Promising Results Push Nivolumab/Chemotherapy Forward in Gastric Cancer

Jaffer A. Ajani, MD

The combination of nivolumab (Opdivo) and chemotherapy has shown a significant benefit across outcomes for patients with gastric cancer. On April 16, 2021, the FDA approved the PD-1–blocking antibody in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma.

The approval was based on results from the phase 3 CheckMate 649 trial (NCT02872116), which showed that patients treated with the combination of nivolumab and either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or CapeOX (capecitabine plus oxaliplatin) chemotherapy achieved a median overall survival (OS) of 13.8 months (95% CI, 12.6-14.6; P = .0002) in 789 patients, compared with 11.6 months (95% CI, 10.9-12.5) in 792 patients treated with chemotherapy alone. The overall response rates were 47% (95% CI, 43%-50%) vs 37% (95% CI, 34%-40%), respectively.

In an interview with OncLive^®, Jaffer A. Ajani, MD, a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, unpacked the performance of the combination regimen in some subgroups of interest.

The primary end point of the CheckMate 649 study was benefit in patients with a combined positive score (CPS) of 5 or higher. What was the rationale for selecting that end point?

The rationale came from previous studies, particularly KEYNOTE-059 [NCT02335411]. There were a series of prior studies before this which already demonstrated that PD-L1 expression makes a difference. If [a patient is] PD-L1 positive, irrespective of the number, it makes a difference.

Incidentally, this was not the primary end point of this study when it was initially designed; this was [adjusted] during the study as more data came in. The primary end point is PFS and OS for CPS 5 or higher. There were 2 other groups: CPS 1 to 4 and all patients. Looking at the survival curves, there is benefit [seen across groups] and the maximum benefit was for those with CPS of 5 or higher for PFS and OS; this was a considerable benefit. The median survival difference was more than 3 months. You don’t get that with gastric cancer very often, and PFS is about 1.6 months. The P values are very strong.

In the microsatellite instability–high (MSI-H) subset, median OS was not reached. What does the future look like for these patients?

In colon cancer, the MSI-H was crystallized [as a marker] in the clinic. A lot of credit goes to investigators at Johns Hopkins [Medicine] who did the initial study in the second-line setting, demonstrating dramatic responses with single-agent immunotherapy. There was a trial in colon cancer in first line that compared pembrolizumab [Keytruda] with chemotherapy [and with] biological therapy, which has been the standard of care for 15 years. Pembrolizumab was better than chemotherapy and biotherapy and has moved into first line for patients with MSI-H colon cancer.

We’ve been looking at all these data and clearly MSI-H is not uncommon. There have been data in KEYNOTE-061 (NCT02370498), KEYNOTE-590 (NCT03189719), and more; it was clear that these patients can benefit.

In this CheckMate 649, the benefit is dramatically better, although both groups did receive chemotherapy. Now, we must wonder, do we even need chemotherapy in this group of patients?

What is the best way to manage treatment–related adverse events with immunologic etiology?

The addition of nivolumab did not produce any alarming new signals. That’s reassuring. There were a bit more than with chemotherapy alone [because] you’re adding another drug. Most of us, at least in the Western world, are very familiar with nivolumab because it’s been around for a while and we know how to handle it. The bottom line is familiarity. The entire team needs to [be aware]. Even in private practices, a group of people are helping the patients. There are certain tasks done by certain people. If you are not aware [of what to expect], then you you’re not going to identify it.

Second is the knowledge of what to do once you became aware of a toxicity that is because of immunotherapy. You must know how to grade it. Third, you must know how to manage it and determine whether it’s getting better or not. Finally, you need to know when to refer. There are a lot of subspecialties that have popped up in the past 5 years. For example, if my patient has pneumonitis, I don’t try to manage it; I send them to my pulmonologist who has become expert because they are seeing not only patients with gastric cancer, but with melanoma, lung cancer, you name it. They know what to do. Same thing for a gastroenterologist for a patient with colitis and hepatitis. You have to understand that there may be other people who are better than you in managing organ-specific toxicities.

Are there treatment options that may benefit patients with GEJC or esophageal adenocarcinoma?

Not that we know. For those with CPS of 5 or higher for gastric, GEJC, and esophageal, there is sufficient benefit. Pembrolizumab and chemotherapy is approved for esophageal adenocarcinoma, and GEJC based on data from KEYNOTE-590.

[In that study], the number of patients with adenocarcinoma was approximately 200. In CheckMate 649 we are talking about 1500 patients. The KEYNOTE data were quite reasonable, but not robust like CheckMate 649. You can trust these data more than KEYNOTE for adenocarcinoma.

Many of my colleagues have been asking major sponsors to launch the next generation of studies, which should add another immunotherapy or targeted therapy to nivolumab plus chemotherapy. This is a good advance, but it’s still not enough. You will see some data coming out with longer follow-up. I don’t know if you can cure some patients with metastatic disease [with the addition of] nivolumab, that we will [find out]. I can tell you it’s not going to be many patients.

Reference

1. Opdivo. Prescribing information. Bristol Myers Squibb; 2021. Accessed July 28, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s091lbl.pdf