Frontline Nivolumab Plus Chemo Shows Practice-Changing Potential in GI Cancers

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Yelena Y. Janjigian, MD, discussed the promise of nivolumab plus chemotherapy in patients with PD-L1–positive advanced gastric cancer, GEJ cancer, and esophageal adenocarcinoma, as well as important biomarkers that should be used to guide sequencing decisions.

Yelena Y. Janjigian, MD

Yelena Y. Janjigian, MD

The combination of nivolumab (Opdivo) plus standard-of-care chemotherapy has demonstrated groundbreaking efficacy and tolerability in patients with PD-L1–positive advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma, according to Yelena Y. Janjigian, MD.

In the phase 3 CheckMate649 trial (NCT02872116), nivolumab plus leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX) or capecitabine (Xeloda) and oxaliplatin (CAPOX) yielded a median overall survival (OS) of 14.4 months versus 11.1 months with chemotherapy alone, translating to a 29% reduction in risk of death (HR, 0.71; 95% CI, 0.59-0.86; P < .0001).1 Based on these data, the FDA has granted a priority review to a supplemental biologics license application for the nivolumab combination in this population; the agency is expected to make a decision by May 25, 2021.2

“This study tested the question of whether or not immunotherapy is worthwhile and effective in the first-line setting,” said Janjigian. “This is a practice-changing study that has already generated a lot of excitement in the field, particularly for the next generation of studies because results did show [survival] benefit with the addition of nivolumab to standard-of-care chemotherapy.”

Beyond PD-L1 expression, other important biomarkers to look for include microsatellite instability (MSI) status, HER2, and Epstein-Barr virus (EBV). “With [regard to] EBV, there’s still a lot of controversy; it’s a very rare biomarker. Certainly, MSI-high [MSI-H] is clear and PD-L1 is a bit complicated, but HER2 is critical,” Janjigian stressed. “Please test all of your patients for HER2 overexpression by immunohistochemistry [IHC] or amplification either by next-generation sequencing [NGS], which is now approved and considered to be a standard by the FDA for advanced-stage cancers, and fluorescence in-situ hybridization [FISH].”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Janjigian, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the promise of nivolumab plus chemotherapy in patients with PD-L1–positive advanced gastric cancer, GEJ cancer, and esophageal adenocarcinoma, as well as important biomarkers that should be used to guide sequencing decisions.

OncLive®: What are some of the recent updates in esophageal and gastric cancer treatment that are generating excitement?

Janjigian: The year 2020 [saw] a renaissance of positive data in gastrointestinal [GI] malignancies; it really was a pivotal and historic year in esophageal and gastric cancer. [At least] 4 positive trials [have recently read out], and these data are most critical for patients with adenocarcinoma and those who are commonly seen in the clinic.

It’s important for us as clinicians, but also as patient advocates, to be aware of these data and to know all the options. As I tell my patients and trainees, this is a marathon, not a sprint. It’s very important to know what all your options are. That way you can plan the treatment paradigm many steps in advance and sequence the therapies to allow for maximum benefit and potential cure, even [for those with] metastatic disease.

One of the key studies that has recently read out was the phase 3 CheckMate-649 trial. What was learned from this effort?

CheckMate649 [was] a first-line trial comparing standard-of-care chemotherapy with FOLFOX or CAPOX compared with chemotherapy plus nivolumab. Notably, patients showed benefit with the addition of nivolumab to standard-of-care chemotherapy.

We will now look into prespecified subgroups of patients, [by examining] PD-L1 [expression] as a biomarker [to determine] the benefits and detriments of that approach.

What did the safety profile of this combination look like?

[Results from] the study demonstrated that the addition of nivolumab to chemotherapy was tolerable and relatively safe, with no new signals. However, [we did see] a slightly higher risk of grade 3/4 toxicity with the regimen; therefore, investigators and treating clinicians need to be aware that these agents do come with adverse effects [AEs]. These agents are feasible in combination with chemotherapy, but patients need to be closely monitored.

The most common AEs [observed] in patients with GI cancers are an asymptomatic rise in liver function tests [LFTs] or other endocrinopathies, such as adrenal insufficiency, thyroid dysfunction, and perhaps diabetes with early-onset [or] type 1, insulin-dependent diabetes. These tests need to be performed regularly. Fortunately, most endocrinopathies can be corrected with close follow-up, and treatment can be continued with nivolumab. If there is autoimmune hepatitis, hepatitis related to immune checkpoint inhibitors [ICIs], pneumonitis, or colitis, the patient will likely need to discontinue nivolumab, although those events are relatively rare. [In that case,] chemotherapy can be considered.

What is your advice for managing toxicities that may arise with this regimen?

It’s a bit tricky [to have a] combination with FOLFOX, for example, because oxaliplatin can also cause mild LFT abnormalities and 5-FU can cause diarrhea or hyperpigmentation and rash. It really takes an experienced clinician and a multidisciplinary [approach that involves an] endocrinologist and an experienced dermatologist who can help you get these patients through these events.

The data suggest that patients with at least some immune-related AEs are the ones who are most likely to have a durable response and to benefit [from this approach]. Often, the patients are quite anxious about stopping therapy, and it’s really on us to [ensure that we are] safe and [that we] continue nivolumab if these AEs, particularly mild rash or endocrinopathies, are tolerable and manageable.

Another key focus in this space is biomarkers. What is your approach for testing and what are some of the key biomarkers to look for to inform treatment?

Biomarker testing in [patients with] metastatic disease is critical; that’s how you sequence and understand what’s in your patient’s best interest. Ideally, you do this in the early- stage setting if your patient has stage II or III disease and is undergoing surgery. We reflexively [test for] HER2, PD-L1 [expression], and EBV. We often do NGS to look at the tumor as a whole but also to analyze the germline predisposition that the patient may have. Irrespective of family history, particularly in gastric cancer [although not so much in esophagus cancer], we do find that germline alterations are potentially critical and now may actually be targetable.

Often, we need to know [a patient’s] MSI status. If the tumor is MSI-H, that patient will be harmed by [receiving] chemotherapy first. The hazard ratio for OS for MSI-H patients who receive chemotherapy first without ICIs suggests that you can harm them. For patients who receive pembrolizumab [Keytruda] or nivolumab first, the hazard ratio for OS is 0.3, which is the best and clearest-cut point of a favorable outcome. As such, it’s important to test [for MSI status].

For [patients with] PD-L1 that is highly positive—a combined positive score of greater than 20 or 30—and/or [those with] EBV-positive tumors, ICIs would have historically been considered [for use] earlier, in second line as opposed to third line, which is what they’re FDA approved for now. Of course, CheckMate649 turned the paradigm upside down, so those patients would be receiving an ICI in the first-line setting anyway. Still, it’s important to know PD-L1 status and, not to forget, HER2 status.

It’s really sobering looking at some of these large phase 3 studies that are mostly enrolling patients outside of the United States. I’m hoping that we do better, but in some of these studies in the first-line setting, HER2 status is not known in up to 40% of patients. This suggests that in those parts of the world where perhaps HER2-directed therapy is not readily available, clinicians don’t even feel compelled to test for HER2; that’s really sobering because HER2 is the most validated and clearest biomarker [that we have] in gastric cancer, to date.

Speaking of HER2 as a target, what is the role of trastuzumab (Herceptin) and the hope for fam-trastuzumab deruxtecan-nxki (Enhertu) in this patient population?

Trastuzumab is a monoclonal antibody directed against HER2. [Results from the] ToGA study [NCT01041404] demonstrated an OS benefit with the addition of trastuzumab to chemotherapy in patients with HER2-overexpressing gastric cancer. What’s interesting is that the ToGA study enrolled patients who were FISH positive or IHC3+ and FISH positive. Some patients had IHC0 or IHC1+ and FISH positivity, and those patients appeared to benefit the least.

In 2009, when ToGA came out, it was very exciting; however, it has been 11 years since we validated HER2 in a large prospective study in gastric cancer. After that, there was a lull and a dark period where several negative studies [read out] one after the other. The issue was the heterogeneity within gastric cancer tumors and also factors such as RAS, both amplifications and rarely mutations, that trump HER2. If [a patient has] a RAS-amplified tumor, their tumor is not as dependent on HER2 signaling, even in the setting of HER2 amplification. Up to 20% to 30% of tumors lose HER2 expression or amplification once trastuzumab stops working; that actually might be why the agent stops working.

HER2 in gastric cancer has been a longer journey than we had hoped, but finally with trastuzumab deruxtecan, we saw a strong, positive study come out of Japan in the third-line setting. That study will probably change practice in the United States as well, in later lines just because very few options are available at this point. Now, we’re working on validating the same findings for the rest of the world in the second-line and first-line settings.

What was learned from all of this research examining HER2 as a biomarker?

The way to really make an impact on patients’ lives is to control the disease as much as possible and perhaps eliminate it completely as early as possible. By the time patients get to the second- and third-line [setting], there’s so much heterogeneity within the tumor that’s further augmented by HER2 inhibition. The pressure of HER2 inhibition with trastuzumab makes it very difficult to induce a second and third response to HER2 inhibition. That’s another reason why the trastuzumab deruxtecan data are so exciting. We have had difficulty because these tumors are quite complex and heterogeneous. Inducing a durable response and survival benefit with HER2-directed therapies is very important.

What is your advice to colleagues caring for patients with gastrointestinal cancers?

It’s important for physicians, patients, and caretakers to know that this field is rapidly evolving. Every 3 to 6 months, there’s a new update and a new study. Please, when you see a patient with gastric cancer, recognize that this patient is scared, it’s a challenging disease, and the patient may be nutritionally compromised. Pause, reach out to a specialist, and check in with [the specialist] because the first treatment a patient receives can make a big difference in their life and their journey; it could potentially impact their long-term survival.

Picking the doses, choosing the agents, and avoiding undue toxicity to allow for maximum response, but also maximizing quality of life while maintaining nutrition and long-term survival, will be critical. This is a tricky area; there are at least 4 or 5 molecularly distinct subtypes if you count conservatively. Be curious and stay on top of the data, because we’re changing the paradigm constantly, and it’s all very exciting.

Editor’s note: This interview was conducted prior to the January 2021 FDA approval of trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.


  1. 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
  2. US Food and Drug Administration accepts for priority review application for Opdivo (nivolumab) combined with chemotherapy as first-line treatment in metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. News release. Bristol Myers Squibb. January 20, 2021. Accessed January 20, 2021.
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