Category: Hem/Onc Updates

FDA Grants Accelerated Approval to BRAFTOVI® with ERBITUX® and mFOLFOX6 for Metastatic CRC with a BRAF V600E Mutation

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SUMMARY: The FDA on December 20, 2024, granted accelerated approval to Encorafenib (BRAFTOVI®) in combination with Cetuximab (ERBITUX®) and modified Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) for patients with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test (Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit). 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 152,810 new cases of CRC were diagnosed in the United States in 2024 and about 53,010 patients died 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 VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), 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. Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations, and BRAF V600E is recognized as a marker of poor prognosis in this patient group. 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.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. 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.

BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The FDA in 2020, approved Encorafenib in combination with Cetuximab (ERBITUX®) for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation, detected by an FDA-approved test, after prior therapy, based on the BEACON CRC trial. However, first line treatment options for this group of patients remains an unmet need.

BREAKWATER is an ongoing, active-controlled, open-label, multicenter, randomized, Phase 3 study in which first line Encorafenib plus Cetuximab plus or minus chemotherapy was compared with Standard of Care chemotherapy alone, in patients with BRAF V600E-mutant mCRC. In this trial, patients were initially randomly assigned 1:1:1 to receive either Encorafenib orally once daily with Cetuximab IV infusion every 2 weeks (Encorafenib plus Cetuximab arm), Encorafenib orally once daily with Cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (Encorafenib plus Cetuximab plus mFOLFOX6 arm), or control group patients who received mFOLFOX6 (Leucovorin, Fluorouracil and Oxaliplatin) or FOLFOXIRI (Leucovorin, Fluorouracil, Oxaliplatin, and Irinotecan), both every 2 weeks, or Capecitabine plus Oxaliplatin (every 3 weeks), each with or without Bevacizumab . The trial was subsequently amended to limit randomization and compare the Encorafenib plus Cetuximab plus mFOLFOX6 group and the control group. Treatment in both groups continued until disease progression, unacceptable toxicity. The Primary endpoint was Progression Free Survival (PFS) and Objective Response Rate (ORR) and Secondary endpoints included Duration of Response, Overall survival, Time to Response and patient Reported Outcomes.

The present FDA accelerated approval was based on the results of the Encorafenib plus Cetuximab plus mFOLFOX6 group, compared to the control group. The major efficacy outcome measure was confirmed ORR assessed by Blinded Independent Central Review and evaluated in the first 110 patients randomly assigned in each treatment group. The ORR was 61% in the Encorafenib plus Cetuximab plus mFOLFOX6 group compared to 40% in the control group. Median Duration of Response was 13.9 months and 11.1 months in the two groups respectively. PFS and OS data in this ongoing trial are immature. The most common grade 3 or 4 laboratory abnormalities were increased lipase and decreased neutrophil count.

In conclusion, a combination of Encorafenib and Cetuximab plus mFOLFOX6 resulted in a statistically significant and clinically meaningful improvement in Response Rate and Durability of Response in treatment-naïve metastatic CRC patients with a BRAF V600E mutation. Continued approval for this indication is contingent upon verification of clinical benefit.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf

Adjuvant KEYTRUDA® Improves Disease Free Survival in Muscle-Invasive Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer were diagnosed and approximately 16,840 patients died of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra.

A third of the patients initially present with locally invasive disease. The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with urothelial carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

AMBASSADOR trial (Alliance A031501) is a randomized Phase 3 study, conducted to evaluate whether Pembrolizumab could enhance Disease-Free Survival (DFS) and Overall Survival (OS) in patients with high-risk Muscle Invasive Urothelial Carcinoma (MIUC) after radical surgery, compared to observation alone. This study enrolled 702 patients with high-risk MIUC who underwent radical surgery (cystectomy or nephroureterectomy) within 4-16 weeks before registration. Patients were considered to have high-risk MIUC if they were not eligible for or declined neoadjuvant cisplatin-based chemotherapy and had pT3 or higher, or pN+, or microscopic positive surgical margins, or if they have persistent muscle-invasive disease (defined as a pathological stage of ypT2 or higher or ypN+ or microscopic positive surgical margins) despite the receipt of neoadjuvant chemotherapy at the time of radical surgery. Patients were randomized in a 1:1 ratio, to receive Pembrolizumab 200 mg IV every 3 weeks for 1 year (N=354) or to undergo observation (N=348). Both treatment groups were well balanced and stratification factors for randomization included PD-L1 status (positive or negative, with positivity defined as a Combined Positive Score of 10 or more using the PD-L1 IHC 22C3 pharmDx assay), prior receipt of neoadjuvant chemotherapy, and pathological stage. The median age was 69 years and patients with upper tract and urethral urothelial carcinoma were included in this study. The coPrimary endpoints were DFS and OS, and key Secondary endpoints included DFS and OS stratified by PD-L1 expression.

As of July 2024, with a median follow-up of 44.8 months, the median DFS was significantly longer in the Pembrolizumab group (29.6 months) compared to the observation group (14.2 months). The Hazard Ratio (HR) for disease progression or death was 0.73 (P=0.003), demonstrating a clear benefit. The DFS benefit was observed across all subgroups, regardless of age, PD-L1 status, receipt of neoadjuvant chemotherapy, pathological stage, or tumor location. PD-L1 status therefore should not be used to select patients for treatment with adjuvant Pembrolizumab. The Overall Survival data remain immature. The safety profile of Pembrolizumab was consistent with previous studies, though Grade 3 or higher adverse events were more frequent in the Pembrolizumab group (50.6%) compared to the observation group (31.6%).

In conclusion, adjuvant Pembrolizumab significantly improves DFS in patients with high-risk MIUC post-radical surgery, offering a promising treatment option for this population. These results, together with emerging tools such as circulating tumor DNA (ctDNA) may enable more precise patient selection and stratification, optimizing the use of adjuvant therapies. As Overall Survival data mature and biomarker research evolves, the role of Pembrolizumab may become even more defined within the broader context of urothelial carcinoma treatment.

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. Apolo AB, Ballman KV, Sonpavde G, et al. N Engl J Med 2025;392:45-55

10 Year Survival Benefit in Advanced Melanoma with OPDIVO® plus YERVOY®

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SUMMARY: The American Cancer Society estimates that in 2024, about 100,640 new cases of melanoma were diagnosed in the United States and 8,290 people died 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) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. YERVOY® in a pooled analysis of data from 12 studies showed a 3-year Overall Survival of 26% among treatment naive patients, and survival up to 10 years in approximately 20% of all patients, with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. OPDIVO® in combination with YERVOY® in a Phase I study resulted in an Overall Survival of 68% at 3 years among patients with advanced melanoma, regardless of prior therapies.

CheckMate 067 is a double-blind Phase III study in which patients with previously untreated advanced melanoma were randomly assigned in a 1:1:1 ratio to receive one of the three regimens: OPDIVO® 1 mg/kg every 3 weeks plus YERVOY® 3 mg/kg every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg every 2 weeks (N=314); OPDIVO® 3 mg/kg every 2 weeks plus placebo (N=316); or YERVOY® 3 mg/kg every 3 weeks for four doses plus placebo (N=315). Randomization was stratified according to BRAF mutation status, metastasis stage, and Programmed cell Death Ligand 1 (PD-L1) status. Treatment was continued until disease progression or unacceptable toxicities. The two Primary end points were PFS and OS in the OPDIVO® plus YERVOY® group, and in the OPDIVO® group versus the YERVOY® group.

The researchers had previously reported the results from the 6.5 year analysis, which showed durable improved outcomes with OPDIVO® plus YERVOY®, and OPDIVO® alone, when compared to single agent YERVOY®, among patients with advanced melanoma. The authors in this publication reported the final 10-year results for the CheckMate 067 trial, including results for Overall Survival and Melanoma-Specific Survival, as well as Durability of Response.

With a minimum follow-up of 10 years, median Overall Survival for patients treated with OPDIVO® plus YERVOY® combination therapy was 71.9 months, for those treated with single agent OPDIVO® was 36.9 months, and 19.9 months with single agent YERVOY®. The Hazard Ratio for death was 0.53 for OPDIVO® plus YERVOY® as compared with YERVOY® and was 0.63 for single agent OPDIVO® as compared with YERVOY®. Median Melanoma-Specific Survival was more than 120 months with OPDIVO® plus YERVOY® combination therapy (Not Reached, with 37% of the patients alive at the end of the trial), 49.4 months with single agent OPDIVO®, and 21.9 months with YERVOY®. Among patients who had been alive and progression free at 3 years, 10-year Melanoma-Specific Survival was 96% with OPDIVO® plus YERVOY®, 97% with single agent OPDIVO®, and 88% with YERVOY®.

In conclusion, these 10-year data have shown ongoing survival benefits with OPDIVO® plus YERVOY® and with single agent OPDIVO®, as compared with YERVOY® monotherapy, in patients with advanced melanoma, potentially offering a curative therapy for responding patients.

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. Wolchok JD, Chiarion-Sileni V, Rutkowsk P, et al. for the CheckMate 067 Investigators. N Engl J Med 2025;392:11-22.

No Additional Benefit When Oxaliplatin is Added to 5-FU Based Adjuvant Chemotherapy in High Risk Stage II Colon Cancer

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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 152,810 new cases of CRC were diagnosed in the United States in 2024 and about 53,010 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

Colon cancer treatment strategies have advanced significantly over the years. Since 2004, the introduction of Oxaliplatin into adjuvant chemotherapy regimens has been a cornerstone in improving outcomes for patients with Stage III colon cancer. The most commonly adopted protocols include FOLFOX (a combination of Folinic acid or Leucovorin, 5-fluorouracil (5-FU), and Oxaliplatin) and a regimen combining Capecitabine with Oxaliplatin. These regimens gained validation through critical trials such as MOSAIC, NSABP C-07, and XELOXA, which demonstrated the survival benefits of Oxaliplatin-based combinations.

However, for patients with Stage II colon cancer, the role of adjuvant chemotherapy remains controversial. While many oncologists recommend adjuvant therapy for Stage II patients, its effectiveness is not universally supported by clinical data. The QUASAR trial showed limited benefits of Leucovorin and 5-FU in this population. Adding Oxaliplatin to adjuvant regimens has been explored to improve outcomes, particularly for high-risk patients. However, Oxaliplatin can be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

High-risk Stage II colon cancer is a heterogeneous group, and definitions of high-risk features vary across studies. High-risk features have included T4 tumors, bowel perforation, obstruction, poor histological differentiation, vascular invasion, or fewer than 10 lymph nodes examined. The heterogeneity of high-risk Stage II colon cancer complicates treatment decisions, with new clinical prognostic factors such as the site of tumor origin in the colon (tumor sidedness), age, and BMI having been described, in addition to the stage of the disease.

To clarify the benefits of Oxaliplatin in Stage II colon cancer, researchers performed a pooled analysis of the MOSAIC and NSABP C-07 trials. These studies collectively included 4,654 patients, of whom 1,595 had Stage II colon cancer, and were treated with either 5-FU and Leucovorin alone or 5-FU and Leucovorin plus Oxaliplatin. The Primary objective was to determine whether the addition of Oxaliplatin to 5-FU and Leucovorin provided a significant survival advantage for Stage II patients, particularly those with high-risk features. The analysis examined outcomes such as Overall Survival (OS) and Time to Relapse (TTR). Prognostic variables included T stage, presence of bowel perforation or obstruction, lymph node count, tumor sidedness, sex, age, and histological differentiation. Multivariable models and Kaplan-Meier survival analyses were employed to assess the impact of these variables. Patients with Stage III colon cancer were included only for interaction tests to compare treatment effects across stages.

The data from this pooled analysis revealed several important findings.
1. Prognostic Factors: Independent prognostic variables for Stage II colon cancer included sex, age, bowel perforation/obstruction, and tumor sidedness. These factors were associated with OS but did not predict a benefit from Oxaliplatin-based treatment.
2. Survival Outcomes: The addition of Oxaliplatin to 5-FU and Leucovorin did not significantly improve OS or TTR in Stage II colon cancer, even among high-risk subgroups. In contrast, a clear benefit was observed in Stage III colon cancer patients, suggesting a differential effect of Oxaliplatin based on cancer stage.
3. High-Risk Subgroup Analysis: Among patients with high-risk features such as T4 tumors or inadequate lymph node sampling, there was no statistically significant OS or TTR benefit from addition of Oxaliplatin to 5-FU and Leucovorin.
4. Interaction Between Stage and Therapy: The analysis confirmed an interaction between cancer Stage (II versus III) and the benefit of Oxaliplatin. Stage II colon cancer patients derived no added advantage from Oxaliplatin, while Stage III patients experienced substantial improvements in survival outcomes.

These results challenge existing guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), which recommend Oxaliplatin-based regimens for high-risk Stage II colon cancer. The findings suggest that current definitions of high-risk features are insufficient to justify the use of Oxaliplatin in this population. Moreover, discrepancies between Disease-Free Survival (DFS) and OS in Stage II colon cancer indicate that DFS is not a reliable surrogate endpoint in this group. The lack of benefit from Oxaliplatin emphasizes the need for more precise prognostic tools to identify Stage II patients who might benefit from adjuvant therapy.

Several limitations affected the study. Key data on biomarkers, such as MicroSatellite Instability (MSI) and MisMatch Repair (MMR) status, were unavailable for nearly half the cohort, preventing their inclusion in prognostic analyses. Emerging tools like circulating tumor DNA (ctDNA), which show promise in identifying relapse risk, were also unavailable during the study period. Despite the lack of benefit observed with Oxaliplatin, novel prognostic approaches are needed to identify Stage II colon cancer patients at a high risk of relapse. Future clinical trials incorporating ctDNA-based stratification may refine treatment approaches and reduce unnecessary exposure to neurotoxic agents like Oxaliplatin.

In conclusion, for patients with Stage II colon cancer, the addition of Oxaliplatin to 5-FU based adjuvant therapy does not improve Overall Survival or Time To Relapse. Current clinical and pathologic criteria for high-risk classification fail to justify the routine use of Oxaliplatin, emphasizing the need for alternative risk stratification tools. These findings call for a reevaluation of treatment guidelines to ensure that therapeutic decisions are informed by robust, individualized risk assessments.

Assessment of the Addition of Oxaliplatin to Fluoropyrimidine-Based Adjuvant Chemotherapy in Patients with High-Risk Stage II Colon Cancer: An ACCENT Pooled Analysis. Chibaudel B, Raeisi M, Cohen R, et al. J Clin Oncology 2024;42:4187-4195

FDA Approves OPDIVO Qvantig® for Subcutaneous Injection

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SUMMARY: The FDA on December 27, 2024, approved Nivolumab and hyaluronidase-nvhy (OPDIVO Qvantig®) for subcutaneous injection across approved adult, solid tumor Nivolumab indications as monotherapy, monotherapy maintenance following completion of Nivolumab plus Ipilimumab (YERVOY®) combination therapy, or in combination with chemotherapy or Cabozantinib. The approval includes indications for renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal carcinoma, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. OPDIVO Qvantig® is not indicated in combination with intravenous Ipilimumab.

The American Cancer Society estimates that 81,610 new cases of kidney and renal pelvis cancers were diagnosed in the United States in 2024 and about 14,390 people died 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.

OPDIVO® (Nivolumab) 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. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. The emergence of immunotherapy has offered new avenues for patients, with Nivolumab demonstrating efficacy across various tumor types. However, the conventional Intravenous (IV) administration of Nivolumab has been associated with significant treatment burden, prompting the exploration of alternative delivery methods. The CheckMate 67T trial aimed to address this challenge by assessing the efficacy and convenience of Subcutaneous (SC) Nivolumab compared to its IV counterpart.

The CheckMate 67T trial is an international, multicenter, randomized, open-label, Phase III study, conducted to evaluate the pharmacokinetics of Subcutaneous OPDIVO Qvantig® versus Intravenous delivery of Nivolumab in patients with locally advanced or metastatic clear cell Renal Cell Carcinoma (RCC). In this study, a total of 495 patients (N=495) were randomly assigned 1:1 to receive Nivolumab 1200 mg SC plus recombinant human hyaluronidase PH20 (OPDIVO Qvantig®) every 4 weeks (N=248), or Nivolumab 3 mg/kg IV every 2 weeks (N=247), until disease progression, unacceptable toxicity or completion of 2 years of treatment. The median age was 65 years, 67% were men and enrolled patients had measurable disease that progressed during or after 1–2 prior systemic regimens, had no prior immunotherapy treatment, and had a Karnofsky Performance Score of 70 or more. Hispanic patients accounted for at least 34% of study participants in both treatment arms, ensuring diverse representation.

The Primary objective of the study was to evaluate the pharmacokinetics of  OPDIVO Qvantig® versus IV delivery of Nivolumab, which included whether blood levels of the drug were comparable in the two groups over time and whether OPDIVO Qvantig® was noninferior to IV Nivolumab. The daily average concentration of the drug in the blood over 28 days and the concentration of the drug at the end of the dosing cycle were measured. Key Secondary endpoint included Objective Response Rate (ORR) by Blinded Independent Central Review (BICR).

The trial revealed compelling findings, indicating that OPDIVO Qvantig® not only matched the pharmacokinetic profile (noninferior) and Objective Response Rate of IV Nivolumab, but also drastically reduced administration time. The ORR for the OPDIVO Qvantig® group was noninferior to the Intravenous group, at 24.2% versus 18.2%, respectively. The Median Progression Free Survival was 7.23 months for the OPDIVO Qvantig® group versus 5.65 months for the IV group. The median treatment duration was under 5 minutes for the OPDIVO Qvantig® group, in contrast to the 30-minute infusion sessions required for IV therapy. Local injection site reactions occurred in 8.1% of patients. Reactions were low grade and transient and most deaths were due to disease progression.

It was concluded that Subcutaneous OPDIVO Qvantig® showed comparable pharmacokinetic profile and Overall Response Rates (ORR) compared to Intravenous Nivolumab, in addition to significant reduction in administration time. With over 20 FDA-approved indications for Nivolumab, the convenience of Subcutaneous administration and its potential impact extends far beyond Renal Cell Carcinoma, promising greater accessibility and streamlined treatment experiences for patients nationwide. By alleviating treatment burdens and enhancing efficiency, this innovative formulation heralds a new era in oncology, offering hope to patients and clinicians alike.

Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. George S, Bourlon MT, Chacon MR, et al. Journal of Clinical Oncology. Volume 42, Number 4_suppl. https://doi.org/10.1200/JCO.2024.42.4_suppl.LBA360.

Ivonescimab may be Superior to Pembrolizumab as First-Line Treatment in NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 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.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby unleashing the T cells. Five year results from the Phase III KEYNOTE-042 study which included eligible patients with locally advanced/metastatic NSCLC without EGFR/ALK alterations and with PD-L1 Tumor Proportion Score (TPS) 1% or more favored Pembrolizumab over chemotherapy, regardless of PD-L1 TPS.

Ivonescimab (AK112) is a novel bispecific antibody designed to target both PD-1 and Vascular Endothelial Growth Factor (VEGF). Its dual targeting mechanism is intended to enhance the therapeutic efficacy against advanced NSCLC, and has shown promising results in early-phase trials. Dual inhibition of PD-1 and VEGF by Ivonescimab might provide synergistic effects, enhancing therapeutic efficacy beyond what is achieved with PD-L1 inhibition alone.

The HARMONi-2 (AK112-303) is a randomized Phase III study designed to evaluate the efficacy and safety of Ivonescimab compared to Pembrolizumab, a well-established PD-1 inhibitor, in patients with advanced NSCLC. In this study, 398 eligible patients (N=398) from 55 centers in China with untreated locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) NSCLC were randomly assigned in a 1:1 ratio to receive either Ivonescimab 20 mg/kg administered IV every 3 weeks or Pembrolizumab 200 mg administered IV every 3 weeks. Patients were required to have PD-L1 positive tumors (TPS 1% or more), and patients with known EGFR mutations, ALK rearrangements, or prior systemic therapy were excluded. Randomization was stratified by histology (squamous versus non-squamous), clinical stage (IIIB/IIIC versus IV), and PD-L1 expression levels (TPS 1-49% versus TPS 50% or more).
The Primary endpoint was Progression-Free Survival (PFS), assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), Investigator-assessed PFS, Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate (DCR), and Safety.

The interim analysis of this study was conducted after a median follow-up of 8.7 months, from November 2022 to August 2023. The median PFS was significantly longer with Ivonescimab compared to Pembrolizumab. Patients receiving Ivonescimab had a median PFS of 11.14 months versus 5.82 months with Pembrolizumab. The Hazard Ratio (HR) was 0.51 (P<0.0001), indicating a 49% reduction in the risk of disease progression or death. The PFS benefit of Ivonescimab was consistent across various subgroups including histology, PD-L1 expression and metastatic sites. Ivonescimab demonstrated superior outcomes in ORR and DCR compared to Pembrolizumab with an ORR for Ivonescimab of 50%, compared to 38.5% for Pembrolizumab. The DCR was 89.9% with Ivonescimab and 70.5% with Pembrolizumab.

Both treatments showed similar safety profiles with no new safety signals for Ivonescimab. Treatment-Related Serious Adverse Events (TRSAEs) occurred in 20.8% of Ivonescimab-treated patients and 16.1% of Pembrolizumab-treated patients. Grade 3 or more immune-related Adverse Events (irAEs) were comparable: 7.1% with Ivonescimab and 8.0% with Pembrolizumab. Specifically, in patients with squamous cell carcinoma, TRSAEs were 18.9% with Ivonescimab and 18.7% with Pembrolizumab. Ivonescimab was associated with slightly higher rates of proteinuria and hypertension but overall demonstrated a manageable safety profile. Overall survival data and long-term safety data are awaited to confirm the clinical benefits of Ivonescimab.

In conclusion, the HARMONi-2 trial provided compelling evidence that Ivonescimab offers a statistically significant and clinically meaningful improvement in PFS compared to Pembrolizumab, in PD-L1 positive advanced NSCLC patients, with manageable safety profile. If subsequent data continue to support these findings, Ivonescimab may be a valuable alternative to existing therapies. One limitation is that the trial was conducted exclusively in China, which might affect the generalizability of the results to other populations.

Phase 3 study of ivonescimab (AK112) vs pembrolizumab as first-line treatment for PD-L1–positive advanced NSCLC: Primary analysis of HARMONi-2. Zhou C, Chen J, Wu L, et al. 2024 World Conference on Lung Cancer. Abstract PL02.04. Presented September 8, 2024. San Diego, CA.

Immune Checkpoint Inhibitor Therapy and Cardiovascular Adverse Events

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SUMMARY: Immune checkpoint inhibitors (ICIs) have dramatically transformed the management and prognosis of various malignancies. By enhancing the immune systems ability to identify and destroy cancer cells, ICIs have provided significant improvements in treatment outcomes across a range of tumor types. However, the introduction of these therapies has also been accompanied by a spectrum of immune-related Adverse Events (irAEs), including those affecting the cardiovascular system. These CardioVascular Adverse Events (CVAEs) present a serious concern due to their potential impact on patient health and treatment outcomes.

The cardiovascular manifestations associated with ICIs encompass a range of conditions such as myocarditis, pericarditis, acute coronary syndrome, heart failure, arrhythmias, conduction abnormalities, and cardiac arrest. Although the incidence of these events is relatively low (less than 1% of patients), their severity can be profound. Myocarditis, in particular, is a critical concern due to its association with a high mortality rate, which can be as high as 60%. This underscores the need for vigilant monitoring and management strategies to mitigate these risks.

The objective of the systematic review and meta-analysis was to elucidate the incidence and outcomes of CVAEs associated with ICIs and to assess the effectiveness of various management strategies for myocarditis. This analysis sought to update the clinical understanding of these adverse effects and provide recommendations based on the most recent data.

The researchers review process involved searching several databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, up to April 4, 2023, and with the gathered data, two separate analyses were performed:
1. Phase 1 to 4 Trials Analysis: Focused on trials involving adults with malignant neoplasms treated with FDA- or EMA-approved ICIs. This analysis aimed to gather data on the incidence of CVAEs associated with these therapies.
2. Case Reports and Retrospective Studies Analysis: Concentrated on clinical manifestations and treatment outcomes for patients who developed CVAEs due to ICIs.

Data were meticulously extracted by two independent investigators, with stringent criteria applied to ensure the relevance and quality of the studies included. For instance, studies with dose escalation, small sample sizes, or non-English publications were excluded. The Primary outcome measure was the incidence of CVAEs.

Incidence of Cardiovascular Adverse Events
The meta-analysis of clinical trials included data from 83,315 participants across 589 trials. The therapies investigated included several ICIs such as Pembrolizumab (KEYTRUDA&reg:), Nivolumab (OPDIVO®), Cemiplimab (LIBTAYO®), Atezolizumab (TECENTRIQ®), Durvalumab (IMFINZI®), Avelumab (BAVENCIO®), and Ipilimumab (YERVOY®). The overall incidence of CVAEs in patients treated with anti-PD-1 or anti-PD-L1 therapies was found to be 0.8%. Notably, Cemiplimab was associated with a higher risk of high-grade cardiovascular adverse events compared to other ICIs (2.91% for Cemiplimab versus 0.69% overall).

The incidence of myocarditis specifically was reported as 0.24% for any grade and 0.2% for high-grade myocarditis. While dual ICI therapy was linked to a higher incidence of myocarditis compared to other regimens, the overall incidence of CVAEs did not significantly differ between dual ICI therapy, ICI plus chemotherapy, or ICI plus Tyrosine Kinase Inhibitors.

Management and Outcomes of Myocarditis
In the analysis of myocarditis cases, which included 223 patients (64.5% men), the majority had received PD-1 or PD-L1 inhibitors. A substantial proportion of these patients had cardiovascular risk factors: 41.1% had hypertension, 16.3% had diabetes, and 46.5% had other risk factors. Among 220 evaluable patients, the mortality rate for myocarditis was alarmingly high at 37.7%.

Management strategies for myocarditis varied, with treatments including high-dose Corticosteroids, Methylprednisolone, IV immunoglobulin, Plasma exchange, Mycophenolate mofetil, Infliximab, and Antithymocyte globulin. Outcomes of these treatments showed mixed results. For instance, high-dose Corticosteroids were associated with a 63.5% improvement rate but also a 26% cardiac mortality rate. Abatacept showed promise with an improvement rate of 91.7% among those who received it. Prospective data suggested that systematic screening for respiratory muscle involvement, active ventilation, prompt use of Abatacept, and the addition of Ruxolitinib might reduce mortality rates. However, the review emphasized that the current management strategies are largely empirical, and there is no definitive evidence on the most effective approach.

Recommendations and Conclusions
The review highlighted a critical need for standardized diagnostic and therapeutic approaches due to the variability in management strategies and the lack of prospective clinical trials. The findings underscore the importance of early recognition, cessation of ICI therapy, and prompt initiation of corticosteroid therapy for optimal management of myocarditis. The review also suggests that further research, including prospective clinical trials and the establishment of international registries, is necessary to enhance the understanding and management of ICI-induced CVAEs.

In summary, while cardiovascular adverse events related to ICIs are rare, their potential severity, particularly myocarditis, warrants heightened awareness and proactive management by clinicians. Early identification and intervention are crucial to improving patient outcomes and reducing mortality associated with these adverse effects.

Immune Checkpoint Inhibitor–Induced Cardiotoxicity. A Systematic Review and Meta-Analysis. Nielsen DL, Juhl CB, Nielsen OH, et al. JAMA Oncol. 2024;doi:10.1001/jamaoncol.2024.3065.

Defining durability with AUGTYRO® (repotrectinib), the next-generation TKI for ROS1+ NSCLC

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Expert opinion: Jyoti Malhotra, MD, MPH
Content sponsored by: Bristol Myers Squibb
Dr. Malhotra was compensated by BMS for her contributions to this article.

Introduction: Unmet need in ROS1+ NSCLC
The identification of ROS1 as a therapeutic target in NSCLC has led to the development and approval of several first-generation TKIs.3-5 Despite this, the median duration of response is ~2 years with these first-generation TKIs.6,7 A different approach is needed.

1L AUGTYRO in locally advanced or metastatic ROS1+ NSCLC
TRIDENT-1, a global, phase 1/2, single-arm, multicohort, open-label trial, led to the approval of AUGTYRO as a treatment option in adult patients for locally advanced or metastatic ROS1+ NSCLC.1,2,8 AUGTYRO is the first and only approved next-generation TKI for this indication.8,9 “This approval has made it possible for newly diagnosed patients to have access to [another] treatment option that may provide disease control,” stated Dr. Malhotra.

                                               TRIDENT-1 Trial Design1,3,10,11In TRIDENT-1, the phase 2 dose expansion cohort included 127 patients who were either TKI-naïve (n=71) or had received a TKI (n=56).2 The primary endpoint was ORR and some of the secondary efficacy outcome measures were DOR and intracranial response. Baseline characteristics were reported for patients who had and had not received a prior TKI.2

There are warnings and precautions associated with AUGTYRO to keep in mind. These include central nervous system adverse reactions, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatinine phosphokinase (CPK) elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.1 Additional information related to warnings and precautions can be found here.

In the primary analysis, efficacy results for the TKI-naïve population (n=71) treated with AUGTYRO were as follows12:

  • ORR of 79% ([95% CI: 68–88]; median follow-up for ORR data: 18.1 months)
    • CR of 6% (n=4)
    • PR of 73% (n=52)
  • mDOR of 34 months ([95% CI: 25.6–NE]; range: 1.4+ to 42.4+ months; median follow-up for DOR data: 24.0 months)1,10
  • icORR observed in 7/8 patients with measurable baseline brain metastasis (median follow-up for icORR data: 18.1 months)1,12

                         Change in tumor burden by BICR in the TKI-naïve population12*

                           *Three patients discontinued study treatment before completing any post-baseline scans.12

In a follow-up analysis, continued response to treatment was seen with AUGTYRO. At the 33.9-month median follow-up, efficacy results for the TKI-naïve population treated with AUGTYRO were as follows9:
• cORR of 79% (n=71; [95% CI: 68–88])
• mDOR of 34.1 months (n=71; [95% CI: 27.4–NE])
• icORR of 89% (n=9; [95% Cl: 52–100]) in patients with measurable baseline brain metastasis

“TRIDENT-1 demonstrated an ORR of 79%, but more notably, a long mDOR of 34 months—this is almost 3 years,” explained Dr. Malhotra.

In TRIDENT-1, the most common reactions reported in ≥20% of 426 patients treated with AUGTYRO at the recommended dose were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and cognitive impairment.1 AUGTYRO was discontinued in 7% of patients, interrupted in 50% of patients, and dosage was reduced in 38% of patients due to adverse reactions.1 Serious adverse reactions occurred in 35% of patients receiving AUGTYRO. The most frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, pleural effusion, and hypoxia. Fatal adverse reactions occurred in 3.5% of patients and included pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.1

AUGTYRO is a next-generation ROS1 TKI with a compact structure that is smaller than currently available ROS1 TKIs.1,13,14
• Potential to decrease the development of ROS1 resistance mutations
• Potential to circumvent known ROS1 resistance mutations
• Physiochemical parameters for enhanced intracranial activity

                                    Mechanism of Action1,13


Dosing of AUGTYRO
The recommended oral dose of AUGTYRO is1:
• 160 mg (4x 40-mg capsules, or a single 160-mg capsule, QD) for the first 14 days
• 160 mg (4x 40-mg capsules, or a single 160-mg capsule, BID) on Day 15 and onward, until disease progression or unacceptable toxicity

“More recently, the 160 mg tablet is also available for use, which is great because now patients only need to take one tablet,” stated Dr. Malhotra. AUGTYRO can be taken with or without food.1 Patients should be advised not to drink grapefruit juice or eat grapefruit while taking AUGTYRO.1 Capsules should be swallowed whole at approximately the same time every day as prescribed.1 Contents of the capsule should not be opened, crushed, chewed, or dissolved.1 If a dose is missed or if a patient vomits at any time after taking a dose, instruct patients to skip the dose and resume at a regularly scheduled time.1 Two doses should not be taken at the same time.1 Adjustable dosing allows for dose modification if needed for adverse reactions. Recommended dosage reductions for adverse reactions are the following1:

  • For the dose of 160 mg QD:
    • First dose reduction: 120 mg QD
    • Second dose reduction: 80 mg QD
  • For the dose of 160 mg BID:
    • First dose reduction: 120 mg BID
    • Second dose reduction: 80 mg BID

A prescription for 40-mg capsules is required for dose reductions.1 Additional detailed dose reduction recommendations are available for key adverse reactions.1

Summary and conclusions
AUGTYRO is the next-generation TKI helping patients with ROS1+ NSCLC start strong.1,2,9 Results from the TRIDENT-1 trial and continued response for TKI-naïve patients at the ~3-year follow-up analysis support its current place in therapy.1,2,9 “AUGTYRO is definitely my preferred drug for 1L ROS1+ NSCLC treatment—we are seeing responses for years,” stated Dr. Malhotra.

1L=first line; ATP=adenosine triphosphate; BICR=blinded independent central review; BID=twice daily; CI=confidence interval; CNS=central nervous system; cORR=confirmed ORR; CR=complete response; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group performance status; EXP=expansion cohort; icORR=intracranial ORR; mDOR=median DOR; mNSCLC=metastatic NSCLC; NE=not evaluable; NSCLC=non-small cell lung cancer; ORR=overall response rate; PFS=progression-free survival; PR=partial response; QD=everyday; QTc=corrected QT; RECIST=Response Evaluation Criteria in Solid Tumors; ROS1=ROS proto oncogene 1; RP2D=recommended phase 2 dose; TKI=tyrosine kinase inhibitor.

INDICATION
AUGTYRO® (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

IMPORTANT SAFETY INFORMATION
Warnings & Precautions
Central Nervous System Adverse Reactions
• Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.
• Dizziness, including vertigo, occurred in 65%; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 11% required dose reduction of AUGTYRO due to dizziness.
• Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 5% of patients, 8% required dose reduction and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia.
• Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction and 0.5% permanently discontinued AUGTYRO due to cognitive adverse reactions.
• Mood disorders occurred in 6% of patients. Mood disorders occurring in >1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% required a dose reduction due to mood disorders.
• Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in >1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% required a dose reduction due to sleep disorders.
• The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.
• Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Interstitial Lung Disease (ILD)/Pneumonitis
• Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
• Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed.
Hepatotoxicity
• Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%.
• Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.
Myalgia with Creatine Phosphokinase (CPK) Elevation
• AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.
• Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement.
Hyperuricemia
• Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
• Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Skeletal Fractures
• Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients.
• Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients less than 12 years of age.
• Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.
Embryo-Fetal Toxicity
• Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose.
Adverse Reactions
• The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Drug Interactions
Effects of Other Drugs on AUGTYRO
Strong and Moderate CYP3A Inhibitors
• Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.

P-gp Inhibitors
• Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO.
Strong and Moderate CYP3A Inducers
• Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.
Effects of AUGTYRO on other Drugs
Certain CYP3A4 Substrates
• Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
• Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.
Contraceptives
• Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
• Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females of childbearing potential to use an effective nonhormonal contraceptive.
Please see US Full Prescribing Information for AUGTYRO.

References:
1. AUGTYRO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
2. Drilon A, Camidge DR, Lin JJ, et al. Repotrectinib in ROS1 fusion–positive non–small-cell lung cancer. N Engl J Med. 2024;390(2):118-131.
3. Lin JJ, Shaw AT. Recent advances in targeting ROS1 in lung cancer. J Thorac Oncol. 2017;12(11):1611-1625.
4. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-1203.
5. US Food and Drug Administration. FDA Approves Crizotinib Capsules. Published March 11, 2016. Accessed October 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-capsules.
6. Drilon A, Chiu CH, Fan Y, et al. Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC. JTO Clin Res Rep. 2022;3(6):100332. Published 2022 Apr 29. doi:10.1016/j.jtocrr.2022.100332.
7. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30(7):1121-1126. doi:10.1093/annonc/mdz131.
8. US Food and Drug Administration. Center for Drug Evaluation and Research. AUGTYRO Label and Approval History. NDA218213. Published November 15, 2023. Accessed October 16, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/218213Orig1s000ltr.pdf.
9. Drilon A, Dziadziuszko R, Camidge DR, et al. Repotrectinib in tyrosine kinase inhibitor (TKI)-naïve patients with advanced ROS1 fusion-positive (ROS1+) NSCLC in the phase 1/2 TRIDENT-1 trial: clinical update, treatment beyond progression and subsequent therapies. Oral presentation at ASCO 2024. Poster 386.
10. Cho BC, Camidge DR, Lin JJ, et al. Repotrectinib in patients with ROS1 fusion-positive non-small cell lung cancer: update from the pivotal phase 1/2 TRIDENT-1 trial. Oral presentation at WCLC 2023. Abstract OA03.06.
11. ClinicalTrials.gov. A study of repotrectinib (TPX-0005) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. Accessed April 19, 2024. https://clinicaltrials.gov/study/NCT03093116.
12. Cho BC, Lin JJ, Camidge DR, et al. Pivotal topline data from the phase 1/2 TRIDENT-1 trial of repotrectinib in patients with ROS1+ advanced non-small cell lung cancer (NSCLC). Oral presentation at ENA 2022. Abstract 2LBA.
13. Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent-front mutations. Cancer Discov. 2018;8(10):1227-1236.
14. Murray BW, Rogers E, Zhai D, et al. Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Mol Cancer Ther. 2021;20(12):2446-2456. doi:10.1158/1535-7163.MCT-21-0632

© 2024 Bristol-Myers Squibb Company. AUGTYRO®, is a registered trademark of
Bristol-Myers Squibb Company.
3600-US-2400322 11/24

Avoiding Chest Wall Irradiation After Mastectomy in Intermediate Risk Breast cancer

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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 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Even though the use of postmastectomy radiotherapy has been widely accepted for patients with four or more positive lymph nodes, the role of postmastectomy radiotherapy for those with one to three positive nodes or node-negative disease remains controversial. Nonetheless, post mastectomy chest wall irradiation is commonly used to treat this intermediate risk group of breast cancer patients.

BIG 2-04 MRC SUPREMO trial is a Phase 3, randomized clinical study, conducted to investigate the impact of adjuvant chest wall irradiation (CWI) following mastectomy and axillary surgical staging among patients with operable breast cancer, at intermediate-risk of loco-regional recurrence. Intermediate risk breast cancer patients are those with 1-3 positive lymph nodes or patients who have no positive lymph nodes but whose cancers exhibit other factors that increase the risk of recurrence, such as grade 3 histology and/or lymphovascular invasion. Enrolled patients had breast tumors 5 cm or less (pT1–2) and 1-3 positive axillary lymph nodes (N1), breast tumors larger than 5 cm (pT3) and node-negative disease (N0), or breast tumors larger than 2 cm but no larger than 5 cm (pT2), N0 disease, and grade 3 histology and/or lymphovascular invasion.

Of the 1,607 eligible patients available for analysis 808 patients were randomly assigned to receive chest wall irradiation after mastectomy (chest wall irradiation group), and 799 patients were randomly assigned to omit chest wall irradiation after mastectomy (no chest wall irradiation group). Patients additionally received guideline-based axillary node clearance and systemic therapies. Chest wall Irradiation consisted of a total dose of 50 Gy in 25 daily fractions over 5 weeks or radiobiologically equivalent schedules including 40 Gy in 15 fractions over 3 weeks. Medial periclavicular/ internal mammary nodal irradiation was allowed but axillary irradiation was not permitted.

At a median follow up of 9.6 years, there were no significant differences in Overall Survival between those who received chest wall irradiation and those who did not (81.4% and 82.0%, respectively). Even though chest wall irradiation reduced the risk of chest wall recurrence by over half, the absolute rate of chest wall recurrence was reduced by less than 2%, which was clinically insignificant. Further, neither patients with N0 disease nor those with N1 disease experienced survival benefits with chest wall irradiation, suggesting that even patients with lymph node-positive disease could safely omit post-mastectomy chest wall irradiation.

It was concluded from the primary analysis of the SUPREMO trial that following mastectomy in patients with 1-3 positive nodes, or in node negative breast cancer patients with other risk factors treated with modern therapeutic interventions, chest wall irradiation has no impact on overall survival and has a clinically insignificant impact on chest wall recurrence.

GS2-03: Does postmastectomy radiotherapy in ‘intermediate-risk’ breast cancer impact overall survival? 10 year results of the BIG 2-04 MRC SUPREMO randomised trial: on behalf of the SUPREMO trial investigators. Presented at SABCS 2024; Presenting Author(s): Ian Kunkler; Abstract Number: SESS-3537

Fixed-Duration CALQUENCE® plus VENCLEXTA® for Previously Untreated CLL

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SUMMARY: The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and non-covalent BTKi, Pirtobrutinib (JAYPIRCA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. Venetoclax is frequently combined with the infusion-based drug Obinutuzumab (GAZYVA®), which can impose a logistical burden on patients. The combination of Acalabrutinib plus Venetoclax, were noted to be synergistic.

The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III study designed to assess the efficacy and safety of Acalabrutinib in combination with Venetoclax, with or without Obinutuzumab, compared to investigators choice of standard chemoimmunotherapy. In this study, 867 patients (N=867) across 171 locations worldwide with previously untreated CLL were randomized 1:1:1 to receive a fixed-duration regimen of Acalabrutinib and Venetoclax with Obinutuzumab (AVO; N=286), Acalabrutinib and Venetoclax without Obinutuzumab (AV; N=291), or Standard-of-Care chemoimmunotherapy with either Fludarabine plus Cyclophosphamide and Rituximab (FCR) or Bendamustine plus Rituximab (BR) (FCR/BR; N=290). The median patient age was 61 years, 64.5% were male, and 58.6% had CLL with unmutated IGHV. Eligible patients had an ECOG performance status of 0 to 2 and active disease, requiring treatment as per the International Workshop on CLL 2018 criteria. Patients with prior CLL-specific treatments, 17p deletions, TP53 mutations, transformation of CLL to aggressive Non-Hodgkin Lymphoma, Central Nervous System involvement, or a history of Progressive Multifocal Leukoencephalopathy were excluded. The Primary endpoint of the trial was Progression Free Survival (PFS) as assessed by an Independent Review Committee (IRC). Key Secondary endpoints included PFS assessed by investigators, undetectable Minimal Residual Disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood in the treatment groups, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Time to next treatment.

At a median follow-up of 41 months, both AVO and AV provided a statistically significant improvement in BICR-assessed PFS over the chemoimmunotherapy control arm (HR for AVO was 0.42, and for AV was 0.65, versus FCR/BR; P<0.0001 and P=0.0038, respectively). Approximately 83% of patients in the AVO group remained progression-free at 36 months, compared to 76.8% of patients in the AV group and 66.5% in the FCR/BR group. Median PFS was not reached in the AVO and AV groups, but was 47.6 months in the FCR/BR group. The BICR-assessed Overall Response Rates (ORR) were 92.7% in the AVO group, 92.8% in the AV group, and 75.2% in the FCR/BR group (P<0.0001 for both comparisons). AV demonstrated an OS benefit trend over FCR/BR (HR=0.33; P<0.0001). Serious Adverse Events occurred in 38.4% (AVO group), 24.7% of patients (AV group), and 27.4% (FCR/BR group). Grade 3 or more neutropenia among the treatment groups, was noted in 35.2%, 26.8% and 32.4%, respectively. COVID-19-related deaths affected 25 patients in the AVO group, 10 patients in the AV group, and 21 patients in the FCR/BR group.

In conclusion, the AMPLIFY study successfully met its Primary endpoint, demonstrating superior PFS with AVO and AV compared to standard chemoimmunotherapy. These combinations offer deep and durable responses, paving the way for an easier, more effective treatment option. AV offers the first all-oral fixed-duration regimen for fit treatment naive CLL patients, providing significant convenience and manageable safety profiles. The addition of Obinutuzumab (AVO) improved efficacy but was associated with higher rates of serious adverse events and COVID-19-related deaths.

Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial. Abstract#1009. Brown JR, SeymourJF, Jurczak W, et al. Presented at ASH Annual Meeting and Exposition 2024.