Nivolumab/Ipilimumab Combo Misses Mark while Nivolumab/Chemo Combo Sustains Clinical Benefit in Frontline Gastric/GEJ Cancer


Data from the phase 3 CheckMate-649 trial showed that the combination therapy of nivolumab and chemotherapy showed a sustained survival benefit in patients with advanced gastric, gastroesophageal junction (GEJ), or esophageal cancer, in contrast to the combination of nivolumab and ipilimumab.

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not significantly improve overall survival (OS) compared with chemotherapy with longer follow-up of patients with advanced gastric, gastroesophageal junction (GEJ), or esophageal cancer, according to data from the phase 3 CheckMate-649 trial (NCT-02872116) that were presented during the 2021 ESMO Congress.1 In contrast, the combination of nivolumab and chemotherapy upheld its improvement in progression-free and overall survival (OS) vs chemotherapy alone.

The median OS for patients with a PD-L1 combined positive score (CPS) of at least 5 was 14.4 months (95% CI, 13.1-16.2) with nivolumab/chemotherapy (n = 473) compared with 11.1 months (95% CI, 10.0-12.1) with chemotherapy alone (n = 482), leading to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.61-0.81). The 2-year OS rates were 31% and 19%, respectively.

Progression-free survival (PFS) was also improved with nivolumab/chemotherapy vs chemotherapy in the PD-L1 CPS 5 or greater subset, with a median PFS of 8.1 months (95% CI, 7.0-9.2) and 6.1 months (95% CI, 5.6-6.9), respectively (HR, 0.70; 95% CI, 0.60-0.81). The 2-year PFS rates were 19% and 11%, respectively.

However, in the arm of nivolumab/ipilimumab vs chemotherapy, the median OS for patients with PD-L1 CPS of 5 or higher (n = 234 and 239, respectively) was 11.2 months (95% CI, 9.2-13.4) and 11.6 months (95% CI, 10.1-12.7), respectively (HR, 0.89; 95% CI, 0.71-1.10; P = .2302), not meeting this secondary end point. The 2-year OS rates were 25% and 17%, respectively.

The longer follow-up findings further support nivolumab plus chemotherapy as a new standard frontline treatment for patients with advanced gastric/GEJ/esophageal cancer, Yelena Y. Janjigian, MD, chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, explained in a virtual presentation during the meeting.

“Nivolumab/chemotherapy continues to demonstrate clinically meaningful benefit in our first-line treated patients; we demonstrated sustained OS, PFS, and objective response rate improvement compared to chemotherapy, and these data have already changed practice; it’s nice to have an additional 12 months of follow-up,” Janjigian said. “Nivolumab and ipilimumab did not significantly OS vs chemotherapy in patients with PD-L1 CPS 5 or greater.”

In April 2021, the FDA approved nivolumab for use in combination with select types of chemotherapy for the frontline treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, based on earlier data from CheckMate-649.2

At a 12-month minimum follow-up, results had showed that nivolumab/chemotherapy led to a median OS of 14.4 months (95% CI, 13.1-16.2) vs 11.1 months with chemotherapy alone (95% CI, 10-12.1) in patients who had a PD-L1 CPS of 5 or greater (HR, 0.71; 98.4% CI, 0.59-0.86; P <.0001).3 Moreover, the nivolumab/chemotherapy regimen was also associated with a 32% reduction in the risk of disease progression or death compared with chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.81; P <.0001).

The third arm of CheckMate-649 included the combination of nivolumab and ipilimumab and was compared with chemotherapy in this patient population. Previously, in the phase 1/2 CheckMate-032 trial, this regimen showed clinically meaningful and durable activity and tolerability in heavily pretreated patients with advanced gastric, GEJ, and esophageal adenocarcinoma.4

In the open-label, international, phase 3 CheckMate-649 trial, 2031 patients with previously untreated, unresectable, advanced or metastatic gastric/GEJ/esophageal adenocarcinoma, irrespective of PD-L1 status, were randomized 1:1:1 to 3 arms: nivolumab at 360 mg plus XELOX chemotherapy every 3 weeks or nivolumab at 240 mg plus FOLFOX every 2 weeks (n = 789); XELOX every 3 weeks or FOLFOX every 2 weeks (n = 833); or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab at 240 mg every 2 weeks (n = 409).

“It’s important to note that the [Data Monitoring Committee] recommended that we stop that study early due to higher toxicity and early death compared to the other 2 arms,” Janjigian noted regarding the smaller size of the nivolumab/ipilimumab arm.

Patients had to have an ECOG performance status of 0 or 1 as well as no known HER2-positive status. Stratification factors included PD-L1 expression on tumor cells (≥1 vs <1%), region (Asia vs United States/Canada vs rest of world), ECOG performance status (0 vs 1), and chemotherapy regimen (XELOX vs FOLFOX).

At the 2021 ESMO Congress, Janjigian presented the first results of the nivolumab/ipilimumab arm, as well as long-term follow-up from the nivolumab/chemotherapy arm of CheckMate-649.

The coprimary end points were PFS and OS via blinded independent central review (BICR; PD-L1 CPS ≥5) with nivolumab/chemotherapy vs chemotherapy alone. Secondary end points included OS in the nivolumab/chemotherapy vs chemotherapy comparison for patients with PD-L1 CPS of at least 1 and in all randomized patients, and OS for nivolumab/ipilimumab vs chemotherapy for patients with a PD-L1 CPS of at least 5 and in all randomized patients.

Baseline characteristics were well balanced across the 3 arms and were consistent with the PD-L1 CPS 5 or greater population. When comparing nivolumab/chemotherapy (n = 789) with chemotherapy alone (n = 792), the median age was 61.5 years (range, 53-69), 69.5% of patients were male, and 76% of patients were non-Asian. Fifty-eight percent of patients had an ECOG performance status of 1, 70% of patients had gastric cancer as their primary tumor location, and 95.5% of patients had metastatic disease; 39% had liver metastases and 17.5% had signet ring cell carcinoma. A total 60.5% of patients had a PD-L1 CPS of at least 5, 16% had PD-L1 n at least 1% of tumor cells, and 87% of patients had microsatellite stable (MSS) disease; 53.5% of patients received FOLFOX or XELOX on the study.

In the nivolumab/ipilimumab (n = 409) vs chemotherapy (n = 404) comparison, the median age was also 61.5 years (range, 22-90), 68.5% of patients were male, and 30% of patients were Asian; 53% had an ECOG performance status of 1 and 69.5% had gastric cancer as the primary tumor location. Ninety-six percent of patients had metastatic disease, 38% had liver metastases, and 19% had signet ring cell carcinoma. A total 59% of patients had PD-L1 CPS 5 or greater, 17% had PD-L1 on at least 1% of tumor cells, and 86% of patients had MSS disease. Forty-seven percent of patients (all on the chemotherapy arm) received FOLFOX/XELOX on study.

At the data cutoff date of May 27, 2021, the minimum follow-up was 24.0 months in the nivolumab/chemotherapy arm and 35.7 months in the nivolumab/ipilimumab arm. The median duration of treatment was 6.8 months (range, 0.1-45.0) for nivolumab chemotherapy, 1.0 months (range, 0.0-24.1) for nivolumab/ipilimumab, and 4.9 months (range, 0.0-45.5) for chemotherapy alone. Most patients across all arms discontinued treatment, most commonly for disease progression in both the nivolumab/chemotherapy vs chemotherapy (69% vs 71%) and the nivolumab/ipilimumab vs chemotherapy comparisons (63% vs 72%, respectively).

Forty-two percent and 47% of all randomized patients to nivolumab/chemotherapy vs chemotherapy and nivolumab/ipilimumab vs chemotherapy, respectively, received subsequent treatment; this was predominantly chemotherapy. Subsequent immunotherapy was given in 2% to 3% of patients in the nivolumab arms and in 9% to 12% of the chemotherapy-alone arms.

Nivolumab/Chemotherapy Data: Practice-Affirming

Further results showed that, in all randomized patients, the median OS with nivolumab/chemotherapy (n = 789) was 13.8 months (95% CI, 12.4-14.5) vs 11.6 months (95% CI, 10.9-12.5) with chemotherapy (n = 792), which showed a 21% reduction in the risk of death (HR, 0.79; 95% CI, 0.71-0.88). The 2-year OS rates were 28% and 19%, respectively.

The median PFS in all randomized patients with 7.7 months (95% CI, 7.1-8.6) with nivolumab/chemotherapy and 6.9 months (95% CI, 6.7-7.2) with chemotherapy, respectively (HR, 0.79; 95% CI, 0.70-0.89). The 2-year PFS rates were 16% and 10%, respectively.

With longer follow-up in the PD-L1 CPS 5 or greater subset, the ORR was 60% (55%-65%) with nivolumab/chemotherapy (n = 378) vs 45% (95% CI, 40%-50%) with chemotherapy alone (n = 390). The 60% ORR comprised a 13% complete response (CR) rate and a 47% partial response (PR) rate; 28% and 7% of patients experienced stable disease (SD) and progressive disease (PD), respectively. The median duration of response (DOR) was 9.7 months (95% CI, 8.2-12.4) with nivolumab/chemotherapy vs 7.0 months (95% CI, 5.6-7.9) with chemotherapy alone, respectively.

The responses were similar in the all-randomized population with nivolumab/chemotherapy (n = 603) vs chemotherapy alone (n = 607) with ORRs of 58% (95% CI, 54%-62%) and 46% (95% CI, 42%-50%), respectively. The 58% ORR included an 11% CR rate and a 47% PR rate; the SD and PR rates were 29% and 7%, respectively. The median DOR was 8.5 months (95% CI, 7.7-10.2) with nivolumab/chemotherapy and 6.9 months (95% CI, 5.8-7.2) with chemotherapy alone.

The magnitude of benefit was greater in patients with microsatellite instability–high (MSI-H) tumors, with a median OS of 38.7 months (95% CI, 8.4-44.8) with nivolumab/chemotherapy (n = 23) vs 12.3 months (95% CI, 4.1-16.5) with chemotherapy alone (n = 21; unstratified HR, 0.38; 95% CI, 0.17-0.84). The ORRs were 55% (95% CI, 32%-77%) and 39% (95% CI, 17%-64%), respectively.

For patients with MSS tumors, the median OS was 13.8 months (95% CI, 12.4-14.5) and 11.5 months (95% CI, 10.8-12.5) for nivolumab/chemotherapy (n = 696) and chemotherapy alone (n = 682), respectively (unstratified HR, 0.78; 95% CI, 0.70-0.88). Here, the ORRs were 59% (95% CI, 55%-63%) and 46% (95% CI, 42%-51%), respectively.

Nivolumab/Ipilimumab Results: End Points Not Met

In addition to the secondary end point not being met with the nivolumab/ipilimumab in the PD-L1 CPS of 5 or greater subset, the median OS was not improved with the immunotherapy regimen (n = 409) vs chemotherapy (n = 404) in all-randomized patients, at 11.7 months (95% CI, 9.6-13.5) and 11.8 months (95% CI, 11.0-12.7), respectively (HR, 0.91; 95% CI, 0.77-1.07; P = not tested). The 2-year OS rates were 23% and 19%, respectively.

“After long-term follow-up after 12 months, there is a crossover in favor of nivolumab/ipilimumab, although this difference was not meaningful or statistically significant,” said Janjigian.

Moreover, in the PD-L1 CPS of 5 or greater subset, the median PFS with nivolumab/ipilimumab was 2.8 months (95% CI, 2.6-4.0) vs 6.3 months (95% CI, 5.6-7.1) with chemotherapy, (HR, 1.42; 95% CI, 1.14-1.76). The 2-year PFS rates were 10% and 11%, respectively.

Responses were evaluated in all randomized patients who had target lesion measurements at baseline per BICR assessment. The ORR was 27% (20%-33%) with nivolumab/ipilimumab (n = 196), which included a 5% CR rate and a 21% PR rate; the SD and PD rates were 27% and 32%, respectively. The ORR with chemotherapy was 47% (95% CI, 40%-54%). Additionally, the median DOR was improved with nivolumab/ipilimumab at 13.2 months (95% CI, 8.3-18.3) vs 6.9 months (95% CI, 5.2-7.6) with chemotherapy, respectively.

In all-randomized patients, the median PFS was 2.8 months (range, 2.6-3.6) and 7.1 months (range, 6.9-8.2 months), respectively (HR, 1.66; 95% CI, 1.40-1.95). Here, the 2-year PFS rates were 8% and 12%, respectively.

The ORRs with nivolumab/ipilimumab (n = 333) and chemotherapy (n = 299) were 23% (95% CI, 18%-28%) and 47% (95% CI, 41%-53%), respectively. The 23% ORR comprised a 6% CR rate and a 17% PR rate; 27% and 34% of patients had SD and PD, respectively. A similar benefit with DOR was seen in the all randomized population, with the median DOR being 13.8 months (95% CI, 9.4-17.7) and 6.8 months (95% CI, 5.6-7.2) with nivolumab/ipilimumab and chemotherapy, respectively.

There was also a greater OS benefit in patients with MSI-H tumors on nivolumab/ipilimumab (n = 11) vs chemotherapy (n = 10), in which the median OS was not reached (NR; 95% CI, 2.7–NR) and 10.0 months (95% CI, 2.0-28.2), respectively (unstratified HR, 0.28; 95% CI, 0.08-0.92). The ORRs were 70% (95% CI, 35%-93%) and 57% (95% CI, 18%-90%), respectively.

In patients with MSS disease, the median OS was 11.6 months (95% CI, 9.4-13.5) for those on nivolumab/ipilimumab (n = 355) compared with 12.0 months (95% CI, 11.0-12.9) for those on chemotherapy (n = 344; unstratified HR, 0.96; 95% CI, 0.81-1.12). The ORRs were 20% (95% CI, 16%-25%) and 48% (95% CI, 42%-54%), respectively.

Regarding safety across all 3 groups, the most common grade 3/4 treatment-related adverse effects (TRAEs) with nivolumab/chemotherapy was neutropenia (15%), decreased neutrophil count (11%), and anemia (6%). The most common grade 3/4 TRAEs with nivolumab plus ipilimumab was increase lipase (7%), increased amylase (4%), and increase alanine aminotransferase and aspartate aminotransferase (4% each). With chemotherapy, these TRAEs were neutropenia (11%-13%), decreased neutrophil count (9%-10%), and diarrhea (3%-4%).

Treatment-related deaths occurred in 16 patients on nivolumab/chemotherapy, 10 patients on nivolumab/ipilimumab, and 7 patients on chemotherapy.

Janjigian noted that the incidence of TRAEs in patients with PD-L1 CPS of 5 or greater was consistent with all treated patients across the study arms.

“It’s important to note that serious TRAEs were highest in the nivolumab/ipilimumab arm, 23%, which is expected with a higher dose of ipilimumab,” Janjigian said, adding that immunologic etiology AEs were mainly grade 1/2. “The side effect profile with nivolumab-containing arms really depends on what you’re going to combine it with. With nivolumab/chemotherapy combination, there are both side effects from chemotherapy and immune-related side effects, and clearly with nivolumab/ipilimumab, these are mostly immune-related side effects.”


  1. Janjigian YY, Ajani JA, Moehler M, et al. Nivolumab (nivo) plus chemotherapy (chemo) or ipilimumab (ipi) vs chemo as first-line (1L) Treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 study. Presented at: 2021 ESMO Congress; September 16-21; 2021; Virtual. LBA7.
  2. FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed September 19, 2021.
  3. Moehler M. Shitara K, Garrido M, et al. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol. 2020;31(4):S1191. doi:10.1016/j.annonc.2020.08.2296
  4. Janjigian YY, Bendell J, Calvo E, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 2018;36(28):2836-2844. doi:10.1200/JCO.2017.76.6212
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