Corey J. Langer, MD
Checkpoint inhibition following chemoradiation has shown remarkable successes for patients with locally advanced non–small cell lung cancer (NSCLC), after more than 2 decades without major advances, according to a presentation by Corey J. Langer, MD, FACP, at the 19th Annual
International Lung Cancer Congress.
Langer, the director of thoracic oncology at the Abramson Cancer Center, and professor of medicine at the University of Pennsylvania, examined past setbacks and current successes in the treatment of patients with locally advanced NSCLC.
Chemoradiation alone has been the standard of care for patients with locally advanced NSCLC, although this has changed recently with the introduction of durvalumab (Imfinzi) in this setting. Durvalumab was FDA-approved and added to NCCN guidelines based on findings from the phase III PACIFIC trial, which examined consolidation therapy with the PD-L1 inhibitor following chemoradiation. “Really, PACIFIC is the first study to show survival benefit in locally advanced [NSCLC] in the past 25 years,” Langer said.
Successes and Failures for Stage 3 NSCLC
Trials have shown a survival benefit for induction or concurrent chemotherapy versus radiation alone, Langer said, but less luck was seen for targeted therapy or adjuvant therapy, when added to chemoradiation.
A meta-analysis of 7 trials looking at concurrent or sequential chemotherapy added to radiation in patients with locally advanced NSCLC demonstrated an absolute overall survival (OS) advantage at 5 years with concomitant chemoradiation therapy (HR, 0.83; 95% CI, 0.73-0.94; P
Langer added that there was a significant increase in grade 3/4 esophagitis seen with concomitant treatment compared with sequential (18% vs 3%), but there were no differences in long-term pulmonary toxicities.
Targeted therapies have failed to show a benefit in combination with chemoradiation in locally advanced NSCLC. In the randomized, 2-by-2 factorial phase III RTOG 0617 trial, for example, cetuximab (Erbitux) in combination with standard dose or high-dose conformal radiotherapy and consolidation carboplatin and paclitaxel in patients with stage IIIa or IIIb NSCLC did not meet its primary endpoint of a significant OS improvement compared with chemoradiation alone.2
The median OS with added cetuximab was 25.0 months (95% CI, 20.2-30.5) versus 24.0 months (95% CI, 19.8-28.6) with chemoradiation (HR, 1.07; 95% CI, 0.84-1.35; P
= .29). The higher radiation dose results also crossed the futility boundaries.
However, among patients with high EGFR
expression, there was a greater signal for survival benefit with added cetuximab. Patients with high EGFR
expression (H score ≥200) demonstrated a median OS of 42.0 months (95% CI, 20.6-not reached) compared with 21.2 months (95% CI, 17.2-29.2) without cetuximab (HR, 1.72; 95% CI, 1.04-2.84; 2-side log-rank P
The addition of a vaccine to chemoradiation has shown potential in locally advanced NSCLC, but has yet to show a significant benefit. The randomized, double-blind phase III START trial investigated the use of tecemotide (L-BLP25), a MUC1 antigen-specific vaccine, versus placebo after chemoradiotherapy in patients with stage III NSCLC.3
Median OS in the tecemotide arm (n = 829) was 25.6 months (95% CI, 22.5-29.2) compared with 22.3 months (95% CI, 19.6-25.5) in the placebo arm (n = 410), which did not amount to a statistically significant improvement (adjusted HR, 0.88; 0.75-1.03; P
Langer noted that the patients who received concurrent chemotherapy with radiation therapy demonstrated more of a survival benefit than patients who received sequential treatment with the addition of tecemotide. The median OS was 30.8 months with tecemotide versus 20.6 months for placebo with concurrent treatment (HR, 0.78; 95% CI, 0.64-0.96; P
= .016) compared with 19.4 versus 24.6 months with sequential therapy, respectively (HR, 1.11; 95% CI, 0.86-1.43).
“Vaccines alone probably don’t work all that well, but maybe in the context of immunotherapy in combination we may see these re-emerge,” Langer commented.
Great Progress With PACIFIC
Despite setbacks with vaccines, immunotherapy, in the form of checkpoint inhibition, did show great benefit following chemoradiation in locally advanced NSCLC, in the phase III PACIFIC trial.
Langer explained that PD-1/PD-L1 checkpoint inhibition is well suited as a consolidation therapy after definitive chemoradiation as checkpoint blocked has potentially enhanced efficacy in minimal disease states and has shown great antitumor activity in lung cancers. Additionally, preclinical models in mice have suggested that anti–PD-1 therapy may enhance the efficacy of radiation therapy. Many immunotherapy trials are ongoing in this setting.