Category: Immuno Oncology

FDA Approves WELIREG® with KEYTRUDA® for Adjuvant Treatment of Renal Cell Carcinoma

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SUMMARY: The FDA on June 12, 2026, approved Belzutifan (WELIREG®) in combination with Pembrolizumab (KEYTRUDA®) or Pembrolizumab and Berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) for the adjuvant treatment of adults with renal cell carcinoma with a clear cell component (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

The American Cancer Society estimates that 80,450 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2026 and about 15,160 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

Adjuvant immunotherapy has become an important component of treatment for patients with clear cell Renal Cell Carcinoma (ccRCC) who are at elevated risk for recurrence following nephrectomy. The role of adjuvant immune checkpoint blockade was established by the Phase 3 KEYNOTE-564 study, which demonstrated that adjuvant Pembrolizumab significantly improves outcomes in this patient population.

Updated results from KEYNOTE-564 with a median follow-up of approximately 57 months confirmed a statistically significant Overall Survival (OS) benefit with adjuvant Pembrolizumab compared with placebo. Median OS was not reached in either group, but treatment with Pembrolizumab reduced the risk of death by 38% (HR 0.62; P=0.0024). At 48 months, the estimated OS rate was 91.2% among patients treated with Pembrolizumab versus 86.0% for those receiving placebo. The survival advantage was consistent across clinically relevant subgroups, including patients with M0 disease, those with M1 disease rendered no evidence of disease (M1 NED), and across PD-L1 expression levels and sarcomatoid histology status.

Building upon these findings, investigators have explored whether combining immunotherapy with other targeted agents could further reduce recurrence risk. The Phase 3 LITESPARK-022 trial evaluated the addition of the Hypoxia-Inducible Factor-2α inhibitor Belzutifan to adjuvant Pembrolizumab in patients with high-risk ccRCC following surgery.

Study Design

LITESPARK-022 is a randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 1,841 patients with ccRCC at increased risk of recurrence after nephrectomy.

Eligible patients included those with:

  • Intermediate-to-high risk M0 disease
    • pT2 tumors with grade 4 or sarcomatoid features, N0
    • pT3 tumors of any grade, N0
  • High-risk M0 disease
    • pT4 tumors of any grade, N0
    • Any pT stage with nodal involvement (N+)
  • M1 NED disease
    • Patients with metastatic disease who had undergone surgery and achieved no radiographic evidence of disease

Participants were randomized in a 1:1 ratio to receive either Pembrolizumab plus Belzutifan (N=921), Pembrolizumab plus placebo (N=920). Treatment consisted of Pembrolizumab 400 mg IV every 6 weeks for 9 cycles (approximately 1 year) and Belzutifan 120 mg orally once daily or placebo. Randomization was stratified according to risk category and tumor grade. The Primary endpoint was Disease-free survival (DFS) assessed by investigators and Secondary endpoints included Overall Survival (OS), Safety and tolerability.

Results discussed here represent the first interim analysis, conducted after a median follow-up duration was 28.4 months. Treatment completion rates were similar between groups (about 70%).

Efficacy Outcomes

The addition of Belzutifan to Pembrolizumab resulted in a statistically significant improvement in Disease-Free Survival, compared to Pembrolizumab plus placebo, meeting the Primary endpoint of the study (HR=0.72; 95% CI: 0.59–0.87; P=0.0003. This corresponds to a 28% reduction in the risk of recurrence or death with the combination regimen. The Median DFS had not yet been reached in either arm at the time of analysis. The estimated 24-month DFS rates were 80.7% in the Pembrolizumab plus Belzutifan group and 73.7% in the Pembrolizumab plus placebo group.

This represents the first Phase 3 adjuvant RCC trial demonstrating superiority of a combination therapy over active immunotherapy alone.

Overall Survival

Overall survival results remain immature. At the time of the interim analysis, only 29% of the events required for the final OS analysis had occurred, preventing definitive conclusions regarding survival benefit.

Safety Profile

As expected with the addition of Belzutifan, the combination regimen was associated with higher rates of treatment-related toxicity. Grade ≥3 Adverse Events for Pembrolizumab plus Belzutifan combination was 52.1% versus 30.2% for the Pembrolizumab plus placebo group. The most frequently reported grade ≥3 events included Anemia (12.1% vs 0.4%), Elevated ALT (6.4% vs 2.0%) and Hypoxia (4.6% vs 0%). Despite increased toxicity, grade 5 adverse events were rare and similar between arms, and no new safety signals were identified.

Clinical Implications

The findings from LITESPARK-022 suggest that combining Belzutifan with Pembrolizumab may further improve outcomes for patients with high-risk ccRCC following nephrectomy. However, the improved DFS must be balanced against the increased toxicity profile. Experts emphasize that careful patient selection will be essential if this regimen is adopted in clinical practice. Patients with baseline pulmonary or cardiovascular comorbidities, who may be more vulnerable to Belzutifan-associated hypoxia or anemia, may require additional consideration.

Furthermore, longer follow-up will be necessary to determine whether overall survival benefit emerges, as well as the impact on quality of life, and long-term safety of the combination regimen.

Key Takeaways for Clinical Practice

  • Adjuvant Pembrolizumab remains a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy.
  • The LITESPARK-022 trial demonstrated a significant improvement in DFS when Belzutifan was added to Pembrolizumab.
  • The combination reduced the risk of recurrence or death by 28% compared with Pembrolizumab alone.
  • Toxicity was higher, particularly with respect to anemia and hypoxia, but was generally manageable with dose modification and supportive care.
  • Ongoing follow-up will determine whether Overall Survival and Patient-Reported Outcomes support broader adoption of this strategy.

Conclusion

The Phase 3 LITESPARK-022 trial represents an important step forward in the adjuvant treatment landscape for clear cell Renal Cell Carcinoma. By demonstrating a clinically meaningful improvement in Disease-Free Survival with the addition of Belzutifan to Pembrolizumab, the study introduces a promising new therapeutic approach for patients at high risk of recurrence after nephrectomy. Continued follow-up will clarify the long-term survival benefit and help define the role of this combination in routine clinical practice.

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. Choueiri TK, Motzer RJ, Karam JA, et al. 2026 ASCO Genitourinary Cancers Symposium. J Clin Oncol 44, 2026 (suppl 7; abstr LBA418)

Late Breaking Abstract – ASCO 2026: Ivonescimab Plus Chemotherapy Delivers Superior Overall Survival Benefit in Advanced Squamous NSCLC

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SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States.

Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non-Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer.

Background

The advent of Immune Checkpoint Inhibitors (ICIs) has fundamentally transformed the treatment landscape of advanced NSCLC. By targeting immune regulatory pathways such as programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), these therapies restore T-cell activity and enhance antitumor immune responses. Biomarkers including PD-L1 expression, Tumor Mutational Burden (TMB), and mismatch repair (MMR) status have become important tools for predicting response; however, many patients, particularly those with low PD-L1 expression, continue to experience suboptimal outcomes.

While PD-1 inhibitors have established immunotherapy as a cornerstone of first-line treatment in advanced NSCLC, therapeutic progress has been slower in patients with squamous histology. Squamous NSCLC accounts for approximately 25% of all NSCLC cases and is associated with poorer clinical outcomes and fewer effective treatment options than nonsquamous disease. In addition, the use of conventional VEGF inhibitors has historically been limited in this population because of concerns regarding severe pulmonary hemorrhage.

Rationale for Dual PD-1 and VEGF Inhibition

Ivonescimab (AK112) is a novel bispecific antibody designed to simultaneously target PD-1 and vascular endothelial growth factor (VEGF). This dual-targeting strategy combines immune checkpoint inhibition with antiangiogenic therapy within a single molecule, with the goal of enhancing antitumor activity while minimizing off-target effects.

Preclinical and early clinical evidence suggests that simultaneous inhibition of PD-1 and VEGF may produce synergistic antitumor effects by improving immune cell infiltration, suppressing tumor angiogenesis, and enhancing T-cell activation. Importantly, previous studies demonstrated encouraging efficacy even among patients with low PD-L1 expression, without the excess bleeding complications traditionally associated with VEGF inhibitors in squamous NSCLC.

TEVIMBRA® (Tislelizumab) is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.

The HARMONi-6 Study Design

HARMONi-6 is a multicenter, randomized, double-blind, Phase III trial conducted across 50 hospitals in China. The study enrolled 532 patients aged 18–75 years with previously untreated, unresectable Stage IIIB, IIIC, or Stage IV squamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The median age was 64 yrs and 93% of patients were male.

Patients were randomized equally to receive:

  • Ivonescimab plus Paclitaxel and Carboplatin for four induction cycles followed by maintenance Ivonescimab, or
  • Tislelizumab plus Paclitaxel and Carboplatin followed by maintenance Tislelizumab.

The Primary endpoint was Progression-Free Survival (PFS), while Overall Survival (OS) served as a key Secondary endpoint.

Improved Disease Control

Earlier analyses from HARMONi-6 demonstrated that Ivonescimab significantly delayed disease progression compared with Tislelizumab. Median PFS improved to approximately 11 months versus 9 months, supporting the potential advantage of combining PD-1 and VEGF inhibition over PD-1 blockade alone.

Overall Survival Benefit

The prespecified interim Overall Survival analysis further strengthened the clinical significance of these findings.

After a median follow-up of 21.4 months, patients receiving Ivonescimab plus chemotherapy achieved a median OS of 27.9 months, compared with 23.7 months for those receiving Tislelizumab plus chemotherapy. This translated into a 34% reduction in the risk of death (Hazard Ratio 0.66; 95% CI 0.50–0.87; P=0.0017).

At the time of data cutoff, 84 deaths had occurred in the Ivonescimab arm compared with 120 deaths in the control arm, demonstrating a durable survival advantage for the investigational regimen.

Consistent Benefit Regardless of PD-L1 Expression

One of the most compelling observations from HARMONi-6 was the consistency of benefit across PD-L1 expression subgroups.

Among patients treated with standard immunochemotherapy, survival remained strongly influenced by PD-L1 status. Individuals with PD-L1 expression ≥1% experienced substantially longer survival than those with PD-L1-negative tumors.

In contrast, patients treated with Ivonescimab demonstrated prolonged survival irrespective of PD-L1 expression. Median OS had not yet been reached in either the PD-L1-high or PD-L1-low subgroups at the time of analysis, suggesting that dual PD-1/VEGF inhibition may overcome one of the major limitations of conventional checkpoint inhibitor therapy.

Safety Profile

The safety profile of Ivonescimab was generally consistent with expectations for combination immunochemotherapy.

Grade 3 or higher treatment-related adverse events occurred in 69% of patients receiving Ivonescimab compared with 59% in the Tislelizumab group. The most common severe adverse events included:

  • Neutropenia
  • Decreased white blood cell count
  • Anemia

Given the historical concern regarding VEGF inhibition in squamous NSCLC, bleeding events were carefully monitored. Grade 3 or higher hemorrhage occurred in 3% of patients receiving Ivonescimab versus 1% of those treated with Tislelizumab, indicating that serious bleeding remained relatively uncommon despite the incorporation of VEGF blockade.

Clinical Significance

Historically, advanced squamous NSCLC has been associated with limited therapeutic advances and inferior outcomes compared with nonsquamous disease. HARMONi-6 is among the few Phase III studies in this setting to demonstrate a median OS approaching 28 months, representing an important milestone for this patient population.

The findings suggest that simultaneous inhibition of PD-1 and VEGF using a bispecific antibody can provide clinically meaningful improvements in both disease control and OS while maintaining a manageable safety profile.

Looking Ahead

Although these results are highly encouraging, confirmation in more geographically diverse populations will be essential. Ongoing global studies, including the Phase III HARMONi-3 trial, will further evaluate the efficacy and safety of Ivonescimab across broader patient populations.

Key Clinical Takeaways

  • Ivonescimab is a first-in-class bispecific antibody targeting both PD-1 and VEGF.
  • HARMONi-6 demonstrated significant improvements in both Progression-Free and Overall Survival compared with Tislelizumab plus chemotherapy.
  • Median Overall Survival improved from 23.7 months to 27.9 months, reducing the risk of death by 34%.
  • Clinical benefit was observed regardless of PD-L1 expression, potentially expanding treatment options for patients with PD-L1-low disease.
  • Serious hemorrhagic events remained uncommon despite VEGF inhibition.
  • Dual PD-1/VEGF blockade represents a promising first-line therapeutic strategy for patients with advanced squamous NSCLC and may redefine future standards of care pending global validation.

Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: Overall survival results of the phase 3 HARMONi-6 trial. Zhiwei C, Yang F, Luo Y, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA4)

Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®). Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy (N=308)
  • Arm B: Zanidatamab plus chemotherapy (N=304)
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy (N=302)

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The median age was 63 yrs, about 53% were Asian, and 60% had PD-L1 status 1% or more.  The dual Primary endpoints were Progression-Free Survival (PFS) by Blinded Independent Review and Overall Survival (OS).

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in PFS with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P<0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The estimated 18-month PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% with Trastuzumab-based therapy. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.004). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.06), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 38.8% with Trastuzumab-based therapy. The 30-month OS was 42.2% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 74% of patients receiving Zanidatamab plus chemotherapy and 83% with the addition of Tislelizumab, compared with 74% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first Phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer. Shitara K, Elimova E, Liu T, et al. for the HERIZON-GEA-01 Investigators. N Engl J Med 2026;394:2002-2014.

Breakthrough Results from the CARTITUDE-4 Trial: A Major Step Forward in Multiple Myeloma Treatment

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 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. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes.

Modern therapies,including Proteasome Inhibitors, Immunomodulatory drugs, and anti-CD38 antibodies, have extended survival to nearly a decade. However, patients whose disease becomes resistant to these treatments face poor outcomes with a median survival of less than 1 year. There is a critical need for novel, effective therapies with new mechanisms of action

B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses.

CAR T-Cell Therapy & BCMA Targeting

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells to upregulate cytokine production and promote the expansion of the engineered CAR T-cells.

Ciltacabtagene autoleucel (Cilta-cel; CARVYKTI®), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy indicated for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to Lenalidomide.

 CARTITUDE-4 Study

CARTITUDE-4 is an ongoing open-label, multicenter, randomized Phase III trial conducted to compare Cilta-cel with the physician’s choice of either of two highly effective standard-of-care therapies, in patients with Lenalidomide-refractory multiple myeloma after one to three lines of therapy. In this study a total of 419 eligible patients (N=419) were randomly assigned in a 1:1 ratio to receive either one of the standard-of-care physicians choice of PVd-Pomalidomide, Bortezomib, and Dexamethasone, DPd-Daratumumab, Pomalidomide, and Dexamethasone (N=211) or a single infusion of Cilta-cel administered after the physician’s choice of bridging therapy with PVd or DPd (N=208). In the standard-of-care group, DPd was administered in 28-day cycles and PVd in 21-day cycles until disease progression. Patients in the Cilta-cel group underwent apheresis, followed by at least one bridging therapy cycle, with the number of cycles based on patient clinical status and Cilta-cel manufacturing time, and lymphodepletion with Cyclophosphamide 300 mg/m2 IV and Fludarabine 30 mg/m2 IV daily for 3 days. Patients then received a single Cilta-cel infusion at a target dose of 0.75X106 CAR-positive T cells/kg of body weight 5-7 days after the initiation of lymphodepletion. The median age was 61 yrs, median time from diagnosis was 3.2 years, about 60% of patients had high risk cytogenetic abnormalities and all patients had received 1-3 previous lines of treatment. In the Cilta-cel group, 14.4% had triple-class drug resistance and 24.0% had resistance to anti-CD38 antibody. The Primary outcome was Progression Free Survival and Secondary outcomes sequentially tested included Complete Response (CR) or better, Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity, and Overall Survival (OS).

In the first interim analysis, a single Cilta-cel infusion resulted in a lower risk of disease progression or death, as well as rapid and deep responses, compared to standard therapies in Lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies

The researchers in this publication reported a prespecified second interim analysis of OS and an updated analysis of PFS in the intention-to-treat population. New data from the CARTITUDE-4 study highlight the significant clinical benefits of Cilta-cel in patients with Lenalidomide-refractory multiple myeloma who have received one to three prior lines of therapy.

Key Efficacy Findings

With a median follow-up of nearly 34 months patients receiving Cilta-cel experienced substantially longer disease control. Median PFS was not reached, compared with 11.8 months for those on standard therapy, representing a 71% reduction in the risk of progression or death.

Overall Survival outcomes also favored Cilta-cel. While median OS was not reached in either group, treatment with Cilta-cel led to a 45% reduction in the risk of death, a statistically significant improvement.

At 30 months, approximately 59% of Cilta-cel patients were alive and progression-free vs 26% with standard care. Around 66% remained treatment-free after a single infusion.

Cilta-cel achieved higher rates of sustained MRD negativity, indicating deeper and more durable responses.

Safety Overview

Safety outcomes were evaluated in 208 patients per group. Grade 3 Adverse Events (AEs) were 14% with Cilta-cel versus 37% with standard of care and Grade 4 AEs were 75% with Cilta-cel versus 56% with standard of care and was most commonly neutropenia in both groups. Treatment-Related Deaths was 3% with Cilta-cel and 2% with standard therapy. Most were linked to infections.

Why This Matters

CARTITUDE-4 is the first Phase 3 trial to demonstrate a significant Overall Survival benefit with CAR T-cell therapy in multiple myeloma. These findings reinforce the potential of Cilta-cel as an earlier-line treatment option. Even as newer therapies continue to emerge, Cilta-cel shows competitive, and in many cases superior outcomes, including notably higher MRD-negative response rates compared with other modern regimens.

Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Einsele H, San-Miguel J, Dhakal B et al. The Lancet Oncology, 2026;27:254-268

FDA Approves OPDIVO® with Chemotherapy for Previously Untreated Hodgkin Lymphoma

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SUMMARY: The FDA on March 20, 2026, approved Nivolumab (OPDIVO®) with Doxorubicin, Vinblastine, and Dacarbazine (AVD) for adult and pediatric patients 12 years and older with previously untreated, Stage III or IV classical Hodgkin lymphoma (cHL).

The American Cancer Society estimates that in the United States for 2026, about 8920 new cases of Hodgkin Lymphoma will be diagnosed, and about 1100 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In the ECHELON-1 study, frontline treatment with Brentuximab Vedotin (BV) in combination with Doxorubicin, Vinblastine and Dacarbazine (AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival, after a median follow up of 6 years. However, frontline BV adds toxicity, and 7-20% of patients still develop Relapsed/Refractory Hodgkin Lymphoma.

The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

SWOG S1826 was an open-label, randomized Phase III trial conducted to compare the combination of Nivolumab plus AVD, to Brentuximab Vedotin plus AVD, in adolescent and adult patients with previously untreated advanced-stage classical Hodgkin Lymphoma (cHL). In this study, 976 newly diagnosed Stage III or IV cHL patients (N=976) were randomly assigned 1:1 to receive either 6 cycles of Nivolumab at 240 mg IV on days 1 and 15 (N=489) or Brentuximab Vedotin 1.2 mg/kg IV on days 1 and 15 (N=487). Both treatment groups also received AVD (Doxorubicin, Vinblastine, Dacarbazine ) IV on days 1 and 15, and treatment was repeated every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte-Colony Stimulating Factor (G-CSF) Pegfilgrastim SC on days 2 and 16, or Filgrastim SC on days 6-10 and 21-25 was optional in the Nivolumab group (N-AVD) but was required in the Brentuximab Vedotin group (BV-AVD). Approximately 54% in the N-AVD group received G-CSF compared to 95% in the BV-AVD group. After completion of cycle 6, patients could receive radiation therapy at the discretion of the treating physician, to metabolically active residual lesions noted on the end of treatment PET. Less than 1% of patients across both treatment groups had received radiotherapy. Patients were stratified by age, International Prognostic Score (IPS) and intent to use radiation therapy. The median age was 27 years, 24% of patients were less than 18 yrs, 76% were Caucasian, 55% were men, 64% had Stage IV disease and 32% had IPS of 4-7. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Event-Free Survival (EFS), Patient-Reported Outcomes (PROs), and Safety.

Sustained Progression-Free Survival Benefit at 3 Years

With a median follow-up of 3.1 years, updated data continue to reinforce the clinical advantage of N-AVD over BV-AVD in patients with advanced-stage classical Hodgkin lymphoma (cHL). The 3-year PFS rate reached 91% with N-AVD, compared with 82% with BV-AVD, translating to a 52% reduction in the risk of progression or death (HR 0.48; P< 0.0001).

Consistent Benefit Across Key Patient Subgroups

The PFS advantage with N-AVD was maintained irrespective of age, disease stage, or baseline risk, as defined by the International Prognostic Score (IPS):

  • Adolescents (12–17 years): 93% vs 82%
  • Adults (18–60 years): 91% vs 85%
  • Older patients (>60 years): 82% vs 58%
  • Stage III disease: 93% vs 86%
  • Stage IV disease: 89% vs 80%
  • IPS 0–3: 92% vs 84%
  • IPS 4–7: 87% vs 77%

Notably, outcomes in Stage IV disease with N-AVD approached those seen in Stage III, highlighting the regimen’s efficacy even in higher disease burden settings. These findings further support current guideline positioning of N-AVD as a preferred frontline treatment approach in advanced-stage disease.

Event-Free and Overall Survival Trends

Beyond PFS, N-AVD also demonstrated a statistically significant improvement in EFS (HR 0.56; P =0.0004). While OS data remain immature, an encouraging trend favoring N-AVD has emerged:

  • 3-year OS: 98% (N-AVD) vs 97% (BV-AVD)
  • Deaths observed: 8 vs 15, respectively

Longer follow-up will be essential to determine whether this early signal translates into a definitive survival advantage.

Safety Profile: Favorable and Manageable

No new safety signals were identified with extended follow-up, reinforcing the tolerability of the N-AVD regimen. Key safety observations include Lower incidence of second malignancies with N-AVD (1.2% vs 2.3%) with BV-AVD. Immune-related adverse events were generally infrequent and peripheral neuropathy was less frequent with N-AVD (7% vs 14%), reflecting reduced neurotoxicity compared with BV-containing therapy. Higher rates of grade ≥3 events occurred with N-AVD (48.4% vs 30.5%), but was not associated with increased infectious complications. G-CSF use was mandatory with BV-AVD but optional with N-AVD, influencing observed rates.

Unique Trial Design: Inclusion of Adolescent Patients

This study represents a landmark effort in Hodgkin lymphoma research, as it is the first large-scale trial to enroll both adolescents and adults in the frontline setting, and adolescents in this trial constituted the largest cohort in which a checkpoint inhibitor has been evaluated as part of initial therapy, providing important insights into younger patient populations.

Clinical Implications and Future Directions

These long-term results confirm that the integration of immune checkpoint blockade into frontline therapy yields durable disease control with a manageable safety profile.

Nivolumab plus AVD:

  • Provides sustained remission benefits
  • Demonstrates consistent efficacy across risk groups
  • Reduces certain long-term toxicities, including neuropathy and second cancers

Collectively, the data support N-AVD as a new standard of care for patients with advanced-stage cHL. Ongoing follow-up will further clarify Long-term overall survival outcomes, Late toxicities and Patient-reported outcomes

Key Takeaways

  • N-AVD significantly improves 3-year PFS vs BV-AVD (91% vs 82%)
  • Benefit is consistent across age, stage, and risk categories
  • EFS is significantly improved; OS data are trending positive
  • Safety profile is favorable, with reduced neuropathy and fewer second malignancies
  • Findings reinforce N-AVD as a preferred frontline regimen in advanced-stage cHL

3-year follow-up of the S1826 study confirms improved progression-free survival with nivolumab-AVD compared to brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma. Herrera A, Leblanc M, Castellino S, et al. Blood (2025) 146 (Supplement 1):151. doi: 10.1182/blood-2025-151.

Teclistamab Plus Daratumumab Sets a New Standard of Care in Early Relapsed or Refractory Myeloma

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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, 36,000 new cases will be diagnosed in 2026, and 10,850 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. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI®), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX®), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med 2026;394:739-752.

Adjuvant Immunotherapy Improves Outcomes in Stage III dMMR Colon Cancer: Results from the ATOMIC Trial

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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. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of CRC in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of CRC cases diagnosed in people under age 50.

It is estimated that 25% of patients diagnosed with Stage III disease have positive regional lymph nodes. These patients often receive 6 months of fluoropyrimidine-based adjuvant chemotherapy. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Approximately 10% to 15% of nonmetastatic CRCs exhibit deficient mismatch repair (dMMR), accounting for an estimated 330,000 cases annually worldwide. Majority of dMMR tumors are sporadic, although some are associated with germline variants in genes that cause Hereditary Nonpolyposis Colon Cancer (HNPCC) or Lynch syndrome. These dMMR tumors are often seen in women, more likely to arise in the right side of the colon, and tend to grow large before they metastasize. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. These tumors respond poorly to Fluoropyrimidine-based chemotherapy alone, especially in the adjuvant setting. While immune checkpoint inhibitors are approved for dMMR colorectal cancer in the metastatic setting, their benefit in earlier stages, particularly post-resection, had not been previously established in a prospective trial.

Atezolizumab (TECENTRIQ®) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

The Phase 3 ATOMIC trial (NCT02912559), sponsored by the National Cancer Institute and conducted across multiple centers including NCTN sites and the German AIO group investigated whether the addition of Atezolizumab, a PD-L1 checkpoint inhibitor, to standard adjuvant chemotherapy could improve Disease-Free Survival (DFS) in patients with resected Stage III dMMR colon adenocarcinoma.

Study Design and Population
The trial enrolled 712 patients with surgically resected Stage III colon cancer confirmed to have dMMR. Eligibility included patients aged 12 years and older (one pediatric patient was enrolled). MMR status was initially determined locally by immunohistochemistry and subsequently confirmed centrally. Participants were randomized 1:1 to receive:

  • Control arm: mFOLFOX6 (5-Fluorouracil, Leucovorin, and Oxaliplatin) for 6 months (N=357)
  • Experimental arm: mFOLFOX6 plus Atezolizumab (840 mg IV every 2 weeks) for 6 months, followed by maintenance Atezolizumab monotherapy for an additional 6 months (N=355)

Median patient age was 64 yr. 55.1% were female, 84% of tumors were proximal, 46% were clinical low risk (T1-3N1) and 54% were high risk (T4 and/or N2). Stratification was based on nodal status (N1/N1c vs N2), tumor depth (T1-T3 vs T4), and tumor location (proximal vs distal colon). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included Overall Survival (OS) and Adverse Event (AE) profile.

Results and Efficacy
After a median follow-up of 40.9 months, the Primary endpoint of DFS was significantly improved in the Atezolizumab arm. The 3-year DFS was 86.3% in the combination arm vs 76.2% in the mFOLFOX6-only arm (Hazard Ratio (HR)=0.50; P<0.001, crossing the prespecified efficacy boundary. This represents a 50% relative reduction in the risk of recurrence or death with the addition of Atezolizumab. Importantly, the benefit was consistent across predefined subgroups, including patients over 70 years old and those with both low and high-risk disease (based on T and N-stage). Tumor location, patient sex, and race did not impact the observed treatment benefit.

Safety and Tolerability
Grade 3 or more treatment-related adverse events occurred in 84.1% of patients receiving Atezolizumab plus chemotherapy, compared to 71.9% in those receiving chemotherapy alone. Although the addition of Atezolizumab resulted in a modest increase in toxicity, the side effect profile was consistent with prior experience with checkpoint inhibitors and considered manageable.

Clinical Implications
The ATOMIC trial is the first large, prospective, randomized Phase 3 study to demonstrate a clear benefit from adding immunotherapy to adjuvant chemotherapy in Stage III dMMR colon cancer. As highlighted by the investigators, current adjuvant treatment recommendations for dMMR tumors have historically been extrapolated from studies in mismatch repair–proficient populations or based on retrospective analyses. The robust DFS improvement observed here provides definitive evidence supporting a new treatment paradigm for this molecularly defined subgroup.

There was no significant difference in Overall Survival noted at this first analysis at a median follow-up of 40.9 months, and longer follow-up is required for mature estimates. Future OS analyses may be complicated by the use of subsequent checkpoint inhibitors in patients who recur. The researchers emphasized the clinical relevance of these findings, noting their applicability to both sporadic dMMR cancers and Lynch syndrome associated tumors.

Future Directions
The ATOMIC trial sets a new benchmark for adjuvant therapy in dMMR colon cancer. However, important questions remain. Chief among them is the optimal duration of immunotherapy in this setting. Atezolizumab was administered for nearly a year, including maintenance. Ongoing research should clarify whether such prolonged treatment is necessary or if shorter regimens could maintain efficacy while reducing toxicity.

Moreover, while this study confirms benefit in the postoperative setting, parallel efforts are warranted to evaluate checkpoint inhibition in the neoadjuvant context. Encouraging responses such as those seen in small studies of neoadjuvant immunotherapy in dMMR rectal cancer highlight the need to explore earlier immunotherapeutic intervention in colon cancer as well.

Conclusion
The ATOMIC trial provides compelling evidence that incorporating Atezolizumab into adjuvant therapy improves Disease-free survival in patients with Stage III dMMR colon cancer, marking a major advancement in the management of this biologically distinct subset. Given these results, the combination of Atezolizumab and mFOLFOX6 should be considered the new standard of care in this setting. This trial also exemplifies the power of cooperative group studies in driving progress for biomarker-defined subsets within common malignancies.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer. Sinicrope F, Ou F-S, Arnold D, et al. N Engl J Med 2026;394:1155-1166.

Extrapulmonary Neuroendocrine Carcinoma: Clinical Overview and Advances in DLL3 Targeted Therapy

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Written by: Dr. Eric Lander
Sponsored by Boehringer Ingelheim

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare and phenotypically aggressive malignancies arising from neuroendocrine cells. While EP-NECs are currently managed with conventional chemotherapy in most cases, numerous therapies are in development which may show promise to improve disease management and prognosis for patients.

EP-NECs originate from neuroendocrine cells located in many different organs, most commonly arising from the GI tract or pancreas, followed by genitourinary tract and gynecologic organs [1]. NECs are often confused with neuroendocrine tumors (NETs). Though both NETs and NECs arise from epithelial neuroendocrine cells expressing pan-cytokeratin, synaptophysin, and Chromogranin A, by definition NETs are well-differentiated while NECs are poorly differentiated. Though NETs can be defined as grades 1-3, they are more commonly grade 1-2 (Ki-67 <20%); NECs must be grade 3 (Ki-67 ≥20% and/or mitotic count >20 per mm2), and the Ki-67 usually exceeds 50%. The remainder of this article will focus on EP-NECs and will not include discussion about grade 3 NETs. Please reference the NCCN Guidelines or the Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society (NANETS) to learn about management strategies for G3 NETs [2].

EP-NECs most commonly result from TP53 and RB1 inactivation, similar to small cell lung neuroendocrine carcinoma (SCLC), though EP-NECs often contribute their own unique genetic mutational background (e.g. BRAF, KRAS, PIK3CA, APC, etc.) based on their site of origin, unlike most SCLC cases. If the primary site of EP-NEC origin is unknown, as occurs in up to one third of cases, encouraging pathology to perform transcription factor IHC can facilitate a site of origin assignment. Certain transcription factors (in parentheses) are unique to each organ: midgut (CDX2); pancreas (PAX6, PAX8, islet 1, or PR); rectum (SATB2); lung (OTP, TTF-1). Delineating site of origin is of particular importance as EP-NEC may be treated according to its primary site of origin at time of relapse following platinum-based chemotherapy.

Since EP-NECs are aggressive, high-grade carcinomas, patients most commonly have metastatic disease at the time of presentation. Many patients initially present for the first time to the hospital because some symptom of their disease, such as severe pain or fracture in the case of bone metastases, necessitated their presentation to the emergency room. Initial workup following tissue diagnosis should consist of imaging of the chest/abdomen/pelvis with CT or FDG-PET/CT imaging. Notably, high grade NECs have lower somatostatin receptor (SSTR) expression than NETs; therefore, FDG is preferred over SSTR-PET radiotracers [3, 4]. For EP-NECs, the incidence of brain metastases is less than 2%; thus, brain MRI should only be considered at time of diagnosis in cases of high disease burden or in symptomatic patients [5].

For molecular workup, since many EP-NECs can harbor mutations in BRAF (particularly in colorectal EP-NECs) and tumor agnostic indications for other therapies exist, NGS testing may be considered. Mismatch repair (MMR) testing or MSI testing is also recommended since 10% of NECs are deficient MMR, opening the door to immunotherapies as therapeutic options. Delta-like ligand 3 (DLL3) is an emerging target in EP-NEC; reserving tissue for DLL3 IHC is recommended in cases where patients may enroll in a clinical trial investigating a drug targeting DLL3 – which will be discussed later.

For the management of localized EP-NEC, discussion at tumor board is recommended to provide a multidisciplinary treatment approach. Data surrounding the long-term curative potential of surgery is mixed based on the tumor site of origin when surgery is often invasive, and patients remain at high risk of metastatic disease recurrence. For this reason, neoadjuvant or adjuvant platinum-based chemotherapy may be paired with surgery. Many experts will favor neoadjuvant platinum/etoposide chemotherapy to test the biology of the disease and decrease theoretical risk of micro-metastasis prior to surgery. However, many patients will present to medical oncology following tumor resection, in which case adjuvant chemotherapy may be discussed with eligible patients. Otherwise, definitive chemoradiation for organ preservation may be considered with platinum plus etoposide as the recommended radiosensitizing agents. The accruing French NEONEC trial will prospectively test neoadjuvant chemotherapy followed by surgery or chemoradiation in patients to hopefully offer clarity regarding the optimal multidisciplinary approach [6].

In the case of metastatic EP-NECs, the treatment paradigm initially parallels that of SCLC. Enrollment in clinical trial when available or platinum plus etoposide for four to six cycles remains the current first-line standard-of-care. Unlike SCLC, atezolizumab is not written into the NCCN guidelines for EP-NEC. EP-NEC patients were not included in the IMpower133 trial, and a subsequent retrospective study of a small EP-NEC patient cohort did not demonstrate a PFS or OS benefit of adding atezolizumab to platinum-based chemotherapy [7]. Larger patient numbers in a prospective trial are likely required to detect a benefit of atezolizumab—an ongoing phase II/III SWOG trial is investigating platinum/etoposide with or without atezolizumab to address this evidence gap [8].

Most patients will achieve significant initial tumor shrinkage or disease control in response to carboplatin or cisplatin plus etoposide, especially if Ki-67 ≥ 55%, but the tumor response is not durable in most cases, and tumors are less responsive to chemotherapy upon disease progression. There is currently no standard second- or third-line treatment option for EP-NEC. When assessing patients’ treatment goals and performance status, best supportive care with hospice is a very reasonable approach in light of EP-NEC’s generally poor prognosis upon time of disease relapse.

When second-line and beyond therapy lines are being considered, enrollment in clinical trial is the preferred option for eligible patients. If patients experienced a durable response lasting at least 6 months following first-line platinum/etoposide, rechallenge may be considered. Among patients with gastrointestinal and pancreatic EP-NECs, second-line treatment with FOLFIRI has the most prospective data and lends a 6-month overall survival rate of 60% [9], while gynecologic EP-NEC has data for topotecan, taxanes, single agent irinotecan, or the combination of topotecan, paclitaxel, and bevacizumab that provided an 8-month median PFS in a small retrospective cohort [10]. For patients with dMMR/MSI-H or TMB-High disease, ipilimumab/nivolumab or pembrolizumab may be considered where dual checkpoint inhibition potentially yields a higher response rate [11]. For patients with BRAF V600E mutations, a STAR trial through SCRI is available to open at most US Oncology practices employing BRAF/MEK inhibition with dabrafenib/trametinib and includes patients with EP-NEC [12].

The most promising emerging therapies for EP-NEC remain those in clinical trials targeting DLL3—this assertion is based on extrapolation of promising data from the DeLLphi trials using tarlatamab in SCLC, and initial results investigating obrixtamig in SCLC and EP-NEC. Both tarlatamab and obrixtamig are DLL3/CD3 bispecific T-cell engagers. While DLL3 is expressed in approximately 90% of SCLC, rates of DLL3 expression in EP-NEC are lower [13]. Despite this, most patients with negative DLL3 expression in the DeLLphi-301 trial employing tarlatamab in refractory SCLC still experienced disease control with tarlatamab monotherapy [14]. Emerging therapeutics targeting DLL3 are mostly either DLL3/CD3 bispecific T-cell engagers or DLL3-targeting antibody-drug conjugates.

There are several clinical trials investigating DLL3/CD3 bispecific T-cell engagers and DLL3 antibody-drug conjugates in EP-NEC patients. At the time of writing, three different phase I studies are open and actively recruiting through US Oncology Network practices that include patients with EP-NEC, all of which require tissue for DLL3 IHC testing [15, 16, 17]. Among investigational DLL3/CD3 bispecific agents, Boehringer Ingelheim’s obrixtamig has shown promising results.  Data presented in 2025 from the phase I dose-escalation trial of obrixtamig showed that heavily-pretreated EP-NEC patients with high DLL3 expression had an overall response rate of 40% and duration of response of 7.9 months [18]. While not open in the US Oncology Network, the phase II DAREON-5 trial with obrixtamig is testing two different doses and includes patients with relapsed EP-NEC [19]. The results of ongoing obrixtamig trials will be important to follow and could potentially alter our future therapeutic approach to EP-NEC.

Standard-of-care options in EP-NEC do not yield survival much past one year in most patients. However, for the first time in decades, numerous emerging therapeutic options afford hope to significantly improve the treatment tolerability and prognosis for patients with this aggressive disease.

References:

  1. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018;124(4):807-815. doi:10.1002/cncr.31124.
  2. Eads JR, Halfdanarson TR, Asmis T, et al. Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer. 2023;30(8):e220206. Published 2023 Jul 11. doi:10.1530/ERC-22-0206.
  3. Tomimaru Y, Eguchi H, Tatsumi M, et al. Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors. Surgery. 2015;157(2):269-276. doi:10.1016/j.surg.2014.09.011.
  4. Majala S, Seppänen H, Kemppainen J, et al. Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT. EJNMMI Res. 2019;9(1):116. Published 2019 Dec 23. doi:10.1186/s13550-019-0585-7.
  5. Alese OB, Jiang R, Shaib W, et al. High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study. Oncologist. 2019;24(7):911-920. doi:10.1634/theoncologist.2018-0382.
  6. Efficacy of neoadjuvant chemotherapy in terms of DFS in patients with locally advanced, poorly differentiated digestive neuroendocrine carcinomas (NEONEC). ClinicalTrials.gov identifier NCT04268121. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT04268121
  7. Ho IW, Chiang NJ, Lai JI, et al. Efficacy of atezolizumab combined with platinum and etoposide in the treatment of extrapulmonary neuroendocrine carcinoma. Oncologist. 2025;30(3):oyae372. doi:10.1093/oncolo/oyae372.
  8. Evaluating the addition of the immunotherapy drug atezolizumab to standard chemotherapy treatment for advanced or metastatic neuroendocrine carcinomas that originate outside the lung (SWOG S2012). ClinicalTrials.gov identifier NCT05058651. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05058651
  9. Walter T, Lievre A, Coriat R, et al. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023;24(3):297-306. doi:10.1016/S1470-2045(23)00001-3.
  10. Frumovitz M, Munsell MF, Burzawa JK, et al. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2017;144(1):46-50. doi:10.1016/j.ygyno.2016.10.040.
  11. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer. 2021;127(17):3194-3201. doi:10.1002/cncr.33591.
  12. ClinicalTrials.gov. Clinical study to further evaluate the efficacy of dabrafenib plus trametinib in patients with rare BRAF V600E mutation-positive unresectable or metastatic solid tumors. Identifier NCT05868629. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05868629
  13. Serrano AG, Rocha P, Freitas Lima C, et al. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024;8(1):268. Published 2024 Nov 19. doi:10.1038/s41698-024-00739-y.
  14. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980.
  15. ClinicalTrials.gov. A study of Peluntamig (PT217) in patients with neuroendocrine carcinomas expressing DLL3 (the SKYBRIDGE study). Identifier NCT05652686. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05652686
  16. ClinicalTrials.gov. A study of IDE849 in patients with DLL3 expressing tumors including small cell lung cancer. Identifier NCT07174583. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT07174583
  17. ClinicalTrials.gov. A Phase Ib/II, open-label, multi-center study of ZL-1310 in participants with selected solid tumors. Identifier NCT06885281. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT06885281
  18. Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial. J Clin Oncol. 2025;43(16_suppl):3004. doi: 10.1200/JCO.2025.43.16_suppl.3004.
  19. ClinicalTrials.gov. DAREON-5: A study to test whether different doses of BI 764532 help people with small cell lung cancer or other neuroendocrine cancers. Identifier NCT05882058. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05882058

Late Breaking Abstract – 2026 ASCO GU Symposium: Advancing Adjuvant Therapy in Clear Cell Renal Cell Carcinoma

RR

SUMMARY: The American Cancer Society estimates that 80,450 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2026 and about 15,160 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

Adjuvant immunotherapy has become an important component of treatment for patients with clear cell Renal Cell Carcinoma (ccRCC) who are at elevated risk for recurrence following nephrectomy. The role of adjuvant immune checkpoint blockade was established by the Phase 3 KEYNOTE-564 study, which demonstrated that adjuvant Pembrolizumab (KEYTRUDA®) significantly improves outcomes in this patient population.

Updated results from KEYNOTE-564 with a median follow-up of approximately 57 months confirmed a statistically significant Overall Survival (OS) benefit with adjuvant Pembrolizumab compared with placebo. Median OS was not reached in either group, but treatment with Pembrolizumab reduced the risk of death by 38% (HR 0.62; P=0.0024). At 48 months, the estimated OS rate was 91.2% among patients treated with Pembrolizumab versus 86.0% for those receiving placebo. The survival advantage was consistent across clinically relevant subgroups, including patients with M0 disease, those with M1 disease rendered no evidence of disease (M1 NED), and across PD-L1 expression levels and sarcomatoid histology status.

Building upon these findings, investigators have explored whether combining immunotherapy with other targeted agents could further reduce recurrence risk. The Phase 3 LITESPARK-022 trial evaluated the addition of the Hypoxia-Inducible Factor-2α inhibitor Belzutifan (WELIREG®) to adjuvant Pembrolizumab in patients with high-risk ccRCC following surgery.

Study Design

LITESPARK-022 is a randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 1,841 patients with ccRCC at increased risk of recurrence after nephrectomy.

Eligible patients included those with:

  • Intermediate-to-high risk M0 disease
    • pT2 tumors with grade 4 or sarcomatoid features, N0
    • pT3 tumors of any grade, N0
  • High-risk M0 disease
    • pT4 tumors of any grade, N0
    • Any pT stage with nodal involvement (N+)
  • M1 NED disease
    • Patients with metastatic disease who had undergone surgery and achieved no radiographic evidence of disease

Participants were randomized in a 1:1 ratio to receive either Pembrolizumab plus Belzutifan (N=921), Pembrolizumab plus placebo (N=920). Treatment consisted of Pembrolizumab 400 mg IV every 6 weeks for 9 cycles (approximately 1 year) and Belzutifan 120 mg orally once daily or placebo. Randomization was stratified according to risk category and tumor grade. The Primary endpoint was Disease-free survival (DFS) assessed by investigators and Secondary endpoints included Overall Survival (OS), Safety and tolerability.

Results discussed here represent the first interim analysis, conducted after a median follow-up duration was 28.4 months. Treatment completion rates were similar between groups (about 70%)

Efficacy Outcomes

The addition of Belzutifan to Pembrolizumab resulted in a statistically significant improvement in Disease-Free Survival, compared to Pembrolizumab plus placebo, meeting the Primary endpoint of the study (HR=0.72; 95% CI: 0.59–0.87; P=0.0003. This corresponds to a 28% reduction in the risk of recurrence or death with the combination regimen. The Median DFS had not yet been reached in either arm at the time of analysis. The estimated 24-month DFS rates were 80.7% in the Pembrolizumab plus Belzutifan group and 73.7% in the Pembrolizumab plus placebo group.

This represents the first Phase 3 adjuvant RCC trial demonstrating superiority of a combination therapy over active immunotherapy alone.

Overall Survival

Overall survival results remain immature. At the time of the interim analysis, only 29% of the events required for the final OS analysis had occurred, preventing definitive conclusions regarding survival benefit.

Safety Profile

As expected with the addition of Belzutifan, the combination regimen was associated with higher rates of treatment-related toxicity. Grade ≥3 Adverse Events for Pembrolizumab plus Belzutifan combination was 52.1% versus 30.2% for the Pembrolizumab plus placebo group. The most frequently reported grade ≥3 events included Anemia (12.1% vs 0.4%), Elevated ALT (6.4% vs 2.0%) and Hypoxia (4.6% vs 0%). Despite increased toxicity, grade 5 adverse events were rare and similar between arms, and no new safety signals were identified.

Clinical Implications

The findings from LITESPARK-022 suggest that combining Belzutifan with Pembrolizumab may further improve outcomes for patients with high-risk ccRCC following nephrectomy. However, the improved DFS must be balanced against the increased toxicity profile. Experts emphasize that careful patient selection will be essential if this regimen is adopted in clinical practice. Patients with baseline pulmonary or cardiovascular comorbidities, who may be more vulnerable to Belzutifan-associated hypoxia or anemia, may require additional consideration.

Furthermore, longer follow-up will be necessary to determine whether overall survival benefit emerges, as well as the impact on quality of life, and long-term safety of the combination regimen

Key Takeaways for Clinical Practice

  • Adjuvant Pembrolizumab remains a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy.
  • The LITESPARK-022 trial demonstrated a significant improvement in DFS when Belzutifan was added to Pembrolizumab.
  • The combination reduced the risk of recurrence or death by 28% compared with Pembrolizumab alone.
  • Toxicity was higher, particularly with respect to anemia and hypoxia, but was generally manageable with dose modification and supportive care.
  • Ongoing follow-up will determine whether Overall Survival and Patient-Reported Outcomes support broader adoption of this strategy.

Conclusion

The Phase 3 LITESPARK-022 trial represents an important step forward in the adjuvant treatment landscape for clear cell Renal Cell Carcinoma. By demonstrating a clinically meaningful improvement in Disease-Free Survival with the addition of Belzutifan to Pembrolizumab, the study introduces a promising new therapeutic approach for patients at high risk of recurrence after nephrectomy. Continued follow-up will clarify the long-term survival benefit and help define the role of this combination in routine clinical practice.

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. Choueiri TK, Motzer RJ, Karam JA, et al. 2026 ASCO Genitourinary Cancers Symposium. J Clin Oncol 44, 2026 (suppl 7; abstr LBA418)

Adjuvant Nivolumab for Resected Melanoma: 9 Year Outcomes

RR

SUMMARY: The American Cancer Society estimates that in the US, approximately 112,000 new cases of melanoma will be diagnosed in 2026 and about 8510 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades.

Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease specific survival rates of 59% and 40% respectively.

Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoint proteins (“gate keepers”) suppress antitumor immunity. Antibodies targeting these 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., block the immune checkpoint proteins and unleash T cells, resulting in T cell proliferation, activation and a therapeutic response.

Ipilimumab (YERVOY®) was approved by the FDA for the adjuvant treatment of patients with completely resected Stage III melanoma, based on an improvement in Relapse Free Survival, when compared to placebo, in a randomized Phase III trial. In this study however, over 50% of the patients treated with the recommended high dose Ipilimumab experienced Grade 3/4 toxicities. There is therefore an unmet need for adjuvant therapies, with improved benefit-risk ratio, for this patient group.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. Monotherapy with Nivolumab, in heavily pretreated advanced melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment.

Study Details

CheckMate 238 trial is a double-blind Phase III study that included 906 patients with completely resected, Stage IIIB/C or Stage IV melanoma. Patients were randomized in a 1:1 ratio to receive either Nivolumab 3 mg/kg IV, every 2 weeks (N=453) or Ipilimumab 10 mg/kg IV, every 3 weeks (N=453) for 4 doses, then every 12 weeks beginning at week 24, for up to 1 year. Both treatment groups were well balanced. Patients were stratified according to disease stage and PD-L1 status (positive vs. negative or indeterminate according to tumor-cell PD-L1 expression with a 5% cutoff). The Primary end point was Recurrence Free Survival (RFS).

Data from the primary analysis showed that adjuvant Nivolumab was superior to Ipilimumab with respect to RFS and Distant Metastasis–Free Survival (DMFS), and had a more favorable safety profile. This benefit was seen regardless of BRAF mutational status with Nivolumab, and was sustained at a minimum follow-up of up to 7 years. The Overall Survival at 4 years and 7 years was 71% with Nivolumab and 69% with Ipilimumab, and was not significantly different.

In this publication, the researchers provided the final results from CheckMate 238, with a minimum follow-up of 9 years (107 months).

Efficacy at 9 Year Follow-up

The median duration of RFS was 61.1 months with Nivolumab and 24.2 months with Ipilimumab (HR for recurrence or death=0.76) and the 9-year RFS was 44% and 37%, respectively. This benefit was seen across nearly all subgroups analyzed.

The median duration of DMFS in Stage III melanoma patients was more than 9 years with Nivolumab and 83.8 months with Ipilimumab, with 9-year survival of 54% and 48%, respectively (HR for distant metastasis or death=0.81).

The median OS was more than 9 years in both treatment groups, with 9-year survival of 69% in the Nivolumab group and 65% in the Ipilimumab group (HR for death=0.88). The rates of death from melanoma at 9 years were 26% with Nivolumab and 30% with Ipilimumab (HR=0.87; 95% CI, 0.67 to 1.13). It is still uncertain whether OS is improved when treatment is administered in the adjuvant setting compared with initiation at the time of metastatic disease. These outcomes indicate that, similar to trends in metastatic therapy, many patients receiving adjuvant treatment now live long enough to succumb to causes unrelated to melanoma.

Fewer patients in the Nivolumab group required subsequent systemic therapy compared to those in the Ipilimumab group (37.3% vs. 44.6%), with no new late-onset adverse events reported.

Conclusion

Final 9-year data from the CheckMate 238 trial confirms that adjuvant Nivolumab provides sustained improvements in Recurrence-Free Survival (RFS) and Distant Metastasis–Free Survival compared to Ipilimumab, in high-risk melanoma patients, maintaining a safer profile. The results highlight the need for ongoing long-term monitoring.

Nivolumab for Resected Stage III or IV Melanoma at 9 Years. Ascierto PA, Vecchio MD, Merelli B, et al. N Engl J Med 2026;394:333-342