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“Immunotherapy for lung cancer is a paradigm shift. I would never have thought when I started my career taking care of lung cancer patients in the mid 1990s that we’d now be substituting chemotherapy with an antibody immunotherapy in 2017. It’s incredible,” commented Roy S. Herbst, MD, PhD, Chief of Medical Oncology and Associate Director for Translational Research at the Yale Cancer Center, New Haven, Connecticut, in an interview with The ASCO Post.
“We can take people with advanced metastatic lung cancer with no driver mutations, and, effectively, [get them to a point where] they are living with moderate disease, with few side effects of the drug,” he elaborated.
However, only about one-third of patients with non–small cell lung cancer (NSCLC) derive substantial benefit from the immune checkpoint inhibitors. So a key focus now is determining how the remaining group can be helped.
“At Yale, we have a lung SPORE (Specialized Program of Research Excellence), and about half of our SPORE right now is devoted to understanding the predictive markers for who responds or who is resistant to immunotherapy, understanding primary and acquired resistance,” Dr. Herbst elaborated. “That’s important because what we will then do is think about how to combine drugs and to do that in the most biologically effective way. Repeat biopsy studies to explore mechanism of action will be essential.” 1
Tumor Biomarker Testing
Testing of tumors for biomarkers of immunotherapy benefit, most notably for programmed cell death ligand 1 (PD-L1), has moved front and center, as successive trials have shown its importance in predicting response to immune checkpoint inhibitors of the programmed cell death protein 1 (PD-1) pathway.
Right now, PD-L1 is our best marker, so I’m recommending it for all of our patients here at Yale.— Roy S. Herbst, MD, PhD
“Right now, given the KEYNOTE-024 data that were recently presented at the European Society for Medical Oncology (ESMO) Congress,2,3 it would be my recommendation that anyone with a new diagnosis of lung cancer should be tested for PD-L1, because if it is above the 50% tumor proportion score using the Merck 22C3 assay, that patient should receive front-line immunotherapy. So testing is standard of care now,” Dr. Herbst maintained.
“Do I believe testing is the whole story? Absolutely not,” he added. “I think [in the future] we are going to use testing along with gene signatures, mutational burden, and other factors to understand who benefits and who doesn’t,” he said. “But right now, PD-L1 is our best marker, so I’m recommending it for all of our patients here at Yale. And in fact, we have it open now as a standard-of-care assay for all of our patients in lung cancer. It’s done as a reflex.”
Two groups of patients in particular highlight some role of factors yet to be identified, according to Dr. Herbst. One is the roughly half of patients with high tumor PD-L1 levels whose disease does not respond to immune checkpoint inhibitors. The other is those patients who despite having tumors that test negative for PD-L1 still have a response to these agents, likely due in part to heterogeneity of the ligand.
Recent data from immunotherapy trials have shaken up the lung cancer field, changing the standard of care for a large share of patients in both the first- and second-line settings, he noted.
In my opinion, the expense is going to be justified by the benefit. We have to avoid using the drugs for people who are clearly not going to benefit and identify them early on.— Roy S. Herbst, MD, PhD
“The first therapy we normally would use now in the 25% to 30% of patients who have high expression of PD-L1 in lung cancer would be pembrolizumab (Keytruda). For the other 70%, they would probably get front-line chemotherapy in standard practice or go on a clinical trial if eligible,” Dr. Herbst explained.
“In the second-line setting, if someone hasn’t had immunotherapy, most people would use immunotherapy now, which is a big shift from second-line chemotherapy,” he continued. “So chemotherapy is often relegated to third line, though we do sometimes use it earlier in people who have disease that is somewhat symptomatic to treat the symptoms.”
The optimal duration of immunotherapy is not yet clear, according to Dr. Herbst. “Most people today believe that you should treat until disease progression.”
Trials to Watch
“There are a host of clinical trials looking at immunotherapies, either alone, with other immunotherapies, or with chemotherapy,” Dr. Herbst said. He cited three ongoing trials that are being watched very closely.
The first is KEYNOTE-042, a first-line trial of the anti–PD-1 agent pembrolizumab in patients with NSCLC having 1% or more PD-L1 positivity in their tumors (NCT02220894) instead of the 50% or more used in KEYNOTE-024, which set the current threshold for clinical use. “That trial’s eagerly anticipated to see if the bar should go lower,” Dr. Herbst commented.
The second is CheckMate 227, another first-line trial in NSCLC, which is comparing the anti–PD-1 agent nivolumab (Opdivo) alone against chemotherapy or against dual immunotherapy with nivolumab plus ipilimumab (Yervoy), an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4; NCT02477826). “These results could be very exciting, and we hope to have them soon,” he said.
The third is MYSTIC, also a first-line trial in NSCLC, which is evaluating the combination of durvalumab (MEDI4736), an investigational anti–PD-L1 agent, with tremelimumab (formerly CP-675,206), another, investigational anti–CTLA-4 agent (NCT02453282).
“These drugs are expensive, but we are seeing patients with metastatic disease have a phenomenal effect,” Dr. Herbst commented. “I think we can make immunotherapy more cost-effective if we use biomarkers and understand who can get single-agent drug, who needs a combination, who needs a combination with chemotherapy. That’s going to be the key.”
“In my opinion, the expense is going to be justified by the benefit,” he maintained. “We have to avoid using the drugs for people who are clearly not going to benefit and identify them early on. That’s better in terms of cost and also in terms of toxicity. The last thing you want is to subject people to toxicity if there is not going to be any benefit from the drug.”
“With immunotherapy, the whole paradigm of lung cancer has shifted for the better. We have these new weapons, and it is time for the science and the clinic to come together, more than ever before,” Dr. Herbst asserted.
“We are only at the tip of the iceberg here. I would say we are only 10% to 20% into how much benefit we are going to achieve with these agents. And we need to think about how to see more people benefit by using the right combinations in the right patients with the predictive biomarkers that have helped us determine that,” he concluded. ■
Disclosure: Roy S. Herbst, MD, PhD, has been a consultant to AstraZeneca, Eli Lilly, Merck, Pfizer, and Genentech/Roche; has received clinical trials/grant support from Genentech and Merck.
1. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.
2. Reck M, Rodríguez-Abreu D, Robinson AG, et al: KEYNOTE-024: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score ≥ 50%. 2016 ESMO Congress. Abstract LBA8_PR. Presented October 9, 2016.
3. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.