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The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

News

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

Early switch to atezolizumab (Tecentriq) following a run-in with vemurafenib (Zelboraf) plus cobimetinib (Cotellic) improved overall survival (OS) rates at 4 and 5 years for patients with 

 V600–positive melanoma. However, this improvement was not statistically significant, according to long-term data from the phase 2 ImmunoCobiVem trial (NCT02902029).

“Yet, a relevant number of patients experienced rapid progression after early switch from targeted therapy to immune checkpoint inhibition [ICI],” Dirk Schadendorf, MD, of the University of Essen and the German Cancer Consortium, Partner Site, in Essen, Germany, said in a presentation of the data at the 2024 ESMO Congress.“The better early tumor control—PFS1—with continuous targeted therapy in arm A and treatment options outside the trial influence the overall effect size for early switch from targeted therapy to ICI within this trial.”

After the 3-month run-in phase of ImmunoCobiVem, patients without progressive disease (PD) were randomly assigned to continue vemurafenib plus cobimetinib (Arm A; n = 69) or switch to atezolizumab (Arm B; n = 66) until first documented PD.2 At a median follow-up of 57 months (IQR, 23-63), final OS data revealed that the median OS was 40.2 months (95% CI, 18.9-not estimable [NE]) in Arm A vs 49.6 months (95% CI, 26.1-NE) in Arm B (HR, 1.17; 95% CI, 0.71-1.91; stratified 

 = .94). The 60-month OS rates were 40% vs 45%, respectively.

Additionally, the final PFS1 data showed that patients in Arm A (n = 68) experienced a median PFS1 of 13.0 months (95% CI, 9.9-15.6) vs 5.9 months (95% CI, 5.5-8.3) in Arm B (n = 65; HR, 0.61; 95% CI, 0.41-0.91; stratified 

 = .006). The 60-month PFS1 rates were 19% vs 15%, respectively.

When examining patients who crossed over, the time to second progression (PFS3) was 2.8 months (95% CI, 2.1-3.3) among those in arm A who received vemurafenib plus cobimetinib and then atezolizumab (n = 21) compared with 6.0 months (95% CI, 2.1-8.8) among those in arm B who received atezolizumab then vemurafenib plus cobimetinib (n = 35; HR, 1.72; 95% CI, 0.93-3.20). The 48-month PFS3 rates were 10% vs 17%, respectively. Furthermore, the total PFS (PFS2) was 12.6 months (95% CI, 8.3-17.0) in arm A vs 14.6 months (95% CI, 8.6-25.6) in arm B (HR, 1.29; 95% CI, 0.70-2.38; 

 = .41); 60-month PFS2 rates were 10% vs 21%, respectively.

“No subgroups were identified for which a targeted therapy run in provided clinical benefit,” Schadendorf added.

“We are trying to answer [the questions of] in those patients where we had tumor control, whether we [can] continue with targeted therapy or are able to maintain the clinical response, that’s the PFS1 primary endpoint. At time of progression, there was crossover possible, PFS3,” Schadendorf said.

ImmunoCobiVem enrolled patients with previously untreated unresectable or metastatic 

 V600–mutated melanoma from November 23, 2016, to December 27, 2019, and the final database lock occurred on July 8, 2024.

Patients were randomly assigned 1:1 to arm A and arm B and stratification factors included serum lactate dehydrogenase (LDH; elevated vs normal), metastatic stage of disease (M1c yes vs no), and receival or previous adjuvant therapy (yes vs no).

Secondary end points included OS, overall PFS2, PFS3, best overall response rate, duration of response, and safety. The primary end point of PFS1 was defined as PFS from the start of the run-in phase to first PD.

All patients received vemurafenib at 960 mg twice daily on days 1 to 28 in combination with cobimetinib at 60 mg once daily on days 1 to 21 of a 28-day cycle in the 3-month run-in phase. Following the run-in phase, random assignment occurred and patients in arm A continued the combination therapy and those in arm B switched to receive 1200 mg every 3 weeks of atezolizumab. If PD occurred, patients the entered the crossover phase and switched to receive the opposite arm’s regimen. If a second PD event occurred, patients were only followed-up.

“The most important thing here is that these are traditional patients [and arms were] well balanced. There is nothing special to notice [on baseline patient characteristics],” Schadendorf said.

Among all patients in the trial (n = 185), the median age was 58 years (range, 19-91) and most patients were male (63%) and had an ECOG performance score of 0 (85%). Additionally, most patients had stage IV disease by AJCC 7th edition staging (93%) which included M1a (22%), m1b (22%), M1c (49%), and M1c with brain metastases (1%). Patients also had normal LDH levels (51%), received prior adjuvant therapy (13%), and had at least 3 disease sites (42%).

When examining objective response rate by phase of treatment, findings showed that at the end of the run-in phase, patients experienced a complete response (CR; n = 8), a partial response (PR; n = 92), stable disease (SD; n = 33), PD (n = 14), and other reason (n = 36).

In the randomized phase, patients in arm A experienced a CR (n = 14), PR (n = 32), SD (n = 4), and PD (n = 12); 37 patients had eventual PD, 27 discontinued treatment for reasons other than PD, and 5 patients are still on treatment. In the crossover phase, among the 21 patients in arm A, CR (n = 3), SD (n = 1), and PD (n = 15) occurred; 2 patients remain on treatment.

Patients in arm B experienced a CR (n = 12), PR (n = 12), SD (n = 4), and PD (n = 33) in the randomized phase; 50 patients had eventual PD, 12 discontinued treatment for reasons other than PD, and 4 patients remain on treatment. In the crossover phase, among the 35 patients in arm B, CR (n = 4), PR, (n = 11), SD (n = 4), and PD (n = 10) occurred; 2 patients remain on treatment and 10 discontinued therapy for reasons others than PD.

Disclosures: Dr Schadendorf reported receiving partial financial support from Roche Pharma for the conduct of this study and drug supply. He also reported receiving support, grants, or contracts from Bristol-Myers Squibb, MSD, Novartis, Pfizer, and Roche; receiving consulting fees or honoraria from Agenus, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Formycon, Immunocore, InFlarX, Merck Serono, MSD, NeraCare, Novartis, NoviGenix, Pfizer, Philogen, Pierre Fabre, Replimune, Sanofi, Regeneron, and Sun Pharma; receiving support for attending meetings or travel support from Pierre Fabre; and has participated on drug safety monitoring or advisory boards for AstraZeneca, BioNTech, Bristol-Myers Squibb, CureVac, Daiichi Sankyo, Erasca, Immatics, Immunocore, InFlarX, IOBioTech, Merck Serono, MSD, NeraCare, Novartis, Pfizer, Philogen, Pierre Fabre, Replimune, Sanofi/Regeneron, and Sun Pharma. He also has leadership roles for EORTC-MG, DeCOG, German Cancer Society, Fiege Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaREg.

1. Schadendorf D, Gogas H, Kandolf L, et al. Early switch from targeted to immunotherapy in advanced BRAFV600-positive melanoma: Long-term OS and final PFS results of the randomized phase II ImmunoCobiVem trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA45.

2. Livingstone E, Gogas H, Kandolf-Sekulovic L, et al. Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial. 

. 2023;190:112941. doi:10.1016/j.ejca.2023.112941

Atezolizumab following vemurafenib and cobimetinib shows improved overall survival in BRAF V600–positive melanoma, but not statistically significant.


Conference News

Canonical

Atezolizumab After Vemurafenib and Cobimetinib Shows Trend Toward Better OS in Melanoma

Nivolumab (Opdivo), either as monotherapy or in combination with ipilimumab (Yervoy), demonstrated a significant and lasting improvement in both overall survival (OS) and melanoma-specific survival (MSS) at 10 years compared with ipilimumab alone in patients with advanced melanoma, according to the final results of the phase 3 CheckMate 067 trial (NCT01844505) presented at the 2024 ESMO Congress and concurrently published in 

Data showed that with a minimum follow-up of 120 months, the median overall survival (OS) was 71.9 months (95% CI, 38.2-114.4) with nivolumab plus ipilimumab vs 19.9 months (95% CI, 16.8-24.6) with ipilimumab alone (HR, 0.53; 95% CI, 0.44-0.65), and 36.9 months (95% CI, 28.2-58.7) with nivolumab alone vs the 19.9 months with ipilimumab (HR, 0.63; 95% CI, 0.52-0.76). Ten-year OS rates were 43%, 37%, and 19% with nivolumab/ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy, respectively, with a HR of 0.85 between the combination and nivolumab alone (95% CI, 0.69-1.05). The OS benefit was upheld across prespecified subgroups.

“The 10-year CheckMate 067 results for nivolumab plus ipilimumab represent the longest median OS in a phase 3 study of an anti–PD-1 agent for any tumor type,” lead study author James Larkin, MD, professor and consultant medical oncologist at The Royal Marsden Hospital in the United Kingdom, said in an oral presentation during the congress. “These results demonstrate the sustained benefit and impact of dual checkpoint inhibitor therapy on the long-term prognosis of patients with advanced melanoma, highlighting the potential for cure in patients who respond to this type of treatment.”

In 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of adult and pediatric patients with metastatic melanoma, based on earlier findings from CheckMate 067.3 Nivolumab is also approved for use as a single agent in this patient population.

In the CheckMate 067 trial, data previously showed that nivolumab combined with ipilimumab, or nivolumab alone, improved OS compared with ipilimumab alone. At 7.5 years, the median OS with nivolumab/ipilimumab was 72 months, 37 months with nivolumab alone, and 20 months with ipilimumab alone.

Additionally, 7.5-year MSS rates were 98%, 97%, and 95% with the combination, single-agent nivolumab, and single-agent ipilimumab, respectively, in patients who were alive and progression free at 3 years.

In the landmark trial, 945 patients with previously untreated, unresectable or metastatic melanoma were randomized 1:1:1 to receive 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses then 3 mg/kg of nivolumab every 2 weeks (n = 314); 3 mg/kg of nivolumab every 2 weeks plus ipilimumab-matched placebo (n = 316); or 3 mg/kg of ipilimumab every 3 weeks for 4 doses plus nivolumab-matched placebo (n = 315) until disease progression or unacceptable toxicity.

The coprimary end points were progression-free survival (PFS) and OS with either the combination or nivolumab alone vs ipilimumab; secondary outcome measures were objective response rate, descriptive efficacy assessments, and safety. An exploratory end point was MSS.

Stratification factors included PD-L1 status (<5% vs ≥5%), 

 mutation status, and AJCC metastasis stage. The final data cutoff date was April 19, 2024, and the final database lock date was May 16, 2024.

Additional results showed that the median MSS was not reached (NR) with nivolumab plus ipilimumab (95% CI, 71.8-NR) and was 49.4 months (95% CI, 35.1-119.4) with single-agent nivolumab vs 21.9 months (95% CI, 18.1-27.4) with single-agent ipilimumab. This led to a HR of 0.48 favoring the combination vs single-agent ipilimumab (95% CI, 0.39-0.59) and a HR of 0.59 of single-agent nivolumab vs ipilimumab (95% CI, 0.49-0.73). In comparing the combination against single-agent nivolumab, the HR was 0.81 (95% CI, 0.64-1.01). The 10-year MSS rates were 52%, 44%, and 23%, respectively.

Larkin noted that the MSS results were consistent by 

 mutation status and PD-L1 expression level.

In patients who experienced a 3-year or greater PFS from earlier data, the 10-year MSS rates were 96%, 97%, and 88% with the combination, nivolumab alone, and ipilimumab alone, respectively.

“In CheckMate 067, PFS plateaued at 3 years, and these analyses were conducted to determine if being alive and progression free at 3 years may be a surrogate for long-term clinical benefit,” Larkin explained. “Indeed, these data suggest that PFS at 3 years is a strong surrogate marker for long-term survival with 10-year MSS rates of greater than 96% in the nivolumab-containing arms.”

Ten-year MSS rates were also evaluated by depth of response and determined to be a second long-term surrogate marker. In the nivolumab/ipilimumab arm, the best tumor burden reduction was 80% or higher in 87% of patients (n = 102) and was between 50% and 80% in 72% of patients (n = 55); these rates occurred in 88% (n = 85) and 75% (n = 32) of those on nivolumab alone, and 80% (n = 24) and 40% (n = 17) in those on the ipilimumab-only arm, respectively.

Furthermore, 36% of patients on nivolumab plus ipilimumab received subsequent systemic therapy compared with 50% of those on nivolumab alone and 67% of those on ipilimumab alone. Regarding safety, there were no new observed safety signals, and no treatment-related deaths have been reported since the 36-month analysis.

Larkin also noted that the incidence of late-emergent, spontaneously reported treatment-related adverse events (TRAEs), defined as occurring more than 100 days following treatment, was low across all 3 arms. In total, any-grade TRAEs occurred in 96%, 87%, and 86% of patients in the combination, single-agent nivolumab, and single-agent ipilimumab arms, respectively; these were grade 3/4 in 63%, 25%, and 30% of patients, respectively.

Any-grade and grade 3/4 TRAEs that led to treatment discontinuation occurred in 45% and 34% of those on the combination arm, respectively, 16% and 9% in those on nivolumab alone, and 17% and 15% of those on ipilimumab alone, respectively. There were 2 treatment-related deaths on the combination arm compared with 1 each on the monotherapy arms.

The median MSS in patients with grade 3/4 TRAEs was not NR (95% CI, 71.9-NR) with the combination, NR in the nivolumab-alone arm (95% CI, NR-NR), and 30.8 months (95% CI, 22.7-62.8) with ipilimumab alone. The 10-year MSS rates in these patients were 54%, 71%, and 29%, respectively.

“TRAEs did not negatively affect survival as 10-year MSS rates in patients with a grade 3/4 TRAE were higher than in the intent-to-treat population within each treatment arm,” Larkin added.

Disclosures: Dr Larkin cited speaker, consulting, or advisory fees with iOnctura, Apple Tree, Merck, BMS, Eisai, Debiopharm, Incyte, Novartis, touchIME, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, Immatics, and TouchEXPERT.

1. Larkin J, Sileni VC, Gaudy-Marqueste C, et al. 10-year survival outcomes from the phase 3 CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. Presented at: 2024 ESMO Congress; September 12-17, 2024; Barcelona, Spain. Presentation LBA43.

2. Wolchok JD, Chiarion Sileni V, Rutkowski P, et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. 

. Published September 15, 2024. doi:10.1056/NEJMoa2407417

3. Opdivo. Prescribing information. Bristol-Myers Squibb; 2024. Accessed September 15, 2024. 

https://packageinserts.bms.com/pi/pi_opdivo.pdf

4. Hodi FS, Chiarion-Sileni V, Lewis KD, et al. Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067. 

. 2022;40(suppl 16):9522-9522. doi:10.1200/JCO.2022.40.16_suppl.9522

5. Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Durable clinical outcomes in patients (pts) with advanced melanoma and progression-free survival (PFS) ≥3y on nivolumab (NIVO) ± ipilimumab (IPI) or IPI in CheckMate 067. 

. 2023;41(suppl 16):9542. doi:10.1200/JCO.2023.41.16_suppl.9542

Nivolumab, alone or with ipilimumab, significantly improved 10-year overall and melanoma-specific survival vs ipilimumab alone in advanced melanoma, according to final phase 3 CheckMate 067 trial data.

10-Year Data From CheckMate 067 Confirms Survival Advantage of Nivolumab in Advanced Melanoma

Adagrasib (Krazati), compared with docetaxel, provided significantly better results for patients with previously treated 

Adagrasib demonstrated superior outcomes to docetaxel in patients with previously treated KRAS G12C-mutated non-small cell lung cancer, even among those with baseline brain metastases.

Holly L. Geyer, MD

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