The year 2017 will be an important one, as we see some of the combination immunotherapy data reading out.— Naiyer Rizvi, MD
Increasing experience with immunotherapy for lung cancer in both the lab and the clinic is helping to refine treatment approaches and point the way forward, according to Naiyer Rizvi, MD, Director of both Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center in New York.
“We have made progress in terms of understanding how the immune system fails [in cancer] and overcoming adaptive immune escape with immune checkpoint therapies,” he commented in a symposium and interview.1 “But we certainly have an opportunity to improve therapies further.”
Circumventing Escape Mechanisms
Immunotherapy agents that inhibit the programmed cell death protein 1 (PD-1) pathway work in only about 10% to 30% of patients with lung cancer, because numerous other molecules and pathways are involved in the tumors’ escape from immune destruction, including cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and the angiogenic protein vascular endothelial growth factor (VEGF). “Our job in the future is to tease out the important pathways of immune resistance and how we can overcome that,” Dr. Rizvi asserted.
Treatment approaches for circumventing immune escape have focused on the two processes required for T-cell activation: antigen presentation to the T cell and co-stimulation involving antigen-presenting cells.
Efforts to enhance antigen presentation with antigen vaccines in lung cancer have been largely negative. “It’s not a bad approach, but we don’t know exactly what the clinically important neoantigens are,” he explained. A related hurdle has been differentiating self-antigens, which are also present on healthy tissues, from neoantigens, which result from patient-specific mutations that lead to unique epitopes.
Shaping of T-cell co-stimulation, either by blocking inhibitory signals or increasing activating signals, has been much more promising. CTLA-4 and PD-1 are likely the main players in this area; the former has activity at the priming phase in the lymph nodes, whereas the latter has activity at the effector phase in the tumor microenvironment. “This is in general why you see more toxicities with CTLA-4 than you do with PD-1,” Dr. Rizvi noted. “But we also know how robust activity can be with the combination of the priming as well as effector T-cell activation.”
Rapid Pace of Clinical Trials
The first-in-human trial of an immune checkpoint inhibitor, nivolumab (Opdivo), in lung cancer was initiated in 2008. “The first patient I treated was in 2009, and we were all pretty floored when saw the activity in lung cancer. Historically, given the failed vaccine trials, we never thought that lung cancer was an immunogenic tumor,” Dr. Rizvi recalled. That patient has been in remission ever since.
“That’s why we are so excited about these therapies and the potential for durable benefit and cure,” he continued. “The longest data that we have now are with nivolumab, where we have a survival of about 20% of patients out at 3 years. Hopefully, we are going to be able to recapitulate some of the experience with ipilimumab [Yervoy] in melanoma, where we have 10-year survival data as we get out further.”
Three agents—nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq)—are now approved by the U.S. Food and Drug Administration for use in the second-line setting. “That’s all happened within the past 2 years, speaking to the rapid pace of clinical trials in this setting,” Dr. Rizvi said. “And we’ve made even further movement with the approval of pembrolizumab in the first-line setting in patients who are programmed cell death ligand 1 (PD-L1)–positive, which is about 30% of patients with non–small cell lung cancer. There has never been a therapy to beat chemotherapy on its own to that magnitude.”
“Potentially, these drugs are more effective in the first-line setting vs as second- or third-line therapy,” he added. “It’s important for early adoption of this approach, where you perform PD-L1 testing and give these therapies first line when you can.”
“Combinations are the future,” Dr. Rizvi predicted, citing the impressive results achieved in melanoma with dual checkpoint inhibitor therapy. “We are seeing activity with CTLA-4–PD-1 combinations in lung cancer as well, but clearly, we are just scratching the surface. How we will use different combinations and in what setting are unknowns at this point.… The year 2017 will be an important one, as we see some of the combination immunotherapy data reading out.”
These combinations should be rationally driven rather than randomly selected, he stressed. For example, it is now recognized that tumors have phenotypes ranging from inflamed, with abundant tumor-infiltrating lymphocytes and PD-L1, to a so-called immune desert.2 The former respond to immune checkpoint inhibitors, whereas the latter generally do not but can be made responsive through the use of combinations that convert them to inflamed.
Additionally, “our understanding is evolving in terms of looking at the mutational landscape, and we can see which tumors may need some chemotherapy, which may need some VEGF therapy, and which may need combination immunotherapies,” Dr. Rizvi added. “Those sorts of translational efforts will help us move the field forward.”
A Role in Early Disease?
Will immunotherapy eventually be used earlier in the treatment of lung cancer, in the adjuvant and even neoadjuvant setting? “Potentially,” according to Dr. Rizvi.
Some noteworthy neoadjuvant trials are investigating nivolumab monotherapy,3 a nivolumab and ipilimumab combination (NCT02998528), and an atezolizumab and chemotherapy combination (NCT02716038). Another trial is testing durvalumab as maintenance therapy after chemotherapy and radiation therapy for unresectable stage III disease (NCT02125461).
“There is definitely a lot of opportunity to move these agents into earlier stages of cancer, sort of stage I to IIIA disease,” Dr. Rizvi concluded. ■
Disclosure: Dr. Rizvi has served as a consultant to AstraZeneca, Bristol-Myers Squibb, Lilly, Merck, Novartis, Pfizer, and Roche and is scientific co-founder of and shareholder in Gritstone Oncology.
2. Hedge UP, et al: Center for Cancer Research. 2016.