Matthew A. Gubens, MD, MS, Assistant Clinical Professor of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, discussed the past, present, and future of immunotherapies for non–small cell lung cancer (NSCLC) at the NCCN 22nd Annual Conference.
“Immunotherapy is not a new idea. It was proposed by William B. Coley, MD, in 1893 as a treatment for cancer. Today, we have immunotherapies directed against PD-1 [programmed death], PD-L1 [programmed death ligand-1], and CTLA-4,” he stated.
The first PD-1 inhibitor was approved by the FDA in 2014 for advanced melanoma in patients who had exhausted other therapies. Since then, checkpoint inhibitors have also been approved for use in NSCLC.
“Looking at somatic mutations that lead to carcinogenesis, the expectation was that treatments that are effective in melanoma could be active in lung cancer,” Dr. Gubens explained.
In 2015, the first PD-1 inhibitor (nivolumab) was approved for the treatment of NSCLC. Approval was based on CheckMate 057, a phase III study that compared nivolumab versus docetaxel in nonsquamous NSCLC after failure of first-line, platinum-based therapy. The study showed improved response rates with nivolumab, longer duration of response (median, 17 vs 5.6 months with docetaxel), and improved overall survival (OS; median, 12.2 vs 9.4 months, respectively).1
The data suggested that PD-L1 expression could be a marker of response. However, patients whose tumors did not express PD-L1 fared similarly on docetaxel and nivolumab, thus suggesting that nonexpressers can also respond to nivolumab.
Pembrolizumab was shown to be more effective than docetaxel in a selected population of patients with PD-L1 expression of ≥1%. Markedly improved survival was observed in patients with PD-L1 expression levels of >50% who were treated with second-line pembrolizumab. Median OS for all patients was 10.4 months with 2 mg/kg of pembrolizumab and 12.7 months with 10 mg/kg of pembrolizumab versus 8.5 months for docetaxel (P=.008 and P<.0001, respectively, vs docetaxel). For PD-L1, in >50% patients, median OS was 14.9 months with 2 mg/kg of pembrolizumab and 17.3 months for 10 mg/kg of pembrolizumab versus 8.2 months for docetaxel (P=.002 and P<.0001, respectively, vs docetaxel). Duration of response was not reached in the pembrolizumab group versus 6 to 8 months for docetaxel. Grade 3 through 5 adverse events (AEs) were less common with pembrolizumab (13% for the 2 mg/kg dose; 16% for 10 mg/kg dose) versus docetaxel (35%) (Figure 1).2 Pembrolizumab was approved as second-line treatment.
OAK was the first phase III trial to evaluate a PD-L1 inhibitor, atezolizumab, versus docetaxel as second- or third-line therapy in unselected patients with NSCLC.3 Atezolizumab significantly improved survival (P=.003), regardless of PD-L1 expression level, including in those with no expression. Atezolizumab was added to the 2017 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC as a second-line option based on this trial.
“When comparing immunotherapy checkpoint inhibitors to chemotherapy, the vast majority of patients have superior tolerability,” Dr. Gubens said.
The rates of commonly reported side effects with chemotherapy are much lower with immunotherapy (eg, nausea, fatigue), and when they do occur, are typically less than grade 3. Immunotoxicity, however, is associated with checkpoint inhibitors. Most of the immune-related AEs are due to inflammation of organ systems and end in “-itis.” They are relatively uncommon, but can be serious when they occur, and oncologists need to be aware of potential immunotoxicity and know how to treat it.2
Take-home messages for the second-line use of PD-1 inhibitors are as follows: nivolumab, pembrolizumab, and atezolizumab all have a similar magnitude of benefit compared with chemotherapy, they have similar toxicities, and are all category 1 recommendations in the 2017 NCCN Guidelines. Nivolumab is approved as second-line therapy for all patients, regardless of PD-L1 expression level; pembrolizumab is approved as second-line treatment for patients whose tumors express >1% of PD-L1; and atezolizumab is approved as second-line therapy for all patients. Nivolumab is given every 2 weeks, and pembrolizumab and atezolizumab are given every 3 weeks.
Immunotherapy is less toxic than chemotherapy, but does have toxicity. Most patients tolerate anti–PD-1 and anti–PD-L1 therapy better than chemotherapy, but virtually any organ can become inflamed while receiving immunotherapy.
For patients on a checkpoint inhibitor, oncologists should have a low threshold for ordering a chest scan to check for pneumonitis and should orderregular thyroid function tests to detect hypothyroidism or hyperthyroidism, and to be aware of a long list of other potential “-itises.” When immunotoxicity occurs, they should consider the use of corticosteroids and other immune modulators and make use of consultants in endocrinology, rheumatology, pulmonology, and others as appropriate.
Dr. Gubens has disclosed that he receives consulting fees/honoraria from AbbVie, ARIAD Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, and Pfizer Inc.; and that he receives grant/research support from Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and OncoMed Pharmaceuticals.
Paz-Ares L, Horn L, Borghaei H et al.. Phase III randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell cancer (NSCLC) [abstract]. J Clin Oncol 2015;33(Suppl):Abstract LBA109.
Herbst RS, Baas P, Kim DW et al.. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016;387:1540–1550.
Barlesi F, Park K, Ciardello F et al.. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC [abstract]. Ann Oncol 2016;27(Suppl 6):Abstract LBA44.
Reck M, Rodriguez-Abreu D, Robinson AG et al.. KEYNOTE-024: Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) >50% [abstract]. Ann Oncol 2016;27(Suppl 6):Abstract LBA8_PR.
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. Reck M Rodriguez-Abreu D Robinson AG KEYNOTE-024: Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) >50% [abstract]. Ann Oncol 2016; 27( Suppl 6): Abstract LBA8_PR.
Socinski M, Creelan B, Horn L et al.. NSCLC, metastaticCheckMate 026: a phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)-positive NSCLC [abstract]. Ann Oncol 2016;27(Suppl 6):Abstract LBA7-PR.
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. Socinski M Creelan B Horn L NSCLC, metastaticCheckMate 026: a phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)-positive NSCLC [abstract]. Ann Oncol 2016; 27( Suppl 6): Abstract LBA7-PR.
Ettinger DS, Wood DE, Aisner DL et al.. NCCN Clinical Practice Guidelines in Oncology for Non–Small Cell Lung Cancer. Version 5.2017. Accessed April 6, 2017. To view the most recent version of these guidelines, visit NCCN.org.