CheckMate 649: Long-Term Data in Gastric Cancer

CheckMate 649: Long-Term Data Support Nivolumab Plus Chemotherapy but Not Nivolumab Plus Ipilimumab in Gastric Cancer

This is a study that is called a Quality-adjusted Time Without Symptoms or toxicity. A Brief Q-TWiST analysis. And we specifically looked at it for the CheckMate 649, which was a study that compared standard of care chemotherapy to chemotherapy plus Nivolumab (Opdivo) in patients previously untreated for gastroesophageal junction and esophageal cancers.

The purpose of the study is basically that the prognosis is very poor for gastroesophageal junction cancer. Sadly patients live on average, less than a year prior to this trial, the Checkmate 649 and what the trial was doing was trying to improve on those outcomes that we can with palliative treatment, hopefully extend a patient’s progression-free survival and lessen their burden of disease.

A Positive Study for Gastrointestinal Oncology

The CheckMate 649 was a positive study that found that patients on average live longer. If they got this combination compared to if they just got chemotherapy. Chemotherapy was typically CAPOX and FOLFOX. And the immunotherapy was Nivolumab (Opdivo). The trial showed that patients now lived slightly over a year compared to the slightly under a year.

When the immunotherapy wasn’t used looking beyond just the numbers of months or week somebody could extend their progression-free survival. We were interested in also saying, how is the person’s life while they’re on this treatment? Cause as a treating physician, it’s important. As we speak to our patients to say what the benefit and the risk is to make an informed decision, whether we would proceed with the treatment or not.

What did the Checkmate 649 Look For?

What this study does is it basically looks at 3 periods of time. One is called the toxicity or toxic, which is a period of time that a patient had an adverse event creative, greater than equal to three. The second period of time is a twist date, which is a time theft symptoms or toxicity. The third and final state is called the relapse date or well state, which is a period of time following a disease progression or death.

We waited these using utilities. So, a utility of one would mean it’s the best of time, the utility of zero. We mean it’s the worst of times. And you feel like you’re near. For the toxicity in real estate, we assigned a utility of 0.5, which was based on prior Q-TWiST studies. We assigned the twist date, which is the time without symptoms or toxicities as a utility of one, which is a better time.

We also in our poster show with a colored figure, what the different outcomes would’ve been. If we assigned the utility differently, For instance, if we made the utility of re or tax anywhere from zero to one, what we found was that we wanted, we redefined our threshold as relative gains of greater than equal to 10% as being clinically important and greater than, or equal to 15% as being clearly clinically important, which was based on prior Q-TWiST literature.

Checkmate 649 Endpoints

We were hoping to find that with this intervention, we would be greater than equal to 10%. We would be even happier if it was greater than equal to 15% to show the positive results of using the combination of chemotherapy and Nivolumab (Opdivo). We looked at both all comers and we also looked at the population that had a combined positive score greater than equal to 5 PDL, one score, which was a biomarker.

That was suggestive of patients who may be more likely to respond to immunotherapy for all comers. What we found was an important gain for clinical oncology from the Q-TWiST of 12.8%. We looked at the utilities, as I said, as well. If we changed them for re or tax from anywhere from zero to one, we found that regardless of the utility as assigned to TOX and REL.

We still met this threshold of greater than 10%. So, we found that there was a clinically significant benefit for all comers on the study. Then we looked at the randomly assigned patients who had a combined positive score greater 1 equal to five, and we found that the Q-TWiST gain was 20.6%, which was clearly clinically significant because it was over that 15% threshold.

Again, we looked at if we. Assign the utilities of Rex differently, anywhere from 0 to 1, would this affect the outcome? And we found that it was still always over 15% thresholds. So, this meant the clearly clinically significant threshold. Finally, we said, how does Q-TWiST compare to other Q-TWiST that were published in the past?

Takeaways From CheckMate-649 in Gastric GEJ Esophageal Cancers

And we found for the overall population gain of 12.8%. This was in the 68%. Better than 68% of the prior published Q-TWiST for oncology therapies that we could find when we looked at the combined positive score, the randomly assigned patients with the combined positive score score of greater than are equal to five, who had the 20.6% Q-TWiST benefit. We found that this was 88% better than 88% of prior published Q-TWiST oncology therapies. So we were trying to emphasize here If you were to compare this to prior acute twist with oncology interventions that this compares favorably.

Why is a PDL 1 CPS biomarker greater than equal to five important for Gastrointestinal Oncology?

So what are the most common questions? My colleagues asked me about this study. I would say that the most common question is this for everyone or is this only for people who have a high combined positive score score, meaning the PDL 1 CPS biomarker greater than equal to five. I would say that for me. It’s an individual decision with the risk benefit with the patient.

I advise my colleagues that I take every case into consideration. Does a patient have a specific history that can make them more at risk for immunotherapy, such as autoimmune conditions like autoimmune colitis or other conditions? And what is a patient’s performance status in age? If somebody’s a younger patient who has a good performance status and knows specific toxicity concerns with the addition of immunotherapy, this could be an opportunity to give them additional time, as well as quality time addition in the Q-TWiST.

I do consider those patients for the combination of chemotherapy and immunotherapy. There are some patients who may have other concerns that they could be higher risk for immunotherapy, and those patients, they may proceed with chemotherapy along.

What is a Q-TWiST and how does it relate to Checkmate 649?

I’m trying to think of other questions we could be asked, I guess just what is a Q-TWiST? Not everyone knows what a Q-TWiST is. So hopefully I answered that part with the initial introduction, but this is a way of looking at the risk and benefit further than just how many months or weeks does somebody live with this intervention.

It’s also looking at how is the quality of life during this time. And our goal is. To give them as much time without toxicity or symptoms, which is the twist component of the Q-TWiST. One of the questions might be well, what was the toxicity when the toxicity date, when somebody might have experienced more adverse events because they were on an additional medicine to just seek chemotherapy.

CheckMate 649 Results Show Sustain Benefit of Nivolumab Plus Chemo for Gastric/GEJ Cancer

What we found was that the most commonly reported additional adverse events or things that might not actually affect the patient’s quality of life so much. We did see more neutropenia and anemia. These are things that we can commonly monitor and, in some cases, treat with a growth factor or with a blood transfusion, depending on what the numbers are.

It’s not necessarily something that a patient would feel. Fortunately, we didn’t see a much higher rate of a neutropenic fever or infection with the combination. When I looked at them. When I looked at the toxicities that patients experienced on this study,

I believe it already has affected clinicians because it did this CheckMate 649 study that the Q-TWiST is based off of did lead to an FDA approval for all patients with first line esophageal carcinoma, gastroesophageal junction, gastric cancer. That they could go for the combination FOLFOX or CAPOX plus Nivolumab (Opdivo).

Some clinicians may have been more hesitant to do the combination because of fears about the potential risk with the treatment. So, what we’re hoping to show in this poster is the benefit that patients could experience for all comers, not just the combined positive score greater or equal to 5. Though, that was the one who did benefit the most, the ones who were combined positive score greater, were equal to 5.

All comers did benefit when we looked at this. And we hope that it helps guide the conversation for the risk benefit that there’s a clearer understanding of beyond just a number of months. Somebody might live what their quality of life might be like with or without Nivolumab (Opdivo). It added to the backbone of the chemotherapy.

As I discussed earlier, the prognosis of gastric cancer, esophageal cancer is very poor, and it’s a devastating disease. The combination of those two cancers actually accounted for the second most cancer deaths in the world last year, only second to one cancer so, while we’re making some incremental progress with the combination of chemotherapy and immunotherapy.

There’s more cancer research to be done, to see if there are ways that we can make these therapies even more effective and hopefully extend patients’ lives longer. One of the challenges of treating advanced gastric cancer and esophageal cancer is that many patients don’t make it to a second-line therapy. So, what you use as your first line therapy, maybe your only opportunity to treat the patient if they were too sick to get to the second line therapy, which happens something I think there was a flat iron study that we referenced that showed that only around one in three patients actually gets to the second line therapy.

We want to improve our first-line treatments. And this is a step in the right direction, but we need to continue the clinical research to see if there’s ways to make potentially more effective immunotherapy, more effective chemotherapy, more effective combination, the combination potentially by adding other agents. So, we do have other trials at MSK that look at the same idea chemotherapy plus immunotherapy, but now adding, for instance, a VEGF inhibitor or other treatments. We hope to see. Continued progress. But I don’t know the results of those studies yet.

I just hope to spread the word that this data does exist. And I encourage people to look at the trial to review our Q-TWiST analysis. I don’t know that every patient will go for chemotherapy plus immunotherapy, but it’s important. Consider that this is an option. It’s an FDA-approved option and NCI guideline as well. That could hopefully improve patient outcomes for oncologists who treat patients with esophageal cancers.

Checkmate 649 Clinical Trial Origins:

Patients who received nivolumab with chemotherapy (NIVO + chemo) had better overall survival (OS), progression-free survival (PFS), and maintained their HRQOL for longer in CheckMate 649 (CM 649), a randomized phase 3 trial of first-line treatment for advanced gastric cancer, gastroesophageal junction cancer , esophageal adenocarcinoma. To assess the net benefits of NIVO + chemo vs chemo alone, we merged effectiveness and HRQOL data from CM-649 into a single metric, quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST).

Checkmate 649 Methodologies:

Time with grade 3/4 toxicity after randomization and before progression (TOX), time without symptoms of disease progression or toxicity (TWiST), and time from relapse or progression until death (TWiST) were used to divide OS into three health states in this study (ie, relapse, REL). The mean Q-TWiST was calculated by multiplying the duration of each state by its utility (U) (U[TWiST], 1.0; U[TOX], 0.5; U[REL], 0.5). Based on established clinical importance thresholds in existing Q-TWiST literature, relative Q-TWiST increases of 10% and 15% (measured as Q-TWiST difference divided by chemo alone OS) were regarded as clinically important and clearly clinically relevant, respectively. Patients whose tumors expressed PD-L1 CPS 5 and all randomized patients had their Q-TWiST differences calculated independently. The TOX and REL utility values were varied between 0 and 1 in a threshold utility study to determine Q-TWiST differences.

Findings:

Treatment with NIVO plus chemo was associated with a Q-TWiST improvement of 2.8 months (95 percent CI 1.0-3.7; relative gain 20.6 percent [clearly clinically important]) in patients with PD-L1 CPS 5, and 1.8 months (95 percent CI 0.9-2.7; relative gain 12.7 percent [clinically important]) in all randomized patients, when compared to chemo alone. Treatment with NIVO + chemo was linked with statistically Q-TWiST significant improvements exceeding minimum clinically meaningful differences across the complete range of TOX and REL utility values when compared to chemo alone, according to threshold analyses.

Outcomes:

In CM-649, NIVO with chemo significantly improved quality-adjusted survival compared to chemo alone in previously untreated patients with gastric cancer, gastroesophageal junction cancer , esophageal adenocarcinoma. Longer periods of time without symptoms of disease progression or toxicity (TWiST) were related to statistically significant and clinically meaningful improvement Q-TWiST gains when NIVO + chemo was used. These Q-TWiST findings add to our understanding of the benefits of NIVO + chemo versus chemo alone in terms of survival and quality of life and may help physicians and patients make management decisions for this patient population.

CheckMate -649 Efficacy, Safety and Median Overall Survival Results in Patients with PD-L1 CPS ≥ 5: FROM BMS Press Release 10-21-21:

Results from CheckMate -649 include:

• OS (minimum follow‑up of 19.4 months): median overall survival was 14.4 months in patients receiving Opdivo plus chemotherapy (95% Confidence Interval [CI]: 13.1 to 16.3) compared to 11.1 months (95% CI: 10.0 to 12.1) in the chemotherapy group alone (Hazard Ratio [HR] 0.69; 95% CI: 0.60 to 0.81).

• PFS (minimum follow‑up of 19.4 months): Median PFS was 8.31 months in patients receiving Opdivo plus chemotherapy (95% CI: 7.03 to 9.26) vs. 6.05 months (95% CI: 5.55 to 6.90) in patients receiving chemotherapy alone (HR = 0.68; 95% CI: 0.59 to 0.79).

• Safety: The most frequent adverse reactions were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), musculoskeletal pain (20%), pyrexia (19%), rash (18%), stomatitis (17%), palmar-plantar erythrodysaesthesia syndrome (13%), cough (13%), oedema (including peripheral oedema) (12%), headache (11%), and upper respiratory tract infection (10%).

About CheckMate -649: FROM BMS Press Release 10-21-21:

CheckMate -649 is a Phase 3 randomized, multi-center, open-label study evaluating Opdivo plus chemotherapy or the nivolumab plus ipilimumabcombination compared to chemotherapy alone in patients with previously untreated, non-HER2-positive, advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma. Patients in the Opdivo plus chemotherapy arm received Opdivo 360 mg plus capecitabine and oxaliplatin (CapeOX) every three weeks or Opdivo 240 mg plus 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) every two weeks. Patients in the Opdivo plus Yervoy arm received Opdivo 1 mg/kg plus Yervoy 3 mg/kg every three weeks for four cycles followed by Opdivo 240 mg every two weeks. Patients in the chemotherapy arm received FOLFOX or CapeOX every two or three weeks, respectively. All patients continued treatment for two years or until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoints of the trial are overall survival (OS) in PD-L1 positive patients with a combined positive score (CPS) ≥ 5 treated patients with Opdivo plus chemotherapy and progression free survival, as assessed by Blinded Independent Central Review (BICR), in CPS ≥ 5 patients treated with Opdivo plus chemotherapy compared to chemotherapy alone. Secondary endpoints include OS in CPS ≥ 1 and all randomized treated patients with Opdivo plus chemotherapy as well as OS and time to symptom deterioration (TTSD) in patients treated with Opdivo plus Yervoy compared to chemotherapy alone.

Author Credentials and Affiliations

Ryan Sugarman, MD, Strategic Partnerships Medical Director, Divison of Solid Tumor Oncology, and Assistant Attending of the Gastrointestinal Medical Oncology Service at Memorial Sloan Kettering Cancer Center. In this video, he speaks about the ASCO GI 2022 Abstract – A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of patients in CheckMate 649: Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma (GC/GEJC/EAC).