But checkpoint inhibitor misses the mark for superiority

Results of the KEYNOTE-062 trial suggest that pembrolizumab, an immune checkpoint inhibitor, is no less effective than chemotherapy in terms of overall survival (OS) for patients with untreated, advanced gastric cancer with PD-L1-positive tumors.

After a median follow-up of 29.4 months (22.0-41.3 months), the median OS in patients with a combined positive score (CPS) of 1 or greater was 10.6 months for pembrolizumab compared with 11.1 months for chemotherapy at a hazard ratio (HR) of 0.91 (95% CI, 0.69-1.18), Joseph Tabernero, MD, PhD, Vall d’Hebron University Hospital, Barcelona, Spain and colleagues reported in JAMA Oncology.

On the other hand, pembrolizumab monotherapy was not superior to chemotherapy in patients with a CPS of 1 or greater nor was pembrolizumab plus chemotherapy superior to chemotherapy in the same group of patients, leading to an OS of 12.3 months compared with 10.8 months, respectively, at a HR of 0.85 (95% CI, 0.70-1.03), researchers add.

Even in patients with greater levels of PD-L1 expression, reflected by a CPS of 10 or higher, OS was not superior with pembrolizumab at 12.3 months compared with 10.8 months for chemotherapy at a HR again of 0.85 (95% CI, 0.62-1.17), the same analysis showed.

“To our knowledge, this is the first global, randomized, phase 3 study of a checkpoint inhibitor as a single agent or in combination with chemotherapy in patients with advanced ERBB2-negative G/GEJ (gastric/gastroesophageal junction) adenocarcinoma in the first-line setting,” Tabernero and colleagues observed.

“In this final analysis, pembrolizumab was noninferior to chemotherapy for OS in patients with PD-L1 CPS of 1 or greater,” investigators concluded.

But editorialists Elizabeth Smyth, MD, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom, and Markus Moehler, MD, University Medical Centre of the Johannes Gutenberg University in Mainz, Germany, thought otherwise.

“[N]oninferiority may have been statistically proven [but] any benefit from pembrolizumab in the cohort with CPS of 1 or greater is questionable,” they observed.

Smyth and Moehler also pointed out the upper boundary of the noninferiority margin of 1.2 as reported by the authors led to a small noninferiority result that was “debatably acceptable” in their view.

Moreover, the finding that median OS with pembrolizumab at 17.4 months (95% CI, 9.1-23.1 months) compared with 10.8 months (95% CI8.5-13.8 months) in patients with a PD-L1 CPS of 10 or greater cannot be deemed as a significant result, as Smyth and Moehler emphasized, as the difference between the 2 treatment arms was not tested as per the statistical analysis plan built into the study design.

“Having a CPS of 10 or greater was clearly more predictive of benefit from pembrolizumab than a CPS of 1 or greater, with an impressive OS,” Smyth and Moehler acknowledged.

“Importantly, [however], in both the group with PD-L1 CPS of 1 or greater and the group with CPS of 10 or greater, objective response rates and progression-free survival [PFS] with pembrolizumab alone were significantly worse than with chemotherapy at 15% and 25% and 2 and 2.9 months, respectively,” the editorialists add.

The same pattern was also seen in patients with a PD-L1 CPS of 10 or greater where median PFS was 2.9 months (95% CI, 1.6-5.4 months) with pembrolizumab compared with 6.1 months (95% CI, 5.3-6.9 months) with chemotherapy.

Trial Design

A total of 763 patients with untreated locally advanced/unresectable or metastatic G/GEJ cancer were randomized into the trial. Relatively equal numbers of patients received either pembrolizumab alone, pembrolizumab plus chemotherapy, or chemotherapy.

Chemotherapy consisted of cisplatin, 80 mg/m2 on day 1 plus fluorouracil, 800 mg/m2 on days 1 to 5 or capecitabine, 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks.

In the final analysis of patients with a PD-L1 CPS of 1 or greater:

  • 46.9% of participants (95% CI, 40.7-52.8%) treated with pembrolizumab were alive at 12 months compared with 45.6% (95% CI, 39.3-51.6%%) of patients treated with chemotherapy; and
  • 26.5% (95% CI, 21.2-32.1%) of patients treated with pembrolizumab were alive at 24 months compared with 19.2% (95% CI, 14.6-24.3%) of patients treated with chemotherapy.

In a subgroup of patients with a PD-L1 CPS of 10 or greater the findings were:

  • 56.5% (95% CI, 45.8-65.9%) of patients treated with pembrolizumab were alive at 12 months compared with 46.7% (95% CI, 36.1-56.5%) of patients treated with chemotherapy
  • 39% (95% CI, 29.1-48.8%) of patients treated with pembrolizumab were alive at 24 months compared with 22.2% (95% CI, 14.3-31.2%) of those treated with chemotherapy.

The authors also carried out an exploratory analysis of patients with high levels of microsatellite instability (MSI-H) tumors with a PD-L1 of CPS of 1 or greater. In this small subgroup of patients, median OS was 71% higher than it was for chemotherapy patients, from not having being reached (95% CI, 10.7-not reached) among those treated with the immune checkpoint inhibitor compared with 8.5 months (95% CI, 5.3-20.8 months) among those treated with chemotherapy at a HR of 0.29 (95% CI, 0.11-0.81), as study authors noted.

Among patients with MSI-H tumors with a PD-L1 CPS of 10 or greater, median OS was 79% longer with pembrolizumab from not having been reached (95% CI, 10.7 months to not reached) compared with 13.6 months (95% CI, 3.8-25.8 months) in chemotherapy patients at a HR of 0.21 (95% CI, 0.06-0.83), they added.

“The survival benefit with pembrolizumab was consistent across most prespecified subgroups,” the authors observed, “although Asian patients appeared to have an enhanced survival benefit with pembrolizumab vs chemotherapy,” they noted.

Drug-related adverse events (AEs) were predictably much higher among those who received chemotherapy either alone or in combination with pembrolizumab. For example, grade 3 or higher drug-related events occurred in 16.9% of patients treated with pembrolizumab alone compared with 73.2% of those who received the combination of the immune checkpoint inhibitor plus chemotherapy and 69.3% of those who received chemotherapy alone.

Significantly more patients discontinued treatment because of drug-related AEs in the chemotherapy arms at 27.6% for patients who received the combination strategy and 18% of those who received chemotherapy alone compared with under 4% of those who received immunotherapy alone.

As Smyth and Moehler pointed out, first-line pembrolizumab may have had fewer toxic effects than chemotherapy. Nevertheless, “it demonstrated no gain in quality of life,” as they pointed out. This suggests that symptom control that can be achieved by shrinking the tumor with chemotherapy may benefit patients in terms of quality of life, they suggested.

The editorialists also pointed out the fact that the statistical noninferiority achieved in the study along with “marginal” survival gains came at a cost. Of the many patients who experienced early tumor progression while being treated with immunotherapy, only about half were treated with subsequent chemotherapy, which may have compromised overall outcomes.

“Moving forward from these results, what is the future for immune checkpoint blockade in advanced GC (gastric cancer)?” the editorialists asked.

As they pointed out, gastric tumors are mostly “immunologically cold,” so if treated with immunotherapy, these agents will need to be combined with others that can manipulate the unresponsive immune environment.

On the other hand, in the small group of KEYNOTE-062 participants with MSI gastric cancer, pembrolizumab was clearly associated with a greater OS benefit than chemotherapy. “As many MSI tumors are inherently chemoresistant, MSI should be tested before any first-line therapy and patients with MSI GC should be saved from futile and toxic chemotherapy in the future,” Smyth and Moehler advised.

  1. Pembrolizumab, an immune checkpoint inhibitor, was found to be noninferior to chemotherapy when given as first-line treatment in advanced gastric and gastroesophageal cancer and was better tolerated among patients.

  2. Immunotherapy was not superior to chemotherapy alone, nor was it superior when given in combination with chemotherapy in patients with untreated advanced gastric cancer.

Pam Harrison, Contributing Writer, BreakingMED™

This study was funded my Merck Sharp & Dohme.

Tabernero reported receiving personal fees from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Genmab Halozyme, Imugene, Inflection Biosciences, Ipsen, Kura Oncology, Lilly, Merck Sharp & Dohme, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, Proteo Design, Rafael Pharmaceuticals, Hoffmann-La Roche, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS, and Roche Diagnostics.

Smyth reported receiving personal fees from Astellas, AstraZeneca, Bristol-Myers Squibb, Celgene, Five Prime Therapeutics, Gritstone Oncology, Merck, Servier, and Zymeworks.

Moehler reports receiving grants and nonfinancial support from Amgen, the European Organisation for Research and Treatment of Cancer, AIO, German Cancer Aid, and the German Federal Ministry of Education and Research as well as personal fees from the Falk Foundation, Eli Lilly, Roche, and MCI Group. He has also received grants and personal fees from MSD, Pfizer, Merck Serono and Bristol-Myers Squibb.

Cat ID: 23

Topic ID: 78,23,730,16,188,23,935,192,925