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Pembrolizumab may provide alternative to chemotherapy for certain gastric, gastroesophageal junction cancers
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CHICAGO — First-line pembrolizumab appeared noninferior to chemotherapy for OS among patients with PD-L1-positive, HER2-negative advanced gastric or gastroesophageal junction cancer, according to findings from the randomized phase 3 KEYNOTE-062 study presented at ASCO Annual Meeting.
Moreover, researchers observed clinically meaningful OS improvement with pembrolizumab (Keytruda, Merck) among patients whose tumors demonstrated high PD-L1 expression levels.
“Right now, pembrolizumab is approved for third or later lines of therapy, but we’re always looking for opportunity to bring it earlier into therapy,” Charles S. Fuchs, MD, the Richard Sackler and Jonathan Sackler professor of medicine (medical oncology) and director of Yale Cancer Center, and physician-in-chief at Smilow Cancer Hospital, said in an interview with HemOnc Today. “If we were to bring it into the first line, could we not only improve the effectiveness, but also make it available for a larger population of patients? Because that’s the hitch of giving third line; not everyone will be healthy enough to get there.”
Gastric cancer is the fifth most commonly diagnosed cancer in the world, with 27,510 new cases and 11,140 deaths from the disease expected this year. Gastroesophageal junction cancer is less common but has been seen with increasing frequency over the past decade, especially in Western countries.
In the randomized, active controlled study, Fuchs and colleagues randomly assigned 763 patients (median age, 62 years; ) at a 1:1:1 ratio to pembrolizumab 200 mg every 3 weeks for up to 2 years (n = 256), pembrolizumab plus chemotherapy (n = 257), or placebo plus chemotherapy (n = 250). Chemotherapy consisted of cisplatin 80 mg/m2 plus either 5-fluorouracil 800 mg/m2 per day on days 1 through 5 every 3 weeks or capecitabine 1,000 mg/m2 twice daily on days 1 through 4 every 3 weeks, per local guidelines.
“Because there is evidence that pembrolizumab does work better if tumors are PD-L1-positive, patients had to have a PD-L1-positive tumor to get into the trial,” Fuchs told HemOnc Today. “Patients also had to have tumors that were at least 1% positive, or what is referred to as CPS [combined positive score] 1 or greater.”
Thirty-seven percent of participants (n = 281) had a PD-L1 CPS of 10 or greater.
The researchers stratified randomization by region, disease status and fluoropyrimidine treatment.
Primary endpoints included OS among patients with a CPS of 1 or higher and CPS of 10 or higher in the pembrolizumab groups vs. the chemotherapy group, as well as PFS, assessed by central review according to RECIST version 1.1 criteria, for pembrolizumab plus chemotherapy vs. chemotherapy alone. Overall response rate per RECIST criteria for pembrolizumab plus chemotherapy vs. chemotherapy served as the secondary endpoint. Researchers also evaluated safety.
The cutoff date for final analysis was March 26, 2019. Median follow-up was 11.3 months.
The researchers found that pembrolizumab was noninferior to chemotherapy in terms of OS among patients with a CPS score of 1 or higher (10.6 months vs. 11.1 months; HR = 0.91; 95% CI, 0.69-1.18).
However, pembrolizumab improved OS compared with chemotherapy among patients with a CPS score of 10 or higher (median 17.4 months vs. 10.8 months; HR = 0.69; 95% CI, 0.49-0.97), although this was not evaluated per the analysis plan. After 2 years of follow-up, 39% of patients receiving pembrolizumab were alive compared with 22% of those receiving chemotherapy.
Pembrolizumab plus chemotherapy did not significantly improve OS compared with chemotherapy alone among patients with a CPS score of 1 or higher (12.5 months vs. 11.5 months; HR = 0.85; 95% CI, 0.7-1.03) or a CPS score of 10 or higher (12.3 months vs. 10.8 months; HR = 0.85; 95% CI, 0.62-1.17), but it demonstrated a favorable trend.
Pembrolizumab plus chemotherapy also did not significantly extend PFS among patients with CPS score of 1 or higher (6.9 months vs. 6.4 months) or 10 or higher (5.7 months vs. 6.1 months), although it did demonstrate a higher ORR vs. chemotherapy alone (48.6%; 95% CI, 42.4-54.9 vs. 36.8%; 95% CI, 30.8-43.1).
Researchers observed the lowest rate of serious adverse events among patients treated with pembrolizumab alone.
Grade 3 to grade 5 drug-related adverse event rates occurred among 16.9% of those assigned pembrolizumab alone, 69.3% among those assigned chemotherapy alone, and 73.2% of those assigned the combination.
“The side effect profile is much better than with chemotherapy; when you compare grade 3 or higher events, it’s 16% vs. 69%,” Fuchs told HemOnc Today. “So, this basically says that this is a legitimate therapeutic option for patients and, to boot, it’s better-tolerated.”
The most common adverse events included nausea and fatigue.
Fuchs said the future of this treatment in terms of FDA approval and widespread use is not yet clear.
“I would say that it certainly looks as though there is a role for patients who are PD-L1 positive to get pembrolizumab, which I think is an important option as opposed to chemotherapy,” he said. “I think it remains to be seen, and further study is needed.” – by Jennifer Byrne
Reference:
Tabernero J, et al. Abstract LBA4007. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosure s : Fuchs reports a scientific advisory role with Merck. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Manish Shah, MD
Chemotherapy is standard for patients with PD-L1 positive, HER2-negative, advanced gastric or gastroesophageal junction cancer. For most patients who don’t have an option for targeted therapy, survival is about a year with chemotherapy. So, there is a lot of room for improvement.
Pembrolizumab was approved in the third-line setting as a single agent for patients who have a CPS score of 1 or greater. Among these patients, the response rate of pembrolizumab is about 10% to 15%, and responses are very durable. In the second-line setting. pembrolizumab was thought to be inferior to chemotherapy and won’t be approved for that indication. So, a lot of us were looking forward to these data.
One of the main findings of this study is that the combination of pembrolizumab and chemotherapy is not better than chemotherapy alone. There is slightly higher median survival, but it is not statistically significant, and the hazard ratio is 0.84.
However, the other finding, when looking at pembrolizumab by itself vs. chemotherapy, was noninferiority. The noninferiority margin was about 20% in this study design, and pembrolizumab met that bar.
As a practicing oncologist, I’m not sure I would agree that a 20% worse outcome is noninferior. However, for many patients who don’t want or are not candidates for chemotherapy, this might offer a nonchemotherapy option. There are very compelling data in the subgroup analysis of patients with CPS of greater than 10. Those patients seem to do much better with pembrolizumab than with chemotherapy only; there were about 90 patients in each arm. It wasn’t enough to call it a phase 3 evaluation, but it is quite compelling.
What we learn is that the combination of chemotherapy with pembrolizumab is not superior. Pembrolizumab may be noninferior to chemotherapy. However, a hybrid approach might be something we look to in the future, where we do chemotherapy and pembrolizumab for a short time, and then continue pembrolizumab. That approach is being studied now.
This is a very important abstract. It moves the field forward and may provide an option for patients who are not chemotherapy candidates, but a lot of work still needs to be done.
Perspective
Back to TopMichael Hall, MD, MS
This is an important abstract as we continue research on which subgroups will best respond to immunotherapy. In this case, we learn that among patients with gastrointestinal cancers that are high expressers of PD-L1, frontline immunotherapy is highly effective. Although this is not a huge group of people, it is a game-changer for that group to avoid frontline chemotherapy.
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