% of patients. In light of this, the PROSPECT trial explored a de-escalation approach to potentially reduce toxicity by omitting routine pelvic radiation in select patients with mid-rectal tumors that do not involve the mesorectal fascia.

This phase III noninferiority trial demonstrated comparable Disease-Free Survival, Overall Survival, and local recurrence between patients treated with neoadjuvant FOLFOX (infusional 5-FU, leucovorin, and oxaliplatin) and those who received standard CRT with 5-FU. With efficacy outcomes being similar, patient safety and quality of life became central in guiding treatment choices.

Clinician-reported Adverse Events (AE) of Grade 3 or more were more common with FOLFOX (41.0%) compared to CRT (22.8%), with neutropenia, pain, and hypertension being the most frequent in the FOLFOX group. In the CRT group, common severe AEs included lymphopenia, diarrhea, and hypertension.

Regarding neuropathy, FOLFOX was associated with a higher rate pre-surgery (19% vs 5%) but showed comparable rates to CRT at 12 and 18 months postoperatively. Patient-reported outcomes revealed that while both groups experienced significant symptoms during treatment (e.g., fatigue, appetite loss, neuropathy, diarrhea), most severe symptoms resolved by 12 months post-surgery.

Sexual function, particularly among men and women in the CRT group, was more negatively impacted at 12 months, but differences between groups diminished by 24 months. Health-Related Quality of Life (HRQOL) was similar across both treatment arms throughout the follow-up period.

Treatment decisions may also be influenced by individual concerns: for example, younger women concerned about fertility might prefer chemotherapy alone, while those seeking to avoid long-term neuropathy might favor CRT. Surgical outcomes, including ostomy rates, also play a role. While data from the PROSPECT trial on surgical outcomes are forthcoming, similar trials (e.g., CONVERT) reported a lower rate of preventive ileostomy with neoadjuvant chemotherapy compared to CRT.

What Is the Timing of Assessment for Clinical Complete Response and Potential Nonoperative Management Following Total Neoadjuvant Therapy?
Although this topic was not formally evaluated in the ASCO guideline, the Expert Panel generally supported the assessment timeline used in the OPRA phase II trial, which evaluated clinical Complete Response approximately 8 weeks (±4 weeks) after completing total neoadjuvant therapy (TNT). Panelists noted that if radiation is given first in the TNT sequence, waiting an additional 8 weeks after chemotherapy might lead to an overly long treatment-free period. In such cases, an earlier response assessment may be appropriate. If the initial evaluation shows a near-Complete Response, reassessment within 8 weeks is advised to monitor for full clinical response and consider nonoperative management, as being studied in the ongoing JANUS trial comparing doublet and triplet consolidation chemotherapy.

What Tools Should Be Used in the Assessment of Patients Who Are Participating in NOM?
This guidance is based on the follow-up procedures used in the OPRA trial for NonOperative Management (NOM) of locally advanced rectal cancer. Patients underwent digital rectal exams and flexible sigmoidoscopy every 4 months during the first 2 years after initial response assessment, then every 6 months for the next 3 years. Rectal MRI was performed at least every 6 months for the first 2 years, with less frequent imaging afterward. If imaging or endoscopy showed signs of regrowth or a decline in response, patients exited the NOM protocol and were referred for surgery. Routine biopsies of the tumor site were not required. Annual CT scans of the chest, abdomen, and pelvis were conducted for all patients.

Does Circulating Tumor DNA Have A Role in the Assessment of Response for Patients Who Have Undergone Neoadjuvant Therapy for Locally Advanced Rectal Cancer?
Currently, there is not enough evidence to support the use of circulating tumor DNA (ctDNA) in predicting treatment response for patients with locally advanced rectal cancer. Ongoing research in this area will be reviewed for potential inclusion in future updates to the ASCO guideline.

Should Endorectal Ultrasonography And/or Computed Tomography Be Used to Assess Locally Advanced Rectal Cancer When MRI Is Not Available?
Traditionally, Endorectal UltraSound (EUS) and sometimes CT scans have been used to evaluate rectal cancer. However, high-resolution MRI provides a more accurate assessment of tumor invasion into the MesoRectal Fascia (MRF). While MRI might not be accessible in all settings, no validated alternative imaging method is currently recommended in this guideline. In cases where MRI is not feasible, EUS and CT may be used, though they do not offer complete tumor staging.

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights. Scott AJ, Kennedy EB, Berlin J, et al. JCO Oncol Pract. 2025 Mar;21:281-286.

Three-Year Overall Survival with OPDUALAG® in Advanced Melanoma

July 17, 2025July 17, 2025 RR

SUMMARY: The American Cancer Society estimates that for 2025, about 104,960 new cases of melanoma of the skin will be diagnosed in the United States and 8430 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by immune checkpoints or gate keepers. With the recognition of immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® (Ipilimumab), a fully human immunoglobulin G1 monoclonal antibody that blocks immune checkpoint protein/receptor CTLA-4 was compared with PD-1 inhibitors, OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab) in patients with advanced melanoma, and both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), and with a better safety profile. In the CheckMate 067, which is a double-blind Phase III study, results from the 6.5 year analysis showed that a combination of OPDIVO® plus YERVOY® demonstrated significant improvement in OS and PFS, when compared to single agent OPDIVO® or single agent YERVOY®.

In an attempt to improve outcomes and enhance the risk-benefit profiles of immunotherapy combinations, alternate immune checkpoints are being explored. LAG-3 (Lymphocyte-Activation Gene 3 (LAG-3), is a cell-surface receptor expressed on immune cells including activated CD4+ T cells, and negatively regulates T-cell proliferation, inhibits T-cell activation and effector T-cell function. LAG-3 is upregulated in several tumor types, including malignant melanoma.

Relatlimab is a first-in-class human IgG4 LAG-3–blocking antibody that binds to LAG-3 and restores the effector function of exhausted T cells, resulting in T cell proliferation, activation and a therapeutic response. In preclinical studies, dual inhibition of LAG-3 and PD-1 showed synergistic antitumor activity, and in a Phase I/II trial, the combination of Relatlimab and OPDIVO®, demonstrated durable Objective Responses in patients with Relapsed/Refractory melanoma following treatment with PD-1 inhibitors.

RELATIVITY-047 is a Phase II/III, global, multicenter, double-blind, randomized trial in which a fixed-dose combination of Relatlimab and OPDIVO® (OPDUALAG®) was compared with OPDIVO® alone, in patients with previously untreated metastatic or unresectable melanoma. In this study, 714 patients were randomly assigned 1:1 to receive OPDUALAG® (Relatlimab 160 mg and OPDIVO® 480 mg in a fixed-dose combination) (N=355) or single agent OPDIVO® 480 mg (N=359). Both regimens were administered as an IV infusion over 60 minutes every 4 weeks, and treatment was continued until disease progression, unacceptable toxicities, or withdrawal of consent. Both treatment groups were well balanced and patients were stratified according to LAG-3 expression (1% or more versus less than 1%), PD-L1 expression (1% or more versus less than 1%), BRAF V600 mutation status, and metastasis stage (M0 or M1 with normal LDH levels versus M1 with elevated LDH levels). More patients in the OPDUALAG® group had Stage M1c disease, and a larger proportion had three or more sites with at least one metastatic lesion. The Primary end point was Progression Free Survival (PFS) as assessed by blinded Independent Central Review. Secondary end points included Overall Survival and Objective Response Rate (ORR).

At a median follow up was 13.2 months there was a statistically significant improvement in progression-free survival (PFS), as well as a numerically higher objective response rate (ORR) with a fixed-dose combination of OPDUALAG®, compared with OPDIVO® alone. This led to the approval of this combination by the FDA in 2022.

The researchers herein reported updated descriptive efficacy and safety results from RELATIVITY-047 with a median follow-up of 33.8 months, which confirmed the sustained efficacy benefit of OPDUALAG®, compared with OPDIVO® alone.

The median PFS was 10.2 months with OPDUALAG® as compared with 4.6 months with OPDIVO® (HR=0.79; [95% CI, 0.66-0.95]).The 3-year PFS rates were 31.8% and 26.9% respectively. The median OS was 51.0 months and 34.1 months, respectively (HR, 0.80 [95% CI, 0.66 to 0.99]). The ORR was 43.7% (95% CI, 38.4 to 49.0) with OPDUALAG® versus 33.7% (95% CI, 28.8 to 38.9) with OPDIVO®.

The PFS benefit was more so with OPDUALAG® across key prespecified subgroups, compared to single agent OPDIVO®. Patients with poor prognosis characteristics, such as visceral metastases, high tumor burden, elevated levels of serum LDH, or mucosal or acral melanoma, had better outcomes with OPDUALAG®, than with single agent OPDIVO®. Further, a benefit with OPDUALAG® was also noted across BRAF mutant and wild-type subgroups, compared to single agent OPDIVO®. Expression of LAG-3 or PD-L1 was not useful in predicting a benefit of OPDUALAG® over single agent OPDIVO® and appears to NOT have a clear role in treatment selection.

Subsequent systemic therapy was received by 38% in the OPDUALAG® group and 39.3% in the OPDIVO® alone group. The median PFS2 was 29.6 months with OPDUALAG® and 20.3 months with OPDIVO® alone, further supporting the long-term benefits of OPDUALAG®.

Grade 3 or 4 toxicities occurred in 18.9% of patients in the OPDUALAG® group and in 9.7% of patients in the single agent OPDIVO® group. The Safety profile of OPDUALAG® appeared favorable, when compared with dual checkpoint inhibition with a CTLA-4 inhibitor and PD-1 inhibitor combination (YERVOY® plus OPDIVO®) in the CheckMate 067 trial, in which adverse events were noted in 59% of patients.

The researchers concluded that RELATIVITY-047 is the first study to show a statistically significant improvement in Progression Free Survival for an immunotherapy combination versus PD-1 monotherapy, in patients with previously untreated metastatic or unresectable melanoma. This is believed to be the first analysis demonstrating that a combination immunotherapy significantly improves Overall Survival compared to anti-PD-1 monotherapy (evidenced by an Overall Survival HR 95% CI upper bound now <1). The authors added that these results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma, and establishes LAG-3 as the third immune checkpoint pathway, thus providing more treatment options for patients with advanced melanoma.

Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047. Tawbi HA, Hodi FS, Lipson EJ, et al. J Clin Oncol 2024;43:1546-1552

BREAKWATER Trial Establishes Encorafenib Combination with Cetuximab Plus mFOLFOX6 as a First-Line Standard for BRAF V600E–Mutated mCRC

July 10, 2025July 10, 2025 RR

SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as Panitumumab (VECTIBIX®) and Cetuximab (ERBITUX®), as well as anti VEGF agent Bevacizumab (AVASTIN®), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency. The FDA in 2020, approved Encorafenib in combination with Cetuximab for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation

Background and Unmet Need
BRAF V600E mutations are found in approximately 8-10% of metastatic CRC and are associated with aggressive tumor biology, poor prognosis, and limited response to conventional first-line therapies. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

Design of the BREAKWATER Study
The Phase 3 BREAKWATER trial addressed this gap by evaluating first-line treatment with Encorafenib and Cetuximab, with or without chemotherapy, in patients with previously untreated BRAF V600E-mutated mCRC. Initially designed with three arms (1:1:1), EC: Encorafenib (300 mg PO QD) + Cetuximab (500 mg/m² IV q2w), EC + mFOLFOX6: As above + Oxaliplatin, Leucovorin, and 5-FU and Control/Standard of Care: mFOLFOX6, FOLFOXIRI, or CAPOX with or without Bevacizumab, the protocol was later amended to focus on the EC+mFOLFOX6 (N=236) versus Standard of Care comparison (N=243). The median age was 61 yrs and stratification was based on ECOG performance status and geographic region. Eligible patients had metastatic colorectal adenocarcinoma with measurable disease and a confirmed BRAF V600E mutation, but no prior systemic therapy for metastatic disease. The Primary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR). Secondary endpoints included Overall Survival (OS), Duration of Response (DoR) and Time to Response.

Efficacy Highlights
The results were compelling across both Primary endpoints (ORR and PFS), as well as key Secondary outcomes:

Objective Response Rate (ORR):
EC+mFOLFOX6 achieved a confirmed ORR of 7%, compared with 37.4% in the Standard of Care arm (Odds Ratio, 2.44; P<0.001), with a median Time to Response of approximately 7 weeks. The median Duration of Response was 13.9 months and 10.8 months respectively
Progression-Free Survival (PFS):
The median PFS was 8 months with EC+mFOLFOX6 versus 7.1 months with standard care (Hazard Ratio [HR] for progression or death, 0.53; P<0.001), representing a 47% reduction in risk.
Overall Survival (OS):
Interim analysis demonstrated a median OS of 3 months with EC+mFOLFOX6, more than double the 15.1 months observed in the Standard of Care group (HR for death, 0.49; P<0.001). Twelve and 24 month survival rates favored the investigational arm (80.1% and 52.0%, respectively) over Standard of Care (66.0% and 29.0%).

Notably, survival outcomes with EC+mFOLFOX6 approached those historically seen in BRAF wild-type mCRC, underscoring the potential for targeted therapy to narrow the survival gap.

Subgroup and Secondary Analyses
Benefits of EC+mFOLFOX6 were consistent across prespecified subgroups, including patients with liver metastases or multi-organ involvement. Additionally, median second Progression-Free Survival was longer with EC+mFOLFOX6, reinforcing its value in delivering durable disease control.

Safety Profile
While the incidence of grade ≥3 adverse events was higher in the EC+mFOLFOX6 group (46.1%) compared to standard care (38.9%), toxicity was manageable, and treatment discontinuations remained relatively low. The safety profile was consistent with expectations for the individual agents, and chemotherapy dose reductions were not substantially increased.

Clinical Implications
These findings firmly establish EC+mFOLFOX6 as a new first-line standard for patients with BRAF V600E–mutated mCRC. The dual-targeted approach combined with chemotherapy offers significantly improved outcomes in a population long characterized by poor prognosis. The results also highlight the importance of early integration of targeted therapy, particularly encorafenib, into the treatment paradigm.

Next Steps in BRAF-Targeted Strategies
Although the EC doublet showed some activity, particularly in patients ineligible for chemotherapy, its efficacy was inferior to the triplet regimen. Enrollment into the EC-only arm was halted, and current exploration includes EC combined with FOLFIRI (ongoing in BREAKWATER cohort 3) and EC plus pembrolizumab in MSI-H/dMMR populations (SEAMARK trial).

Conclusion
The BREAKWATER trial demonstrated that first-line treatment with EC+mFOLFOX6 significantly improves Response Rates, Progression-Free Survival, and Overall Survival, compared to standard chemotherapy regimens, in BRAF V600E–mutated mCRC. This represents a transformative advance, closing the gap in outcomes between BRAF-mutated and wild-type mCRC, and setting a new benchmark in precision oncology.

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. Elez E, Yoshino T, Shen L, et al., for the BREAKWATER Trial Investigators. N Engl J Med 2025;392:2425-2437

FDA Approves Perioperative KEYTRUDA® for Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma

July 10, 2025July 10, 2025 RR

SUMMARY: The FDA on June 12, 2025, approved Pembrolizumab (KEYTRUDA®) for adults with resectable locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) whose tumors express PD-L1 Combined Positive Score (CPS) of 1 or more, as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with Radiotherapy (RT) with or without Cisplatin after surgery, and then as a single agent.This is the first approval for HNSCC in 6 years and the first overall perioperative approval for locally advanced HNSCC.

The American Cancer Society estimates that 59,660 new cases of cancer involving the oral cavity and pharynx will be diagnosed in the US in 2025 and 12,770 will die of the disease. The Head and Neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma (SCC) of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.

The Standard of Care for patients with Stage III–IVA Head and Neck Squamous Cell Carcinoma (HNSCC) has remained largely static for nearly 2 decades: surgery followed by risk-adapted adjuvant radiotherapy, with or without concurrent chemotherapy. Despite refinements in technique and supportive care, relapse rates remain high, particularly among patients with adverse pathological features such as extranodal extension and positive margins.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-689, a landmark Phase 3 trial, has provided the most compelling evidence to date that perioperative immunotherapy, specifically Pembrolizumab, can significantly improve clinical outcomes for patients with resectable, locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC). This international, randomized, placebo-controlled study enrolled 714 patients (N=714) with newly diagnosed, resectable, Stage III–IVA HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx.

Patients were randomized 1:1 to receive:

Investigational arm (N=356):
- 2 cycles of neoadjuvant Pembrolizumab (200 mg IV Q3W) starting about 3 weeks before surgery.
- Standard-of-care surgery.
- Up to 3 doses of Pembrolizumab administered concurrently with adjuvant chemoradiotherapy, with Cisplatin (depending on pathologic risk- positive margins <1 mm or extranodal extension present at surgery was considered high risk).
- 12 additional adjuvant doses of Pembrolizumab Q3W (total treatment duration: about 1 year).
Control arm (N=358):
- Identical treatment structure, substituting placebo for Pembrolizumab.

PD-L1 expression was assessed via Combined Positive Score (CPS), and stratification included CPS ≥1 and CPS ≥10 subgroups, recognizing the prognostic and potentially predictive value of PD-L1 expression. The Primary endpoint was Event-Free Survival (EFS) by Blinded Independent Central Review, defined as time from randomization to disease progression, local/regional recurrence, distant metastasis, or death from any cause. Secondary endpoints included Overall Survival (OS) and Major Pathological Response.

The trial met its Primary endpoint of EFS. At median follow-up of 38.3 months, patients in the investigational arm had significantly improved EFS compared with the Standard of Care arm (median 51.8 months vs. 30.4 months; HR=0.73; P=0.0041). Patients who received Pembrolizumab who had a CPS score ≥10 derived the greatest benefit (median 59.7 months vs. 26.9 months; HR = 0.66; P=0.002) whereas the median EFS in the CPS ≥1 subgroup was 59.7 vs. 29.6 months (HR, 0.70; P = .0014).

Major pathological response defined as 90% or more tumor regression was also notably improved. Among all patients, the major pathological response rate was 9.4% with Pembrolizumab vs. 0% with Standard of Care (P < 0.00001). In the CPS ≥10 subgroup, the major pathological response rate reached 13.7%.

While the interim analysis did not demonstrate a statistically significant OS benefit, trends were favorable, particularly in the CPS ≥10 group (HR, 0.72; P =0.02). Further OS follow-up is ongoing.

Adverse events were consistent with known profiles of checkpoint inhibitors. Grade 3 or more Treatment-Related Adverse Events (TRAEs) occurred in 44.6% of the Pembrolizumab group and 42.9% in the Standard of Care group. Immune-mediated adverse events were observed in 43.2% of the Pembrolizumab arm, with hypothyroidism being the most common (24.7%). Mortality attributable to treatment was slightly higher with Pembrolizumab (1.1% vs. 0.3%).

The researchers concluded that perioperative Pembrolizumab is now emerging as a new standard of care in the treatment of resectable locally advanced HNSCC. The findings from this study underscore the importance of harnessing the immune system both before and after surgery. Neoadjuvant administration may prime the immune response when tumor antigen burden is highest, while adjuvant therapy may help eliminate residual microscopic disease.

Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Uppaluri R, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago.

Late Breaking Abstract – ASCO 2025: Targeting ESR1 Mutations in Advanced Breast Cancer: Phase 3 VERITAC-2 Validates Vepdegestrant as a Promising Next-Generation Endocrine Therapy

July 3, 2025July 24, 2025 RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background and Clinical Unmet Need
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, with up to 50% of patients acquiring ESR1 (Estrogen Receptor gene alpha) mutations after exposure to prior endocrine therapy in combination with CDK4/6 inhibitors. These mutations enable constitutive activation of the estrogen receptor, rendering tumors less responsive to traditional endocrine agents. Although Selective Estrogen Receptor Degraders (SERDs) such as Fulvestrant and Elacestrant are often used in this setting, their clinical activity is modest and limited by pharmacokinetic and mechanistic constraints, especially in heavily pretreated, endocrine-resistant disease.

A Novel Approach: Vepdegestrant and the PROTAC Platform
Vepdegestrant represents a first-in-class, oral PROteolysis TArgeting Chimera (PROTAC) designed to degrade the ER through direct engagement of the ubiquitin-proteasome system. Unlike traditional SERDs, which bind to and inactivate the ER before relying on indirect degradation pathways, Vepdegestrant forms a ternary complex between the ER and an E3 ubiquitin ligase. This results in efficient and targeted ubiquitination and subsequent degradation of the ER protein. Early-phase trials demonstrated that Vepdegestrant was well tolerated and exhibited promising antitumor activity in patients with heavily pretreated ER+/HER2-negative advanced breast cancer. This laid the foundation for VERITAC-2, the first Phase 3 study evaluating a PROTAC agent in oncology.

VERITAC-2: Study Design and Patient Population
Study Overview:
VERITAC-2 is a global, randomized Phase 3 trial comparing oral Vepdegestrant 200 mg once-daily continuously with Fulvestrant 500 mg intramuscularly days 1 and 15 of cycle 1 and day 1 of subsequent cycles, in postmenopausal women and men with ER+/HER2-negative advanced breast cancer, previously treated with a CDK4/6 inhibitor plus endocrine therapy. An additional line of endocrine therapy was permitted. However, patients previously exposed to SERDs or chemotherapy in the metastatic setting were excluded. A total of 624 patients (median age 60 years; 43% with ESR1mutation tumors) were randomized 1:1 to receive Vepdegestrant (N=313) or Fulvestrant (N=311). Approximately 80% were postmenopausal, and 20% had received two prior lines of therapy in the advanced setting. Patients were stratified by ESR1 mutation status and presence of visceral disease. The Primary endpoint was Progression-Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR), first in the ESR1mutations subgroup and then in the overall population contingent on statistical assumptions. Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Clinical Benefit Rate (CBR), and Safety.

Key Efficacy Findings

In the ESR1-Mutant Population:

Median PFS: 5.0 months with Vepdegestrant vs 2.1 months with Fulvestrant
Hazard Ratio: 0.57 (95% CI, 0.42–0.77); P=0.0001
6-Month PFS Rate: 45.2% with Vepdegestrant vs 22.7% with Fulvestrant
Objective Response Rate: 18.6% vs 4.0% (P=0.001)
Clinical Benefit Rate: 42.1% vs 20.2% (P<0.001)

There was a 43% relative reduction in the risk of disease progression or death with Vepdegestrant compared with Fulvestrant. These results represent a statistically significant and clinically meaningful improvement in PFS and response outcomes among ESR1mutated patients, reinforcing the hypothesis that targeted ER degradation via PROTAC technology can overcome a key mechanism of endocrine resistance.

In the Overall Population:

Median PFS: 3.7 months (Vepdegestrant) vs 3.6 months (Fulvestrant)
HR: 0.83 (95% CI, 0.68–1.02); P=0.07

Although trends favored Vepdegestrant, the PFS difference in the unselected population did not reach statistical significance, underscoring the critical role of ESR1 mutation status as a biomarker of response to this agent.

Safety and Tolerability
Vepdegestrant was generally well tolerated, with most Adverse Events (AEs) being Grade 1 or 2. Grade 3 or more Treatment-Emergent AEs occurred in 23.4% receiving Vepdegestrant versus 17.6% with Fulvestrant. The most toxicities with Vepdegestrant were fatigue, elevated ALT/AST, nausea, vomiting and diarrhea. Discontinuation due to AEs occurred in only 2.9% of patients receiving Vepdegestrant. Importantly, gastrointestinal side effects, often limiting with oral SERDs, were infrequent and generally low-grade, reflecting the favorable tolerability of this novel agent.

Clinical Implications and Future Directions
The VERITAC-2 trial offers a landmark clinical validation for PROTACs in oncology. For patients with ER+/HER2-negative advanced breast cancer harboring ESR1 mutations, Vepdegestrant offers a statistically significant and clinically relevant advantage in Progression-Free Survival over Fulvestrant. The favorable safety profile, oral dosing convenience, and mechanistic novelty support its development as a next-generation standard of care in this biomarker-defined subgroup.

Although benefit was not observed in the all-comer population, the compelling results in ESR1mutated disease position Vepdegestrant as a precision endocrine therapy option that could reshape the treatment landscape. Ongoing investigations will clarify its role in earlier lines of therapy and in combination strategies, including with targeted or immunotherapeutic agents.

Conclusion
Vepdegestrant has emerged as a promising, targeted therapy for patients with ESR1-mutated ER+/HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy. As the first PROTAC to reach Phase 3, its success in VERITAC-2 signals the clinical viability of targeted protein degradation platforms in hormone receptor–driven malignancies.

Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. Hamilton H, De Laurentiis M, Jhaveri K, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1000)

Late Breaking Abstract – ASCO 2025: Tarlatamab Sets New Standard in Recurrent Small Cell Lung Cancer: Results from DeLLphi-304

July 3, 2025July 24, 2025 RR

SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Nearly all patients with SCLC experience disease recurrence during or after standard platinum-based chemotherapy, underscoring the need for novel treatment strategies Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-Like Protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab (IMDELLTRA®) is a first-in-class bispecific T-cell engager immunotherapy that directs the patients T cells to cancer cells expressing Delta-Like Ligand 3 (DLL3), independent of Major Histocompatibility Complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

In May 2024, the U.S. FDA granted accelerated approval to Tarlatamab for adult patients with extensive-stage SCLC whose disease progressed after platinum-based chemotherapy. This decision was based largely on early clinical benefit observed in the Phase 2 DeLLphi-301 trial, where Tarlatamab demonstrated a 40% Overall Response Rate (ORR) in previously treated patients. Now, confirmatory results from the Phase 3 DeLLphi-304 trial further support the role of Tarlatamab in the treatment landscape, and mark a potential new standard of care for recurrent SCLC.

Phase 3 DeLLphi-304: Study Design and Population
DeLLphi-304 was a global, randomized, open-label trial comparing Tarlatamab, with standard-of-care chemotherapy which included Topotecan, Lurbinectedin, or Amrubicin, in patients with extensive-stage SCLC, whose disease progressed after platinum-based chemotherapy. A total of 509 patients were randomized 1:1 to receive either Tarlatamab (N=254) or chemotherapy (N=255). Stratification factors included prior PD-L1 inhibitor treatment, chemotherapy-free interval, presence of brain metastases, and intended chemotherapy regimen. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Patient-Reported Outcomes (PROs), and Safety.

Tarlatamab Demonstrates Significant Survival Benefit
At a median follow-up of approximately 11 months, Tarlatamab demonstrated a statistically and clinically significant improvement in OS:

Median OS: 13.6 vs 8.3 months (HR 0.60; 95% CI: 0.47–0.77; P<0.001)
Median PFS: 4.2 vs 3.2 months (HR 0.72; 95% CI: 0.59–0.88; P<0.001)

This translated to a 40% reduction in the risk of death for patients receiving Tarlatamab. The survival benefit extended across all prespecified subgroups, including age, gender, race, and prior anti–PD-L1 therapy. The ORR was 35% in the Tarlatamab group and 20% in the chemotherapy group.

Improved Symptom Control and Quality of Life
Beyond survival, Tarlatamab provided clinically meaningful improvements in Patient-Reported Outcomes, including relief from hallmark symptoms of SCLC:

Dyspnea score improved at 18 weeks: –1.94 with Tarlatamab vs +7.20 with CTx (mean difference –9.14; P< 0.001)
Cough improvement: 16% vs 9% (Odds Ratio 2.04; P = 0.012)
Chest pain improvement: 9% vs 4% (Odds Ratio 1.84; P = 0.100)

These findings reflect an overall better patient experience and potential Quality-of-Life benefit with Tarlatamab therapy.

Safety Profile and Tolerability
Tarlatamab was associated with a more favorable safety profile compared to chemotherapy:

Grade 3 or more Treatment-Related Adverse Events (TRAEs): 27% (Tarlatamab) vs 62% (Chemotherapy)
Discontinuations due to TRAEs: 3% vs 6%
Most common Grade 3 or more TRAEs with Tarlatamab were neutropenia (4%) and lymphopenia (4%)
Cytokine Release Syndrome (CRS) occurred in 56% of patients (mostly grade 1-2) and was manageable in clinical settings

These safety results support Tarlatamab as a more tolerable alternative to conventional chemotherapy.

Looking Ahead: Optimizing Treatment Sequencing
While the DeLLphi-304 trial has established Tarlatamab as an effective option post-platinum therapy, questions remain regarding its integration into the broader SCLC treatment paradigm. PD-L1 inhibitors already form part of standard first-line and maintenance therapy. Early-phase studies have shown that Tarlatamab can be safely combined with anti–PD-L1 agents, and this is being further evaluated in the ongoing DeLLphi-305 trial, a Phase 3 study assessing Tarlatamab plus PD-L1 inhibition as first-line maintenance following chemotherapy. Additionally, biomarker-driven analyses from DeLLphi-304 are underway to help identify patients most likely to benefit from Tarlatamab and those who may achieve durable responses.

Conclusion
The DeLLphi-304 trial positions Tarlatamab as a practice-changing therapy for patients with SCLC that has progressed after platinum-based chemotherapy. With significant improvements in Overall and Progression-Free Survival, better symptom control, and a favorable safety profile, Tarlatamab redefines second-line treatment for a historically underserved patient population. These results not only represent a meaningful advance in SCLC therapy but also signal a broader shift toward targeted immunotherapy strategies in aggressive thoracic malignancies.

Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): Primary analysis of Ph3 DeLLphi-304. Rudin C, Mountzios G, Sun L, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA8008)

Late Breaking Abstract – ASCO 2025: AMPLITUDE Trial: Defining a New Treatment Paradigm in HRR-Altered mCSPC

June 26, 2025June 26, 2025 RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is a heterogeneous disease. Despite therapeutic advances, outcomes vary significantly based on underlying tumor biology. Approximately 25% of patients with mCSPC harbor Homologous Recombination Repair (HRR) gene mutations, including BRCA1, BRCA2, CHEK2, CDK12, PALB2, and others. Among these, BRCA1/2 mutations account for nearly half of HRR alterations and are particularly associated with aggressive disease biology, resistance to Androgen Receptor Pathway Inhibitors (ARPIs), and shortened Progression-Free and Overall Survival. The integration of AR-pathway inhibitors such as Abiraterone Acetate plus Prednisone into first-line treatment has meaningfully improved outcomes in the general mCSPC population. However, patients with HRR mutations, especially those with BRCA1/2, derive significantly less benefit from these agents alone, highlighting a substantial unmet clinical need.

Rationale for PARP Inhibition in HRR-Altered Prostate Cancer
Cancer cells with HRR deficiencies are vulnerable to PARP (Poly ADP-Ribose Polymerase) inhibition, which blocks DNA repair pathways and induces synthetic lethality. Prior landmark trials, MAGNITUDE (Niraparib with Abiraterone Acetate plus Prednisone) and TALAPRO-2 (Talazoparib plus Enzalutamide), demonstrated the value of combining PARP inhibitors with ARPIs in Castration-Resistant Prostate Cancer (mCRPC) with HRR mutations. However, whether such a combination could offer meaningful benefit earlier in the disease course, in the castration-sensitive setting, remained unknown, until now.

AMPLITUDE Trial Design and Methods

Study Overview
The AMPLITUDE trial (NCT04497844) is a global, Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate whether combining the PARP inhibitor Niraparib with Abiraterone Acetate plus Prednisone improves clinical outcomes in patients with mCSPC (metastatic Castration-Sensitive Prostate Cancer) and HRR gene alterations.

Patient Population

Total enrolled: 696 men with mCSPC and at least one HRR gene mutation (germline or somatic)
Mutation profile: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L
BRCA1/2 prevalence: 55.6% of enrolled patients
Metastatic disease burden: 78% were high-volume M1disease, 87% had de novo M1disease and 16% had prior therapy with Docetaxel.
Prior therapies allowed:
- 6 months or less of Androgen Deprivation Therapy (ADT)
- 6 cycles or less of Docetaxel
- 45 days or less of prior Abiraterone and Prednisone

Randomization and Treatment Arms

Patients were randomized 1:1 to:

Experimental arm: Niraparib 200 mg once daily plus Abiraterone acetate 1000 mg daily and Prednisone 5 mg daily (N=348)
Control arm: Placebo plus Abiraterone acetate 1000 mg along with Prednisone 5 mg daily (N=348)
All patients continued on ADT.

Endpoints

Primary: Radiographic Progression-Free Survival (rPFS), assessed by investigator
Secondary: Time to Symptomatic Progression (TSP), Overall Survival (OS), Safety/tolerability

Key Results and Interpretation

Efficacy Outcomes

Radiographic Progression-Free Survival (Primary Endpoint)

Median rPFS:
- Niraparib plus Abiraterone and Prednisone: Not reached
- Abiraterone and Prednisone alone: 5 months (95% CI, 25.8–NR)
Hazard ratio: 0.63 (P=0.0001)
BRCA1/2 subgroup: HR =0.52 (P<0.0001)

This translates into a 37% relative risk reduction in progression or death in the overall population, and a 48% reduction in the BRCA1/2 subgroup, indicating a clear therapeutic effect in genetically defined populations.

Time to Symptomatic Progression

HR (overall): 0.50 (P<0.0001)
BRCA1/2 subgroup: HR 0.44 (P=0.0001)

This is clinically meaningful, and delaying symptom onset can preserve quality of life and extend time before additional therapies are needed.

Overall Survival (Interim Analysis)

HR (overall): 0.79 (95% CI, 0.59–1.04; P=0.10)
BRCA1/2 subgroup: HR 0.75 (95% CI, 0.51–1.11; P=0.15)

Although OS data are not yet mature, the trend suggests a potential survival benefit with longer follow-up.

Safety Profile
The safety of Niraparib plus Abiraterone and Prednisone was consistent with known profiles of both agents. Grade 3-4 AEs in the Niraparib plus Abiraterone and Prednisone was 75.2% versus 58.9% with Abiraterone and Prednisone alone, with the most common higher Grade 3-4 AEs noted in the Niraparib plus Abiraterone and Prednisone group (Anemia: 29.1% vs 4.6% and Hypertension: 26.5% vs 18.4%). The discontinuation rates due to AEs in the Niraparib plus Abiraterone and Prednisone group was 11.0% vs 6.9% in the Abiraterone and Prednisone group. These AEs were manageable with appropriate monitoring. No new safety signals were identified.

Conclusion
The AMPLITUDE trial marks a milestone and provides robust evidence to support Niraparib plus Abiraterone and Prednisone as a new first-line option in mCSPC patients with BRCA1/2 or other HRR gene mutations. By demonstrating that Niraparib plus Abiraterone and Prednisone improves Progression-Free outcomes in HRR-altered mCSPC, especially those with BRCA mutations, it paves the way for a more personalized, biology-driven approach to therapy in this setting. Ongoing follow-up will determine whether this translates into improved survival, but the current data already support Niraparib plus Abiraterone and Prednisone as a new treatment benchmark for this high-risk subgroup.

Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. Attard G, Agarwal N, Graff J, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)

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Author: RR