Author: RR

FDA Approves LUMAKRAS® with VECTIBIX® for KRAS G12C-mutated Colorectal Cancer

RR

SUMMARY: The FDA on January 16, 2025, approved Sotorasib (LUMAKRAS®) with Panitumumab (VECTIBIX®) for adult patients with KRAS G12C-mutated metastatic ColoRectal Cancer (mCRC), as determined by an FDA-approved test, who have received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. The FDA also approved the therascreen KRAS RGQ PCR Kit (QIAGEN GmbH) as a companion diagnostic device to aid in identifying patients with colorectal cancer whose tumors harbor KRAS G12C mutations and who may be eligible for LUMAKRAS® with VECTIBIX®.

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.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab (ERBITUX®) and Panitumumab. 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. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive Regorafenib (STIVARGA®), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies, however, have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells to cancer cells. KRAS is the most frequently mutated oncogene in human cancers and these cancers are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis.

Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

The present FDA approval was based on CodeBreaK 300 trial, which is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR) and Duration of Response (DOR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively and the median DOR was 4.4 months in the 960 mg Sotorasib/Panitumumab group. Overall Survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960 mg dose appeared to yield more clinically significant benefits than the 240 mg dose, across all efficacy endpoints, without additional toxic effects. The final analysis of PFS for patients randomized to the 240 mg Sotorasib/Panitumumab arm compared to the standard of care groups was not statistically significant.
Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that Sotorasib 960 mg in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher Objective Response Rate than standard of care treatment. Ongoing analysis and longer follow-up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

FDA Grants Accelerated Approval to BIZENGRI® for Non Small Cell Lung Cancer and Pancreatic Adenocarcinoma

RR

SUMMARY: The FDA on December 4, 2024, granted accelerated approval to Zenocutuzumab-zbco (BIZENGRI®) for adults with advanced, unresectable, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy. This represents the first FDA approval of a systemic therapy for patients with NSCLC or pancreatic adenocarcinoma harboring an NRG1 gene fusion.

Genomic rearrangements involving the neuregulin 1 (NRG1) gene have been implicated in a variety of solid tumors, including lung, breast, pancreas, ovarian, and prostate cancers. NRG1 fusions are rare oncogenic drivers occurring in less than 1% of solid tumors, highly enriched in KRAS-wild-type pancreatic adenocarcinoma and invasive mucinous adenocarcinoma of the lung. NRG1 fusions produce chimeric ligands that activate the ERBB Receptor Tyrosine Kinase (RTK) family, a group of proteins frequently exploited by cancer cells to promote tumor growth. In lung cancer, NRG1 fusions are associated with poor prognosis in patients with lung cancer, with low Response Rates to standard chemotherapy and immunotherapy, and a short Overall Survival.

The ERBB RTK family includes EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These proteins mediate crucial cell signaling pathways that regulate growth and survival. They can be oncogenically activated by ligand stimulation such as NRG1 fusion proteins binding to HER3 or HER4, mutations and translocations that may confer constitutive enzymatic activity, such as EGFR kinase domain mutations, the EGFRvIII variant (where the extracellular region of EGFR is deleted), EGFR fusions or gene amplification, or protein overexpression resulting in increasing receptor abundance on cell surfaces to amplify signaling.

NRG1 preferentially binds to HER3 and HER4, promoting their heterodimerization with other ERBB family members like HER2 and EGFR. This interaction is critical because HER3, a pseudokinase, lacks intrinsic enzymatic activity and depends on phosphorylation by its heterodimer partners. The activated HER3 forms docking sites for SH2-domain proteins, triggering multiple downstream signal transduction pathways like the PI3K pathway, which drive proliferation and survival.

Zenocutuzumab is a bispecific humanized immunoglobulin G1 (IgG1) containing two different Fab arms targeting the extracellular domains of HER2 and HER3. The HER2-targeting arm binds HER2, concentrating the antibody locally and positioning it (Dock) to block NRG1 binding to HER3 (Dock-and-block mechanism). The HER3-targeting arm prevents HER3 from undergoing the conformational changes necessary for heterodimerization with HER2 and EGFR. This dual targeting halts HER3 phosphorylation, disrupting downstream oncogenic signaling. Moreover, the glycoengineered IgG1 backbone of Zenocutuzumab enhances its affinity for Fc receptors, boosting Antibody-Dependent Cellular Cytotoxicity (ADCC)-a mechanism by which immune cells destroy antibody-coated tumor cells.

The present approval is supported by the Phase 1/2 eNRGy ongoing trial, which is an open-label, multicenter, multicohort, dose-escalation study of Zenocutuzumab, in patients with solid tumors with a NRG1 fusion. Enrolled patients had a median of one prior line of therapy, including platinum chemotherapy (72%) and Afatinib (11%). The median patient age was 64 years and most were female (62%), and 51% were Asian. The most common NRG1 fusion partners were CD74 (57%), SLC3A2 (22%), SDC4/7 (9%), and CDH1/2 (3%). Most NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%). Patients received Zenocutuzumab 750 mg IV every 2 weeks until disease progression. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) and Duration of Response (DOR), determined by Blinded Independent Central Review.

The ORR for NSCLC was 33% and median DOR was 7.4 months. The ORR for pancreatic adenocarcinoma was 40% and the DOR was 3.7-16.6 months. In the pooled safety population, the most common adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase, anemia, thrombocytopenia and hyponatremia.

It was concluded from this analysis that Zenocutuzumab provided robust and durable efficacy in advanced NRG1 positive NSCLC and pancreatic adenocarcinoma, with a well-tolerated safety profile, and represents a potential first and best-in-class therapy for patients with NRG1 fusion solid tumors.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic

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

RR

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

RR

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®

RR

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.