Expert Point of View: John Heymach, MD, PhD, and Leena Gandhi, MD

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John Heymach, MD, PhD

John Heymach, MD, PhD

“THIS STUDY represents a true milestone in the field of lung cancer. For the first time, the vast majority of patients with non–small cell lung cancer (NSCLC) can receive immunotherapy with pembrolizumab (Keytruda),” said ASCO expert John Heymach, MD, PhD, of MD Anderson Cancer Center, Houston, speaking at an ASCO press conference. “Before this study, only one-third of patients who had high programmed cell death ligand 1 (PD-L1) expression could receive pembrolizumab. This doubles the population that can initiate therapy with immunotherapy in the first line, assuming the U.S. Food and Drug Administration (FDA) modifies the pembrolizumab label. This is yet another promising result with immunotherapy in lung cancer that brings new momentum to the treatment of this notoriously difficult disease.” 

Dr. Heymach continued: “This is a double win for immunotherapy. Pembrolizumab extends life and has substantially less toxicity, which impacts the daily life of patients. They don’t have to suffer hair loss, nausea, or peripheral neuropathy associated with chemotherapy. The toxicities of immunotherapy are easily managed.” 

Words of Caution 

LEENA GANDHI, MD, Director of Thoracic Medical Oncology at Perlmutter Cancer Center at NYU Langone, New York, was cautious about applying these results to all patients with any level of PD-L1 expression. 

Leena Gandhi, MD

Leena Gandhi, MD

“There are multiple caveats to making pembrolizumab standard of care for all patients with PD-L1 expression. The benefit of pembrolizumab monotherapy in this trial is clearly driven by higher PD-L1 expression. PD-L1 is an imperfect biomarker, but it should be used. Tumor mutational burden may complement PD-L1 expression and further subdivide patients into selected slices of the NSCLC ‘pie.’ Emerging biomarkers may improve our ability to select patients for immunotherapy,” she told listeners. 

“Looking at this study on its own, not in the context of other studies, it showed that pembrolizumab was more effective and less toxic for NSCLC patients with PD-L1 expression. We have to ask for which patients is this benefit worth it. Within the ASCO Value Framework, this study does not necessarily meet the goal for all patients. Within the squamous subset, the study meets the target hazard ratio, but not in the nonsquamous subset,” she continued. 

Cost and Magnitude of Clinical Benefit 

WE NEED to consider cost and the magnitude of clinical benefit, she added. The magnitude of clinical benefit for pembrolizumab is not as robust as it is for anaplastic lymphoma kinase (ALK) inhibitors in ALK-mutated NSCLC, for example. “All ALK-positive patients obtain benefit. Selection is what matters,” she said. 

“PD-L1 is not a black and white marker, as is epidermal growth factor receptor (EGFR) and ALK. PD-L1 does not select which patients won’t benefit. It is a dynamic biomarker that changes over time, and there are inconsistencies in tests for PD-L1. Tumor mutational burden is a suggested biomarker for the benefit of nivolumab (Opdivo) or nivolumab/ipilimumab (Yervoy), but it is also not a black and white marker and is subject to the same factors as PD-L1,” Dr. Gandhi stated. “Tumor mutational burden may be complementary to PD-L1. Experience in small numbers of patients suggests that those with a high tumor mutational burden and a high PD-L1 expression derive the most benefit from immunotherapy. Other potential biomarkers are emerging.” 

“NSCLC cannot be lumped together. Just as targeted therapy defined heterogeneous malignancies in the lungs, we will see immune biomarkers define a ‘pie’ for NSCLC,” she predicted. 

Treatment Scenarios 

DR. GANDHI presented the following theoretical treatment scenarios: For patients with 90% PD-L1 expression and a low tumor mutational burden, pembrolizumab monotherapy; for patients with no PD-L1 expression and a high tumor mutational burden, nivolumab plus ipilimumab; for patients with 0% to 20% PD-L1 expression and a low tumor mutational burden, pembrolizumab/platinum/ pemetrexed (Alimta); for patients with 20% PD-L1 expression, a low tumor mutational burden, liver metastases, and EGFR mutations, carboplatin/paclitaxel/bevacizumab (Avastin)/atezolizumab (Tecentriq). 

“In lung cancer, it no longer can be said that one size fits all. Biomarkers should be used to select the best possible option for individual patients,” she stated. ■

DISCLOSURE: Drs. Heymach and Gandhi reported no conflicts of interest. 

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