Mark A. Socinski, MD
Recent approval of immunotherapy in the first-line setting for treatment of patients with locally advanced and metastatic non–small cell lung cancer (NSCLC) without driver mutations represents “a fundamental change in care,” according to Mark G. Kris, MD. However, he and other experts who participated in an OncLive
panel agreed that integrating the recently approved agents into clinical practice will be the next challenge moving forward.
The panelists discussed the importance of testing for PD-L1 expression and managing immune-related toxicities early, as well as the ongoing trials of immunotherapy/chemotherapy and immuno/immuno (I/O) combinations. They agreed that combinations with immunotherapy may allow for effective chemotherapy-free regimens and introduce the possibility of longterm survival in settings with poor prognosis, such as unresectable NSCLC, but that clinicians need to be aware of the unique immune-related adverse events (AEs).
“Obviously, we need to be very [vigilant] in these patients,” said Kris. “But I do think that the chance of a cure justifies more risk.”
Testing for PD-L1 Expression
PD-1/PD-L1 inhibitors have changed the therapeutic paradigm for lung and other types of cancer since they demonstrated durable clinical activity in a subset of patients with treatment-refractory disease.1 In NSCLC, patients with EGFR mutations or rearrangements in ALK or ROS1 remain candidates for first-line targeted therapies but the role of immunotherapy is rapidly changing. The KEYNOTE-0012 and KEYNOTE-0103 trials showed that patients with high PD-L1 expression (≥50% of tumor cells) had a higher response rate to pembrolizumab (Keytruda) in the first-line setting than those with lower or absent PD-L1 expression, which supports inclusion of PD-L1 immunohistochemistry in the standard testing panel, according to Kris. “You have to meet with your pathologist and make sure that it’s clearly explained why you need this test.”
Although some experts have indicated concern about variability among the PD-L1 testing platforms, a recent analysis4 showed greater than 90% agreement among 3 validated, commercially available PD-L1 immunohistochemistry assays at multiple expression cutoffs ranging from 1% to 50%. D. Ross Camidge, MD, PhD, stated that this high level of agreement is reassuring for widespread implementation of affordable assays in community practices (although he noted that the assay associated with atezolizumab [Tecentriq] may not correspond as well with the others). However, he also emphasized the importance of looking at PD-L1 expression as a continuous variable when analyzing the results of clinical trials or considering treatment options for patients. “By setting something that says, ‘we’re including people in our trial who are above this,’ they don’t suddenly all become homogeneous above that level.”
The panelists also commented that toxicities associated with PD-1/PD-L1 inhibitors, such as pneumonitis and inflammation of the pancreas, liver, or thyroid, are distinct from chemotherapyrelated AEs and may not be apparent immediately. David R. Spigel, MD, pointed out that colitis that may occur with immunotherapy often resembles the diarrhea associated with other therapies and appears minor at first, but can lead to hospitalization if not addressed early with a course of steroids or temporary withdrawal of the immunotherapy drug.
Although some oncologists are concerned that steroids may reduce the efficacy of immunotherapy, Spigel stated that steroids may allow patients to continue receiving the PD-1 inhibitors and have not been shown to reduce efficacy with melanoma. Additionally, he stated that many participants were taking steroids in the pivotal trials that showed positive outcomes with PD-1 inhibitors. Mark A. Socinski, MD, moderator of the panel, also noted that erring on the side of early, aggressive management of toxicities is of primary importance, particularly with the lack of convincing data showing an interaction between steroids and PD-1 inhibitors. Kris also added that infliximab is a less toxic, often overlooked option that should be considered before steroids, particularly in patients who cannot tolerate steroids.