First-Line Nivolumab/Chemotherapy Could Benefit Patients With Gastric/GEJ/Esophageal Cancers

In an interview with Targeted Oncology, Ryan Sugarman, MD, discussed the CheckMate 649 trial and Q-TWiST results to provide a further understanding of survival and quality of life benefit of nivolumab plus chemo versus chemo alone.

Gastric cancer, gastroesophageal junction (GEJ) cancer, esophageal adenocarcinoma are some of the leading causes of cancer-related mortality, and while chemotherapy is a standard of care for these patients, the prognosis is poor.

In the randomized phase 3 trial, CheckMate 649 (NCT02872116), of first-line treatment of patients with advanced gastric cancer, GEJ cancer, and , esophageal adenocarcinoma receiving nivolumab (Opdivo) combined with chemotherapy experienced superior overall survival (OS), progression-free survival, and maintained their health-related quality of life for longer duration versus chemotherapy alone.

OS was divided into 3 health states within the study: time with grade 3 or higher toxicities (TOX), time without symptoms or toxicities before disease progression (TWiST), and time from relapse or progression until death.

Compared with chemo alone, Q-TWiST for the experimental arm showed that treatment with chemo plus nivolumab had a clinically significant benefit of 12.8%. In regard to those with the high PD-L1 score greater than or equal to 5, a clearly clinically significant benefit was demonstrated as 20.6%.

In an interview with Targeted OncologyTM, Ryan Sugarman, MD, Strategic Partnerships Medical Director, Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, discussed the CheckMate 649 trial and Q-TWiST results to provide a further understanding of survival and quality of life benefit of nivolumab plus chemo versus chemo alone.

In the clinic, what are the key complaints you hear from patients with advanced gastric cancer or gastroesophageal junction cancer being treated with immunochemotherapy in the frontline setting?

When I see patients with advanced gastric and GE junction or gastroesophageal cancer, sadly, their disease is causing most of the symptoms. Many of my patients have difficulty swallowing, some of them even require feeds through an enteral tube like a J tube or a G tube, and they could have pain from the cancer. Our hope with these treatments is to lessen their burden of disease and symptoms of disease. Most of my patients tolerate the treatment well, but what we see is with oxaliplatin, the more you've had a especially over three months, the more likely you are to run into toxicities from that chemotherapy with neuropathy, numbness, and tingling, and this is seen through all disease types, not just esophageal gastric, but also with colon and pancreas.

What I commonly do is I monitor the neuropathy for the blood counts. If somebody is developing worsening symptoms of the neuropathy, I consider lowering the dose or even eliminating oxaliplatin after around three months. We're giving this treatment with a palliative intent to help the patient and the last thing we want to do is give them a severe, long lasting, disabling side effect like a severe neuropathy.

As far as immunotherapy, most of my patients tolerate it really well. The things that we run into commonly are hypothyroidism, which is usually easily treated with thyroid replacement pills, synthroid [Levothyroxine]. There are some patients who can get itching as well which we're usually able to manage either with cream or with medications. The severe toxicity of immunotherapy is very rare and more commonly seen in combination immunotherapy like nivolumab ipilimumab compared to the nivolumab alone.

Can you provide a recap of the Checkmate 649 trial and how it laid the groundwork for your health-related quality of life analysis?

The CheckMate 649 was a pivotal study in gastroesophageal cancers where it looked at the addition of immunotherapy to the standard of care, chemotherapy. The purpose of the trial is that we're not doing well enough with this esophageal gastric cancer. Sadly, this is one of the leading causes of cancer death worldwide. Despite the treatments we have, patients generally live for less than a year on average, when this trial was conducted.

We were very happy to see that the survival was improved when we did this combination. In the frontline setting, it seems like this might be the best time to consider immunotherapy early rather than later on. We also wanted to see the progression free survival and how a patient's quality of life was while they were on this treatment compared to the standard of care chemotherapy alone. That was the purpose of us doing the Q-TWiST analysis.

Can you explain the study design and methods used within that study?

This study was a phase 3 clinical trial, where there was the standard of care chemotherapy which was either FOLFOX or CAPOX. FOLFOX being the infusional fluorouracil and CAPOX being the oral capecitabine plus IV oxaliplatin plus or minus the experimental drug, nivolumab. Patients would either receive nivolumab or they would just receive the chemotherapy alone.

There was a third arm with the combination immunotherapy but given toxicity concerns and seeing the same benefit, this arm was discontinued. We focused on the FOLFOX or CAPOX plus immunotherapy versus chemotherapy alone.

This was also a multi-institutional study and the patients were randomized based off of their PD-L1 score. We would hypothesize that patients who have a higher CPS or PDL-1 score would respond better to the immunotherapy, but we were also curious if somebody had a low score, could they also benefit because we have such limited treatment options for advanced esophageal gastric cancer. We wanted to give all patients the potential benefit, so we investigated both arms.

What we were happy to see was that there seemed to be an overall survival benefit not only for those with the high CPS score, but also those with the low score. That was the primary end point, overall survival. We also looked at progression free survival and adverse events. While there was an increase in adverse events, about a 15% increase for the nivolumab plus chemo arm versus chemo alone, these seem to be mostly manageable with surveilling the blood work, in some cases giving transfusions. It seemed like patients were overall able to tolerate this arm well, and it led to FDA approval last year for the combination versus just the chemotherapy alone in the first-line setting.

What were the results of your health-related quality of life analysis that you presented during ASCO GI?

I'm one of the GI medical oncologists who enrolled patients at Memorial Sloan Kettering on the CheckMate 649, and one of my concerns was, how do we explain these results of the patient? Obviously, we're happy with the survival, but the patient might rightfully wonder, I might live longer, but what's my quality of life while I'm living longer? Is it worth the potential toxicities?

What we did was we did a Q-TWiST analysis where we tried to better characterize not only how long somebody lives, but how they live during that time. We broke it up into 3 components, based on prior Q-TWiST studies, where there's 3 states. One is called the TOX, which is the toxicity state, 2 is called the TWiST state, which is the period without symptoms or toxicities before you progress, and then the third state is a relapse state, which is the time after somebody's progressed. We give different utilities for each of these states based on how well we would consider someone's life to be during those states.

The way we chose the utilities was based on prior Q-TWiST analyses looking at prior oncology therapies and how they made the utility. A utility of 1 would mean that somebody is having a great quality of life, and a utility of 0 would mean that they feel near death, or the worst quality of life. The twist state we consider to be the best state, and we consider that a 1.0. The TOX state and relapse state we put at 0.5, somewhere in between. This was based on how priority twists have defined the utilities.

We were happy to see that when we looked at the Q-TWiST for the experimental arm, the chemo plus nivolumab versus chemo alone, there was a clinically significant benefit for all comers. Clinically significant is defined as greater than 10%, and when we looked at our overall population, we had 12.8%, which means a clinically significant threshold. When we looked at those we said, what about those with the high PDL-1 score greater than or equal to 5? When we looked at those, we saw a clearly clinically significant benefit, which is defined as greater than 15%, and this was 20.6%, relative to twist gain.

We then said, how did you come up with 0.5, and I explained. But what if somebody's quality of life was closer to feeling like near death while they had the toxicity and the relapse state? We looked at not only at the 0.5., but we also looked at if we made the utility 0 for TOX and relapsed, and we saw that these benefits were maintained. So even if you consider it a worse utility when you're in those TOX and relapsed states, we still saw a clinically significant benefit greater than 10% for all comers, and still saw clearly clinically significant benefit greater than 15% for the CPS greater than or equal to 5, which is shown in a color graph in our diagram for the poster presentation.

Finally, we looked at how we compare it to previous Q-TWiST studies for oncology therapies. We looked at the previously published Q-TWiST data for oncology therapies, and we were happy to see that for all comers, this 12.8% benefit was better than 68%. For the CPS greater than or equal to 5, we were better than 88% of previously published Q-TWiST analyses. This shows another way to explain to the patient why we consider the combination of chemotherapy and immunotherapy especially for CPS greater or equal to 5, but also for those who have a lower score, that there could be this benefit and that we should consider this therapy.

What should colleges take away from this research?

The number one takeaway is the FDA approved this and it can be an important thing to consider when treating in the first-line because as I mentioned earlier, esophageal gastric cancer is sadly a deadly cancer that is one of the worldwide lead killers of cancer. The combination is just second to only lung cancer for worldwide killer cancers. When we think about our first-line therapy, we want to give the best we can because sadly, very few patients make it to a second-line therapy. Most patients don't because they had progression of disease and may not be able to tolerate further chemotherapy when they progress. For patients who have a CPS greater than or equal to 5, the benefit is very clear.

We're also happy to report that for all comers, there seems to be a benefit. I would consider the combination of chemotherapy plus immunotherapy as a standard first-line consideration for any patient with advanced esophageal gastric cancer. I would be careful in those patients who have a history of autoimmune disease or other immunotherapy concerns. If the patient is older or more frail, I would be careful in these situations too, especially if the CPS was low. But for those greater than 5, I would try in most patients to start this therapy, and I would also give when less than 5 if it is a fit for a younger patient.

Were there any studies read out that were exciting for you at ASCO GI this year?

I was happy to see that there's further evidence that less oxaliplatin could be acceptable for resected colon cancer. One of the things I mentioned earlier in this talk was that oxidative planning can be a truly devastating neurotoxicity for some patients, the more you've had it. If we can give 3 months to get the benefit and spare the patients the severe neuropathy that could affect them, potentially long term, that's a wonderful thing, so I was happy to see that.

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