Nivolumab Plus Chemotherapy Shows Potential as New SOC in Gastric and GEJ Cancers

Patients with advanced or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) cancers represent a patient population in need of an alternative to standard chemotherapy. A new option is necessary for this population to improve upon the poor overall survival (OS) results.¹

In the 2017 ATTRACTION-2 study (NCT02267343), a signal of survival improvement was observed when nivolumab (Opdivo) was compared with placebo as treatment of gastric and GEJ cancers. At a median follow-up of 8.87 months (interquartile range [IQR], 6.57-12.37) in 330 patients in the nivolumab group and 8.59 months (5.65-11.37) in the placebo group, the median OS was 5.26 months (95% CI, 4.60-6.37) in the nivolumab group and 4.14 months (95% CI, 3.42-4.86) in the placebo group (HR, 0.63; 95% CI, 0.51-0.78; P <.0001).²

Based on these study results, it was hypothesized that nivolumab may be the new option oncologists need for the treatment of gastric and GEJ cancers. Thus, ATTRACTION-4 (NCT02746796) was designed and in the study, nivolumab was added to chemotherapy in 2 arms. One arm received nivolumab with S-1 and oxaliplatin (SOX) and the second received nivolumab with capecitabine plus oxaliplatin (CapeOx).³

In ATTRACTION-4, the median OS was not reached (NR) in both groups. Median progression-free survival (PFS) was 9.7 months (95% CI, 5.8-NR) with nivolumab/SOX and 10.6 months (95% CI, 5.6-12.5) with nivolumab/CapeOx. Investigators considered this to be encouraging efficacy for nivolumab with chemotherapy and the next step was to compare nivolumab plus chemotherapy versus chemotherapy alone in a head-to-head trial. This step was fulfilled with the phase 3, randomized, open-label CheckMate 649 study (NCT02872116).

In an interview with Targeted Oncology, Markus Moehler, MD, PhD, the head of Gastrointestinal Oncology at Mainz University Clinic, reviews the potentially practice-changing data from the phase 3 CheckMate 649 clinical trial.

TARGETED ONCOLOGY: What served as the basis for this research?

Moehler: As many oncologists know, immunotherapy has not yet been established in gastroesophageal or gastric cancer. What is even worse, stand-up first-line chemotherapy for advanced or metastatic gastric cancer results mostly in only poor OS with a median survival of less than 1 year. So, there was a high medical need to test immunotherapy in this indication.

TARGETED ONCOLOGY: Can you explain the study design and the key end points of the study?

Moehler: Nivolumab has given excellent results in many diseases like lung cancer and melanoma. Nivolumab also provided superior OS versus placebo in heavily pretreated, advanced gastric cancer in the ATTRACTION-2 study. Also, nivolumab plus chemotherapy showed promising anti-tumor activity in first-line advanced gastric cancer in the phase 2 part of the ATTRACTION-4 study. Recently, we competed the worldwide CheckMate 649 study, which was a randomized, open-label phase 3 trial, in which more than 2000 patients were randomized in 3 arms. I did not report on the first arm, which was immunotherapy alone with nivolumab. This is still blinded and will be reported maybe 1 or 2 years in the later meeting. I have reported at the on the 2 arms with chemotherapy consisting of XELOX or FOLFOX, plus or minus nivolumab. A total of 1581 patients were included and 60% of these patients were PD-L1 combined positive score (CPS) 5 or higher. The 2 primary end points were OS and PFS.

TARGETED ONCOLOGY: What were the key baseline characteristics observed in this study?

Moehler: As I mentioned, we included more than 1580 patients, and in the primary population, PD-L1 CPS 5 or higher. The baseline characteristics were well balanced, and this was also consistent with all randomized patients. Mostly non-Asian patients with clear metastatic disease were included. Also, it is of note that we not only included gastric cancer, but also GEJ cancer, and esophageal adenocarcinoma.

TARGETED ONCOLOGY: Looking at the study results, what did you observe in terms of OS and PFS in the overall and PD-L1–positive populations?

Moehler: I think this is a landmark study and a game changer. The OS improvement was statistically significant and clinically meaningful. So, with regards to median OS in the primary population, the median OS went up from 11.1 months for chemotherapy to 14.4 months with nivolumab plus chemotherapy. So, there was an improvement of 3.3 months and the hazard ratio was 0.71. The P value was also highly statistically significant at 0.0001.

So, with regards to 1-year survival rate, the survival increased with the combination nivolumab plus chemotherapy 46% with chemotherapy alone to up to 57%. It's an 11 percentage point increase of the 12-month survival rate with the combination.

With regards to the PFS, the co-primary end point, this was also highly met for CPS 5 or higher. There was an increase in PFS from 6.0 to 7.7 months with a hazard ratio of 0.68. Again, the P value was .0001.

TARGETED ONCOLOGY: Was the benefit observed across the key subgroups?

Moehler: Yes, mostly all pre-specified subgroups favored the combination of nivolumab plus chemotherapy. I would particularly point out that the region, the ECOG status, and also the tumor location was in favor of nivolumab plus chemotherapy. Multiple pre-specified subgroups were positive for the combination. In the microsatellite unstable subgroup, there was an even higher median OS than in the microsatellite stable patients.

TARGETED ONCOLOGY: Were responses durable in this study?

Moehler: The duration of response was also better for the combination nivolumab plus chemotherapy. The OS rate was 60%, which is very high for this patient population, versus 44% with chemotherapy only. The duration of response also increased from 7 months to 9.5 months from chemotherapy to nivolumab/chemotherapy, respectively.

TARGETED ONCOLOGY: What is important to note about the safety of this combination?

Moehler: There was numerically higher treatment-related adverse events with the addition of nivolumab, but there were no new safety signals. More or less, the safety signals we have seen were already the known safety profile for the individual compounds. The immunological adverse events were also very low.

TARGETED ONCOLOGY: What is the significance of these data?

Moehler: It is now really clear this represents a new potential standard first-line treatment for patients with advanced gastric, GEJ, and esophageal adenocarcinoma. I'm very confident that it will be approved in many countries around the world since this increase of 3.3 months has never been seen before. With regard to chemotherapy alone, there has never been such a good signal in these patients.

_References:

_{1. Moehler M, Shitara K, Garrido M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: first results of the CheckMate 649 study. Ann Oncol. 2020 31 (suppl_4): S1142-S1215. doi: 10.1016/annonc/annonc325}

_{2. Kan YK, Boku N, Satoh T. et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461-2471. doi:10.1016/S0140-6736(17)31827-5}

_{3. Boku N, Ryu MH, Kato K, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol. 2019;30(2):250-258. doi:10.1093/annonc/mdy540}