Daniel V.T. Catenacci, MD, Associate Professor of Medicine and Director of the Gastrointestinal Oncology Program at the University of Chicago, was the JAVELIN Gastric 100 study’s invited discussant. After offering an extensive background on the use of immunotherapy in gastric or gastroesophageal junction cancer, Dr. Catenacci asked: “Does so-called switch maintenance, in this case switching to immunotherapy after 3 months of induction chemotherapy, improve outcomes in the intention-to-treat analysis or any subgroups? And if not improving efficacy, can it at least be considered noninferior and better tolerated?”
Daniel V.T. Catenacci, MD
Dr. Catenacci pointed out that although he and many other physicians routinely use maintenance therapy (primarily chemotherapy), it is not a universally established treatment standard. “There are others who feel there is limited evidence and that we should just stop therapy altogether after 4 to 6 months. But for me, I do not like to stop something that is actually working in this aggressive and deadly disease,” he noted. The JAVELIN 100 investigators, he continued, “should be commended for this large study, the only one of its kind evaluating this question,” exploring the benefit of maintenance with a checkpoint inhibitor.
‘A Brilliant Strategy’ That Did Not Work
Dr. Catenacci noted that “some fallout” after 3 months of induction therapy of patients who fared well enough to be randomly assigned for maintenance was largely because of progressive disease, toxicity, death, “or just not being able to go on to further therapy…. In the end, this was a brilliant strategy, in a way, because what we’ve learned from other studies is that patients with rapidly progressing disease, those with poor performance status, or those having a heavy burden of disease are not the ones who will benefit from monotherapy checkpoint inbibitors. This selection strategy may therefore help to enrich the outcome for those most likely to benefit, and thus merited this study.”
“Unfortunately, it didn’t work, ” noted Dr. Catenacci, “and the classic Yin-Yang survival curve seen in prior studies was again observed.” The Yin-Yang curve, he explained, represents “two distinct populations of patients, one doing worse than the control arm and the other doing better. Despite 40% of patients coming off study [and not entering maintenance] and enriching the study for those 60% of patients who were initially doing well on chemotherapy, the median survival was still only between 13 and 14 months (starting from induction). This is disappointing and frustrating for all of us.”
The subgroup analysis did identify a potential for benefit in subgroups previously noted to be responsive to immunotherapy: patients with microsatellite instability–high disease, those with a low tumor burden, and those with a programmed cell death ligand 1 (PD-L1) Combined Positivity Score (CPS) > 1. “However, in some prior studies, enrolling sites in Asia showed improved outcomes compared to non-Asian sites, but this was not observed in this study,” he said.
He added that the trial did not meet the primary endpoint not because it used a PD-L1 inhibitor as opposed to a programmed cell death protein 1 (PD-1) inhibitor, where positive data have been reported in the third-line setting of this disease. “In studies like this one, looking at thousands of patients with lung cancer and comparing the subtleties of drugs (anti–PD-L1 vs anti–PD-1), there is no appreciable difference in efficacy or toxicity rates. At this point, we have to consider them interchangeable,” Dr. Catenacci said.
Moving Forward
“So, is switch maintenance therapy a standard of care? No, not in a biomarker-unselected population—it was not better nor can it be considered noninferior but better tolerated,” he concluded. “Even though on the surface, you see that the toxicity is higher in the chemotherapy arm, the grade 3 toxicity is equal in both.”
For Dr. Catenacci, this study does not really change anything for him at this time. “If there is anything I am compelled to do now, contrary to what is standard and by the book, it’s to move immunotherapy into the first line for patients harboring microsatellite instability–high tumors, given that this signal has been repeatedly observed in this subgroup of patients across all studies, including in the first-line setting.”
DISCLOSURE: Dr. Catenacci has received honoraria from Amgen, Astellas, Bristol-Myers Squibb, Five Prime Therapeutics, Foundation Medicine, Roche/Genentech, Guardant Health, Lilly, Merck, Seattle Genetics, and Taiho Pharmaceutical.
