Yelena Y. Janjigian, MD, further discusses the clinical significance of the FDA approval of nivolumab plus chemotherapy in the frontline treatment of patients with gastric cancer.
Nivolumab (Opdivo) plus chemotherapy is the first regimen in over a decade to significantly improve survival in treatment-naïve patients with advanced or metastatic gastric cancer, according to Yelena Y. Janjigian, MD, who added that other novel combinations are under exploration to further expand on the benefit achieved with this recently approved approach.
Data from the phase 3 CheckMate-649 (NCT02872116), which supported the April 2021 FDA approval,1 showed a median overall survival (OS) improvement with nivolumab plus leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOx) over chemotherapy alone in patients with PD-L1–positive advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma.2
At a minimum-follow-up of 12 months, the median OS was 14.4 months (95% CI, 13.1-16.2) vs 11.1 months (95% CI, 10.0-12.1) in those with a PD-L1 combined positive score (CPS) of 5 or greater (HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001). Nivolumab/chemotherapy also resulted in a 32% reduction in the risk of disease progression or death vs chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.81; P < .0001).
“Data from CheckMate-649 are certainly practice changing and will set the standard for the future. The next frontier will be built on that,” Janjigian said. “How long it will take us to improve on [what was achieved in] CheckMate-649 is to be determined. Certainly, the lower hanging fruit is to keep our patients well and healthy so that they are able to receive second- and third-line therapy and live longer as a result.”
In an interview with OncLive®, Janjigian, the chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, further discussed the clinical significance of the FDA approval of nivolumab plus chemotherapy in the frontline treatment of patients with gastric cancer.
Janjigian: CheckMate-649 (NCT02872116) was a first-line study that compared standard-of-care chemotherapy with chemotherapy plus nivolumab. It is an important study because it's the first in over a decade that led to the FDA approval of a targeted agent in [this] setting.
What's unique about CheckMate-649 is that it's a study that focuses on [patients with] adenocarcinoma and includes those with esophageal, GEJ, and stomach cancer. This was an important distinction, because for our Western population of patients [who have these diseases], this is an exciting opportunity. [There has been] an unmet need for a new, approved checkpoint blockade agent in the first-line setting. Additionally, what's unique about the study is that patients were enrolled irrespective of PD-L1 status.
This was a large study, one of the largest done to date, with 780 patients treated per arm. As such, this is a robust dataset that allowed us to really demonstrate a survival benefit for [adding] immunotherapy in the first-line setting. The prespecified analysis was done in the all-comer population, but the primary end point was particularly in patients with PD-L1–positive tumors, using the cutoff of a CPS of 5 or greater. For that population, the benchmark OS in the chemotherapy plus nivolumab arm was 14.4 months, which is truly transformative and clinically and statistically significant; the HR was 0.71. For the first time, in a long time, we were able to demonstrate a meaningful separation in survival curves with a difference of over 3 months, which has not been seen in [this] disease in many years. This is what led to the FDA approval.
What is important to note in all randomized patients, the median OS was also improved, with a median OS of 13.8 months in the combination arm, with a HR of 0.80, suggesting that those with a high PD-L1 status are still the ones who derive the deepest benefit and the most dramatic benefit. However, there are some populations of patients, perhaps in whom PD-L1 status was inconclusive or [who have] some heterogeneity of disease, who still benefit. Based on that, a mandate for PD-L1 positivity was not included in [the] FDA [indication].
However, it is still important to test your patients for PD-L1 status in the first-line setting to understand where they will fall on this spectrum. The field is evolving at such a rapid pace that within a few weeks, a pembrolizumab [Keytruda] approval was [withdrawn] in the third-line setting for [patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express a] PD-L1 CPS of 1 [or more]. As such, it becomes even more critical to consider using an immune checkpoint inhibitor in the first-line setting for these patients because you may not have access to it later.
It’s also critical to know your patients MSI status; it becomes less urgent because immunotherapy is now available for all patients in the frontline setting. However, one of the most striking HRs in the subgroup analysis that was presented is the OS [with the regimen in] MSI-high patients. That HR of 0.33 suggests that you can potentially harm your patients if you don't offer immunotherapy [to them] in the first-line setting; that's an important datapoint to really highlight and drive home. Immunotherapy works in [these] patients.
[Safety] is an important factor [to consider], particularly since we're giving patients immunotherapy in combination [with chemotherapy] and some of them can be quite frail. Even in a phase 3 setting, where these patients potentially are carefully monitored and followed, the rate of grade 3 or 4 AEs certainly was higher in the combination arm, as expected. [However,] most of these toxicities are reversible with close monitoring, dose reductions, [and dose] interruptions.
The immune-related effects that are associated with this regimen include endocrinopathies, so alterations in the thyroid function tests, which need to be monitored; this is on par with our expectations. Patients also may present with adrenal insufficiency that is subclinical and so that's why it's important to be aware of those findings. Certainly, gastrointestinal toxicity (GI), elevation in aspartate aminotransferase and alanine aminotransferase, and hepatic alterations like bilirubin elevation, are all AEs that need to be considered.
For GI toxicity, diarrhea is one of the AEs that we monitor for and it may be important to determine between whether it is 5-FU related or nivolumab related. Typically, the 5-FU–related toxicity is much easier to manage and it is not as persistent. As such, if there's any concern for colitis related to nivolumab on imaging or clinically, certainly immunotherapy needs to be interrupted.
Other AEs that we see is rash, and this is usually self-limiting, is resolved with topical steroids, and is not something that you would need to change or stop treatment for. Also, kidney toxicity or acute interstitial nephritis, can be quite important to monitor for and [can be reason] to stop therapy. The rule of thumb is that for endocrinopathies and skin-related toxicities, we would typically treat through; however, any other major GI toxicities, liver function test abnormalities, or renal toxicity, we will interrupt nivolumab.
That's a great question. It has been a historic year for our [patients with] upper GI [cancer]; many exciting trials have read out and [we have also seen] approvals one after the other through the FDA. We were keeping the regulatory authorities busy, as well as the investigators, [with] all these trials. The standard of care has shifted several times now. The challenge that remains is, are we doing a good enough job at managing this disease and curing patients in the end? The short answer is, no. This is just the beginning, and the best is yet to come.
For the standard patient in practice, this is an easy regimen to give. Oncologists are accustomed to giving FOLFOX, and nivolumab lends itself very well for combination; that's why we designed the study [the way that we did]. We wanted to make [the regimen] very user friendly, as opposed to the 3-drug regimen and cisplatin use, which is more toxic to patients. However, would you treat every single patient in the clinic with this regimen? My clinic is unique; patients [tend to be] fitter and much more motivated. As such, if there's an opportunity to enroll someone in a clinical trial, [we] may certainly consider that. [However,] if you have a very frail patient, where toxicity is a risk, and you think the benefit may be low because the tumor has very low PD-L1 expression, you may decide not to do combination.
However, most of our patients will receive FOLFOX plus nivolumab in the first-line setting, or at least an immune checkpoint inhibitor in first-line setting in combination with chemotherapy. Because unlike, for example, Asia, where nivolumab still has approval in the third-line setting, in the United States, we don't have immunotherapy approved in [that] setting [anymore]. As such, if your patients won't receive it in first line, they may not have access to it outside of a clinical trial otherwise.
Absolutely. We are already doing a lot of work to build on this, and there's a lot of excitement about the synergy that we see with certain agents that target tumor biology and the microenvironment. [These agents are] not necessarily immune checkpoint inhibitors, but they augment immune response and further allow the checkpoint inhibitors to expand the T-cell population that's tumor directed. That’s where a lot of the future lies.
The problem with some of these combination strategies is that the more agents you add, the more toxicity [you see], so that's going to be the next big hurdle to overcome. How do we start curing patients, outside of the MSI population, with these combinations? It has been years since the last FDA approval in the first-line setting and I'm hoping that the next one will come quicker. However, realistically, this disease is challenging, as patients can be quite sick; the CheckMate-649 data suggest that even in clinical trial and academic settings, very few patients still get to second- and third-line treatment outside of Asia and the United States. We need to improve on this.
It’s important to highlight that, on the trial, we typically continued maintenance 5-FU and nivolumab; that's still the standard in most centers, to reduce oxaliplatin or discontinue it if there's cumulative toxicity but try to continue with maintenance therapy because it appears to be beneficial—especially for patients who are tolerating treatment. The question remains: How long is enough? On the trial, we typically stopped after 2 years and that has become somewhat of an industry standard for other clinical trials. We don't know if that's the right answer, but it seems to be that you need to at least continue maintenance therapy and not stop altogether after you achieve a maximum response.