PD-L1 Testing "Name of the Game" in First-Line Treatment of NSCLC

The word “giddy” was circled in the 2014 New York Times article that Matthew A. Gubens, MD, MS, used to start his update on the use of checkpoint inhibitors in non—small cell lung cancer (NSCLC). The thoracic oncologist reminded attendees at the 2019 annual conference of the National Comprehensive Cancer Network (NCCN) that it’s been less than 5 years since the approval of pembrolizumab, the first cancer drug based on characteristics of a tumor, rather than where the tumor was located.

The giddy phase may be over. But Gubens, of the University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, said the excitement has given way to an immuno-oncology tsunami: 940 agents in clinical testing, 303 targets, 864 companies, and 3042 trials with enrollment of 577,076 patients.

Much of that progress has come in NSCLC, and Gubens appeared at NCCN Thursday with an update on new guidelines for first-line recommendations in immunotherapy and biomarker testing. Following Gubens, Marianne Davies, DNP, RN, CNS, ACNP-BC, AOCNP, of Yale Cancer Center, presented updates on strategies for managing adverse events.

“PD-L1 testing is really the name of the game,” Gubens said, referring to assays that measure the level to which tumors overexpress the programmed death ligand-1 (PD-L1) protein. As Gubens explained, the KEYNOTE-024 trial showed that pembrolizumab in patients with NSCLC more than doubled median overall survival compared with chemotherapy if PD-L1 expression was at least 50%, making that level an important cut point in treatment decisions. If PD-L1 expression is below 50%, treatment decisions turn on whether the cancer is squamous or nonsquamous.

Several guidelines that took effect in January 2019 combine pembrolizumab with chemotherapy. Although this brings greater toxicity, Gubens said, clinicians and patients alike “will consider the higher disease burden with the idea that, ‘I want a response now, I may not get to second-line.’”

With greater shared decision making, he said, savvier patients understand that choosing more aggressive therapies brings the higher response.

New guideline based on KEYNOTE-024. Pembrolizumab is preferred as first-line therapy for NSCLC when PD-L1 expression is 50% or greater. This is a Category 1 guideline, which means there is uniform consensus that the intervention is appropriate. This guideline applies to both adenocarcinoma and squamous cell carcinoma.

New guideline based on KEYNOTE-189. But what about when PD-L1 expression is less than 50%? Gubens reviewed the KEYNOTE-189 results, a phase 3 trial that studied patients with metastatic nonsquamous NSCLC with no prior treatment. Patients were randomized 2:1 to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab or placebo. Patients could cross over if they progressed on the control arm. While survival was more pronounced on those with 50% or greater PD-L1 expression, improved survival was seen across the board. Based on these results, the new guideline update adds the following as preferred Category 1 initial systemic therapy options (ECOG performance status 0-1) for advanced or metastatic adenocarcinoma in NSCLC (if no contraindications to adding pembrolizumab): pembrolizumab/carbolizumab/pemetrexed or pembrolizumab/cisplatin/pemetrexed.

What if patients cannot take pemetrexed? Based on the guideline, Gubens said the best option for patients with adenocarcinoma in NSCLC is to take the next recommended Category 1 combination, atezolizumab/carboplatin/paclitaxel/bevacizumab.

New guideline based on KEYNOTE 407. A study published in November 2018 in the New England Journal of Medicine, KEYNOTE 407, is reflected in the guideline update for combination therapies in squamous NSCLC. The preferred Category 1 recommendations are pembrolizumab/carboplatin/paclitaxel or pembrolizumab/carboplatin/albumin-bound paclitaxel.

Biomarker testing. Gubens said as important as PD-L1 testing is now, this is the just the beginning. He covered the growing importance of understanding patients with high tumor mutation burden as a distinct population from those with high PD-L1 expression and said forthcoming blood assays could be promising in predicting which immunotherapies will work.

“In 5 years, PD-L1 might be archaic. Stay tuned for multidimensional and serial testing,” referring to tests that occur throughout cancer treatment, not just at the start.

Guidelines for Immune-Related Adverse Events

The overall NCCN guideline, Management of Immunotherapy-Related Toxicities, received a substantial update in January 2019 from its February 2018 version, notably including a new section on management of effects for chimeric antigen receptor (CAR) T-cell therapy. Davies focused on updates relating to adverse events (AEs) from checkpoint inhibitors in lung cancer, noting that onset can occur between 5 and 12 weeks and may take place concurrently or sequentially. “Every organ system in the body can be involved, and we need to be cognizant of that,” she said.

She reviewed AEs from 8 recent trials (4413 patients with NSCLC) that contributed to the guideline updates, and then a meta-analysis that showed that 46.53% of patients had high-grade AEs from chemotherapy, including 13.92% that caused them to discontinue therapy; 14.26% had high-grade AEs from PD-1/PD-L1 treatments, including 5.94% that caused them to stop therapy. Patient deaths attributable to AEs were seen in 1.12% of chemotherapy and 0.48% of PD-1/PD-L1 patients. By far, the most common AE was fatigue.

The guideline contains specific algorithms for dermatological, gastrointestinal, endocrine, pulmonary, renal, ocular, cardiovascular, and hepatic AEs, including when to temporarily or permanently discontinue immunotherapy or switch therapies. Steroids, both topical and prednisone, are frequently indicated, and with long-term use vitamin D and calcium are indicated.