Questions Surrounding Therapeutic Sequencing for NSCLC
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
Roy S. Herbst, MD, PhD: One of the hardest things that we deal with now is patients who don’t respond at all to a PD-L1 inhibitor, or respond and benefit to a small extent, and then progress. Options there are quite limited. Of course, if they haven’t had chemotherapy, one could use chemotherapy. There were a number of interesting presentations highlighted at the 2017 ASCO Annual Meeting where people have quantitated their approach, and their response rates do look minimally higher for chemotherapy in that setting versus chemotherapy without immunotherapy first. Now, in the best of cases, you would want to understand what the reason for the refractory disease is. Are there regulatory T cells in the tumor? Is there a lack of information? If you understood that, you could, perhaps, think about immune combinations that might work in that setting. There’ll be a host of clinical trials in the next few years to deal with that. But chemotherapy, or even chemotherapy with an immunotherapy, at that point would probably be the standard approach.
Anti-VEGF antibodies we actually use, mostly, with chemotherapy. We’re not using as many of them. The place where we’re using the anti-VEGF antibodies now would be in combination with immunotherapy. Some of the trials with atezolizumab now are looking at bevacizumab, and you can also block VEGF with small molecule inhibitors of VEGFR2, such as ramucirumab. I’ve been quite intrigued by the combination of pembrolizumab and ramucirumab, which is a phase I to II trial that I’ve actually led. In 24 patients with lung cancer, we’ve seen response rates in the 30% range, including large responses in patients that don’t have PD-L1 positivity, and a median progression-free survival of almost 10 months in a second- to fourth-line setting. What does that mean? I think that when you use an angiogenesis inhibitor, there is some effect on dendritic cells and antigen presentation. There is some effect in bringing T cells into the tumor. This is something that needs to be further explored.
Sequencing immunotherapies is the future. How are we going to treat a tumor and see the best effect? If the patient doesn’t respond, or responds and then the tumor grows again, we are going to need to think about how to really harness all the power of the immune system, not just the PD-1, PD-L1. We see that. At the 2017 ASCO Annual Meeting, we saw hundreds of posters about different combinations and approaches to ways to alter the tumor microenvironment to make the tumor more sensitive to checkpoint inhibition—ways to bring immune infiltrating to the tumor. All of these things are really ripe for the picking. We need more clinical trials—research. These are options that are all available to patients as we learn how to do this best.
Vassiliki A. Papadimitrakopoulou, MD: With the approval of immunotherapy in the frontline setting, and the availability of immunotherapy in the second-line setting for patients that did not receive it as frontline therapy, we have seen a significant change in the use of chemotherapy and chemotherapy in combination with VEGF inhibitors. What used to be our frontline therapy has frequently moved to the second-line setting, and what was second-line therapy has moved to the third-line setting. There are no specific recommendations regarding any modifications in these regimens when they’re used as second- or third-line regimens, and we continue to use them on all patients that make it to these lines of therapy.
In my practice, the majority of the patients that progress after immunotherapy are being considered for clinical trial participation. However, for the patients who are being treated with standard of care, my recommendation is standard chemotherapy or combination chemotherapy with a VEGF inhibitor. The data that we saw at the 2017 ASCO Annual Meeting suggest that chemotherapy’s activity, post-progression, from an immunotherapy agent may be slightly higher than what we were previously experiencing in the setting.