Justin F. Gainor, MD
Immune-based therapies continue to show promising signals for patients with small cell lung cancer (SCLC) and mesothelioma, but better predictive biomarkers are needed to determine who is most likely to benefit, according to Justin F. Gainor, MD.
The rationale for immunotherapy in SCLC is growing because it is a very molecularly complex disease, Gainor said in a presentation during the 5th Annual Miami Lung Cancer Conference. While PD-L1 expression is infrequent in this space, SCLC tumors can be characterized by relatively high tumor mutation burden (TMB).
"We've seen responses with PD-1 monotherapy as well as with dual checkpoint blockade regardless of PD-L1 status," said Gainor, assistant professor of medicine at Harvard Medical School and an assistant in medicine at Massachusetts General Hospital. "The combination of PD-1/CTLA-4 is associated with a higher response rate compared with nivolumab alone, but this benefit appears to be most pronounced in high TMB patients."
Signals with checkpoint inhibitors were first reported with pembrolizumab (Keytruda) in the multi-cohort KEYNOTE-028 trial, which showed that the PD-1 inhibitor pembrolizumab was associated with a 33% overall response rate (ORR) in patients with PD-L1-positive SCLC.1
Of all patients enrolled on the study, 31.7% tested PD-L1 positive, defined as ≥1% PD-L1 expression in tumor and inflammatory cells or stroma.
Nivolumab (Opdivo) has also been investigated in several SCLC studies. The open-label, phase I/II CheckMate-032 trial, for example, evaluated 216 patients with progressive SCLC who had received ≥1 prior platinum-containing regimen and were not stratified for PD-L1 expression. Patients were randomly assigned to single-agent nivolumab or the combination of nivolumab and ipilimumab (Yervoy) at 1 of 2 doses.2
In an exploratory analysis of the trial, the combination of nivolumab and ipilimumab (Yervoy) was associated with a 46% ORR in patients with recurrent disease with high TMB compared with a 21% ORR with nivolumab monotherapy. In patients with medium and low levels of TMB treated with the combination, the ORR was 16% and 22%, respectively. The ORR was 7% and 5%, respectively, among those in these populations treated with nivolumab alone.
In the pooled intent-to-treat (ITT) population, the overall ORR was 11% with nivolumab alone and 22% with nivolumab plus ipilimumab.
"We can see that the response rate to nivolumab monotherapy is actually lower than what we see in an unselected patient population in non-small cell lung cancer, for example, so only about 11 to 12% of patients are responding to monotherapy," Gainor explained. "By contrast, the response rate to the combination is about double, at about 21% to 22%."
PD-L1 did not seem to be a reliable predictor for benefit based on an analysis of CheckMate-032.
"If you look at responses based on PD-L1 expression, there are responses in people who are PD-L1 positive and PD-L1 negative, so it is not a fantastic predictor of benefit," Gainor said.
Ongoing phase III studies are taking these clinical data a few steps further. In the phase III CheckMate-451 trial, approximately 810 patients with SCLC are being randomized in a 1:1:1 ratio to receive nivolumab, nivolumab plus ipilimumab, or placebo (NCT02538666). The primary endpoints are overall survival (OS) and progression-free survival (PFS).
Additionally, the CheckMate-331 study compares OS outcomes with nivolumab versus topotecan (Hycamtin) or amrubicin in patients with SCLC who did not previously receive treatment with CTLA-4, CD-137, or PD-1/PD-L1/PD-L2 inhibitors (NCT02481830).
Aside from PD-1 therapy, DLL3 is another target being explored in SCLC, Gainor explained. DLL3 is normally expressed during Golgi development, can be aberrantly expressed in SCLC tumor-initiating cells, and interacts with and inhibits NOTCH1
signaling. It may also mediate NOTCH inhibition downstream of ASCL1.
Rovalpituzumab-tesirine (Rova-T) is a DLL3-targeted antibody-drug conjugate that demonstrated encouraging single-agent antitumor activity with a manageable safety profile in a phase Ib trial for the treatment of patients with recurrent SCLC.3
In the study, 11 of 60 evaluable patients (18%) who received an active dose of Rova-T achieved a confirmed objective response, and 30 patients (50%) had stable disease. The median PFS was 2.8 months (95% CI, 2.5-4.0).
An exploratory analysis of available tumor tissue samples (n = 34) from this trial showed an overall response rate of 38% (n = 10) among 26 DLL3-high patients compared with 0% in DLL3-low patients. The median PFS was 4.3 months (95% CI, 2.8-5.6) versus 2.2 months (95% CI, 1.3-2.5), respectively.