Updated CheckMate 649 Data Reinforce Nivolumab Plus Chemo as Frontline SOC in Advanced Gastric Cancers

Kohei Shitara, MD

Four-year survival data from the phase 3 CheckMate 649 study (NCT02872116) validates the use of chemotherapy plus nivolumab (Opdivo) as a standard of care (SOC) option in the first line for patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma, according to Kohei Shitara, MD.¹

The randomized, open-label, global study previously met its primary end point of improved progression-free survival (PFS) and overall survival (OS) in patients with a PD-L1 combined positive score (CPS) of 5 or more. Based on these findings, the FDA approved the use of nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy in April 2021 for the first-line treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma. Notably, the PD-1 inhibitor was the first immunotherapy agent to receive approval in the United States in this population.²

Data presented at the 2024 Gastrointestinal Cancers Symposium showed that at a minimum follow-up of 48.1 months, the median OS in the overall population was 13.7 months (95% CI, 12.4-14.5) with the combination (n = 789) vs 11.6 months (95% CI, 10.9-12.5) with chemotherapy (n = 792; HR, 0.79; 95% CI, 0.71-0.88). Patients with a PD-L1 CPS of 5 or greater experienced a median OS of 14.4 months (95% CI, 13.1-16.2) vs 11.1 months (95% CI, 10.1-12.1) with the combination (n = 473) and chemotherapy (n = 482), respectively (HR, 0.70; 95% CI, 0.61-0.81). In those with a PD-L1 CPS of 1 or higher, the median OS was 13.8 months (95% CI, 12.4-14.8) and 11.4 months (95% CI, 10.7-12.3), respectively (HR, 0.75; 95% CI, 0.67-0.85).

The median progression-free survival (PFS) in the overall population was 7.7 months (95% CI, 7.1-8.6) with nivolumab plus chemotherapy vs 6.9 months (95% CI, 6.7-7.2) with chemotherapy alone (HR, 0.80; 95% CI, 0.71-0.89). In the group of patients with a PD-1 CPS of 5 or higher, the median PFS was 8.3 months (95% CI, 7.0-9.3) and 6.1 months (95% CI, 5.6-6.9 in the nivolumab/chemotherapy and chemotherapy arms, respectively (HR, 0.71; 95% CI, 0.61-0.82); in the subgroup with a PD-L1 CPS of 1 or higher, the median PFS was 7.5 months (95% CI, 7.0-8.4) and 6.9 months (95% CI, 6.2-7.1), respectively (HR, 0.77; 95% CI, 0.68-0.88).

“Chemotherapy plus nivolumab is implemented [in practice] as the current SOC, and these results clearly support the continued use of this treatment for patients in the first-line indication,” said Shitara, who was the lead study author, as well as a medical oncologist and chief of the Department of Gastrointestinal Oncology of the National Cancer Center Hospital East in Kashiwa, Japan.

In an interview with OncLive^®, Shitara highlighted long-term survival and safety data with the nivolumab combination from CheckMate 649, discussed the optimal use of this combination in patients according to PD-L1 CPS status, and detailed the importance of investigating immunotherapy plus targeted therapy combinations to continue moving the field forward.

OncLive: Could you briefly provide some background on the CheckMate 649 study, including findings from previously reported interim analyses?

Shitara: CheckMate 649 is a global, pivotal trial [that set out] to establish chemotherapy plus nivolumab as a standard for patients with [untreated] HER2-negative gastric or GEJ adenocarcinomas. This study met its primary end points of PFS and OS benefit with this combination at a minimum of 1 year of follow-up at the first interim analysis. [These data were] published in The Lancet almost 3 years before and led to regulatory approval [of the regimen] in many countries. We also published [findings from] a 2-year follow-up analysis in Nature Medicine. We [shared] 3-year follow-up data last year [and this was published] in the Journal of Clinical Oncology. This time, we are showing 4-year survival data [from the trial].

What patient population was evaluated in the study?

This is a first-line population with no previous chemotherapy [exposure] and known HER2-negative disease, [so those with] HER2-positive [disease] had to be excluded. Otherwise, the usual first-line population was a target for this trial. We do have a subgroup analysis [of patients according to] PD-L1 CPS, but [this was not required to be known in the] all-comer population.

What long-term survival data were presented at the meeting?

The 4-year survival rate reported with chemotherapy plus nivolumab [in patients with a PD-L1 CPS of 5 or greater] was 17% compared with 8% with chemotherapy alone; that is a 9% actual difference in 4-year survival rate. This is a benchmark in gastric cancer because usually survival is not high enough. To achieve [prolonged and] and durable survival is very difficult, even with any kind of chemotherapy. After the introduction of the checkpoint inhibitor, we have durable survival [rates and] responses that are confirmed by this long-term follow-up. [In the] all-comer population, there was a 5% difference in 4-year survival rate [between the arms] and the same difference in PFS.

There was no update on response rate because responses were usually achieved at a relatively early stage of treatment. We did show an improvement in PFS2, which was the [time from randomization] to progression [after subsequent] chemotherapy, and some data stratified by the response rate at the 18-week [landmark timepoint.] Patients achieved a [numerically higher] response rate at 18 weeks [with the combination vs chemotherapy alone]. This predicts a very nice survival outcome.

Were there any updates with regard to the toxicity profile of the regimen?

Safety profile is another important aspect of this kind of treatment, because sometimes [patients] experience delayed onset of immune-mediated adverse effects after using a checkpoint inhibitor. However, there was no difference in terms of grade 3 or higher toxicity or treatment-related deaths [between the] 3- and 4-year survival data. No new safety concerns [were identified] in this update.

Should this regimen be primarily administered to patients with a higher PD-L1 CPS score, or for all patients regardless of PD-L1 CPS score?

This is a very difficult question. There is no doubt [that the combination should be given to patients with] a CPS score of 5 or higher if they have enough performance data, such as [adequate] organ function. [We saw a] durable benefit in terms of our efficacy end point [for these patients]. For [those with a] CPS less than 5, the PFS and OS benefit [derived with the regimen] was relatively limited even after this long-term follow-up, with a hazard ratio of 0.75 [for OS and 0.77 for PFS]. There is still data to suggest that a continuous benefit in response rate [can be achieved with the combination in this population].

I’m always considering not only [a patient’s] CPS score but also other clinical factors, including a patient’s symptoms, their wish to receive intensive treatment, other comorbidities, family support, toxicity from immunotherapy, etc. [At my] institution, most of these patients with good performance data are enrolled in clinical trials. I tend to use chemotherapy alone in patients with a low CPS, but if I have a patient with good performance who could be a candidate for a clinical trial, I may use the chemotherapy/nivolumab combination.

Does this research inspire any future avenues of investigation?

We have some new candidates [that are under exploration]. For example, Claudin 18.2– targeted therapy has already improved outcomes [for patients with CLDN18.2-positive gastric and GEJ adenocarcinoma.] Combining a checkpoint inhibitor with this kind of targeted therapy should be the next step, and some ongoing trials are examining this. FGFR is another important target in gastric cancer, and agents [targeting FGFR are] already [being] investigated. [These targeted therapies] in combination with a checkpoint inhibitor could hopefully further improve patient outcomes.

References

1. Shitara K, Moehler M, Ajani, J, et al. Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4 year (yr) follow-up of CheckMate 649. J Clin Oncol. 2023;42(suppl 3):306. doi:10.1200/JCO.2024.42.3_suppl.306
2. FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed January 29, 2024.