Richard D. Hall, MD
Immunotherapy has continued to expand its role in the non–small cell lung cancer (NSCLC) treatment landscape over the last few years. Now, recent data with combinations and a growing understanding of molecular abnormalities have raised questions over who is best eligible for immunotherapy and where it will optimally work, said Richard D. Hall, MD.
In a presentation at the OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Hall, assistant professor, Hematology/Oncology, University of Virginia Health System, recapped updates from the 2018 AACR Annual Meeting and the 2018 ASCO Annual Meeting. Hall discussed the potential impact of recent combination trials in NSCLC prior to addressing the question of whether immunotherapy is for all-comers with this disease.
KEYNOTE-189 was presented at the 2018 AACR Annual Meeting and was published simultaneously in the New England Journal of Medicine
In this trial, patients with stage IV nonsquamous NSCLC were given either pembrolizumab (Keytruda) plus pemetrexed (Alimta) with either cisplatin or carboplatin, or placebo plus pemetrexed (Alimta) with either cisplatin or carboplatin.
The median overall survival (OS) was not reached (NR) in the pembrolizumab arm versus 11.3 months in the placebo arm. Moreover, the addition of pembrolizumab reduced the risk of death by 51% in patients with NSCLC without EGFR
"One of the components of KEYNOTE-189 that is important to point to out is that all of the patients had to have their PD-L1 status evaluable," explained Hall. "Negative patients were enrolled, and in all of the groups, whether they were negative, intermediate, or had high levels of PD-L1 expression, the pembrolizumab combination showed a superior OS that was statistically significant."
Findings from KEYNOTE-189 have provided clinicians with a new standard of care for patients with nonsquamous NSCLC, said Hall. In August 2018, the FDA granted a full approval to the frontline combination for patients with metastatic nonsquamous NSCLC based on these data followed an accelerated approval in May 2017.
A second trial, CheckMate-227, evaluated nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with treatment-naïve stage IV NSCLC. Patients were separated into 2 groups. Those with PD-L1 ≥1% were randomized to 1 of 3 arms: nivolumab plus ipilimumab, platinum-doublet chemotherapy, or nivolumab monotherapy. Patients with PD-L1 <1% were randomized to 1 of 3 arms: nivolumab plus ipilimumab, platinum-doublet chemotherapy, or nivolumab plus platinum-doublet chemotherapy.
In results presented at the 2018 AACR Annual Meeting and published simultaneously in NEJM
the 2 nivolumab plus ipilimumab arms from each group were combined and compared with the platinum-doublet chemotherapy arms. Patients who were evaluable for tumor mutational burden (TMB) were specifically looked at. Progression-free survival (PFS) was measured by TMB.
"TMB is defined as the number of mutations per megabase pair of DNA," explained Hall. "Lung squamous and lung adenocarcinoma are the 2 and 3 most mutated of cancers in this cohort. There has been this thought that TMB might help us understand and explain why lung cancer responds to immunotherapy."
In patients with high TMB ( ≥10 mutations/megabase [mut/mB]), the 12-month PFS was 42.6% in patients treated with nivolumab plus ipilimumab versus 13.2% with chemotherapy (HR, 0.58; 97.5% CI, 0.41-0.81; P
<.001). In patients with low TMB (<10/ mut/mB), the 1-year PFS was 25% for nivolumab plus ipilimumab versus 17% for platinum-doublet chemotherapy (HR, 1.07; 95% CI, 0.84-1.35).
Hall said that one of the takeaways from this trial was that TMB was able to predict patients who would respond to combination immunotherapy, whereas PD-L1 expression did not.
"There is no difference, statistically, between these 2 curves,” said Hall. “In both groups, nivolumab plus ipilimumab showed a significant improvement in PFS, but PD-L1 did not seem to be particularly important.”
Following the presentation of these results at the 2018 AACR Annual Meeting, overall PFS by TMB for the PD-L1–low group (<1%) was presented at the 2018 ASCO Annual Meeting. The 1-year PFS for the full unselected population with nivolumab plus chemotherapy versus chemotherapy was 5.6 and 4.7 months, respectively (HR, 0.74; 95% CI, 0.58-0.94).3