Insights From: Roy S. Herbst, MD, PhD, Yale School of Medicine; Corey J. Langer, MD, University of Pennsylvania; Vassiliki A. Papadimitrakopoulou, MD, University of Texas MD Anderson Cancer Center
Corey J. Langer, MD: There’s tremendous interest in exporting PD-1 and PD-L1 inhibitors into the curative setting. The Hoosier Oncology Group trial that is looking at consolidative pembrolizumab is just 1 example. This is a straightforward phase II effort looking at single-agent pembrolizumab in a consolidative setting after the completion of concurrent chemoradiation in locally advanced non–small cell lung cancer, stage 3 disease. Nearly 100 patients were accrued. The majority received a paclitaxel, carboplatin, and radiation platform regimen. A sizable minority received etoposide-platinum, and maybe 3 or 4 patients received pemetrexed and a platinum. Those individuals who did have untoward toxicity or disease progression went on to receive pembrolizumab. One of the more gratifying observations is that there was a relatively low incidence of pneumonitis—1 of the big fears that comes up when we’re assessing these agents, the checkpoint inhibitors, after radiation. It was only 3%, grade 3 or higher. Otherwise, there were no new toxicities—certainly, in what we would normally observe.
It’s way too early to gauge long-term benefits of either progression-free survival or overall survival. And to be frank, we need prospective randomized trials. The PACIFIC trial is an example of that. This is a trial that’s completed accrual. There was a very recent press release that showed a PFS advantage for the use of durvalumab in the same setting—a PD-L1 inhibitor after full-dose concurrent chemoradiation.
We’ve seen none of the results. We do not know what the hazard ratio or the P value is. There’s no inkling yet of any survival benefit. Given what we’ve observed in the advanced disease setting, it’s absolutely essential that we assess these agents potential benefit in the curative setting. The ultimate goal is to improve survival rate. And, in that regard, there are ongoing adjuvant trials.
Virtually every one of the major agents, the 3 agents that have been approved, plus durvalumab, are being assessed prospectively in the adjuvant setting after surgery and after standard adjuvant chemotherapy. Again, just to give an example, the ANVIL Study is a National Clinical Trials Network cooperative group effort, as part of the larger ALCHEMIST trial, where we take individuals who do not appear to have an oncogenic driver and, post-resection, post-receipt of standard, 4 cycles of platinum-based therapy, they are randomized to control observation or to intravenous nivolumab for up to a year.
Then, again, there’s also tremendous interest in looking at these agents, potentially immune-oncology (I/O) combinations, as induction regimens. And certainly, there are ongoing studies evaluating nivolumab and ipilimumab in combination in locally advanced patients prior to resection. What’s particularly nice about that is you can get initial biopsy results and then, at the time of surgery, really see what’s happened on a cellular, molecular, level with the combination of I/Os or I/Os and chemotherapy. So, it’s very exciting. The work is very early. It’s very preliminary, but at least the PACIFIC trial has given us a hint of long-term benefit.
Vassiliki A. Papadimitrakopoulou, MD: Pembrolizumab is being evaluated in patients with unresectable stage 3 non–small cell lung cancer in sequence after the combination of chemotherapy and radiation therapy. The theoretical principle behind using immunotherapy in this setting is the potential of enhancing responses to radiation therapy through the abscopal phenomenon, and also the theoretical premise that radiation therapy may increase release of antigens from the tumor. The same principle is being investigated in a clinical trial utilizing nivolumab after concurrent chemoradiation therapy versus placebo.