Locally Advanced NSCLC Paradigm Benefits From Checkpoint Inhibitors

Corey J. Langer, MD

The use of checkpoint inhibition in patients with locally advanced non—small cell lung cancer in combination with chemoradiation has shown the first significant survival benefits in almost 25 years, Corey J. Langer, MD, expressed during the19thAnnualInternational 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 III 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= .0026).¹Langer 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 highEGFRexpression, 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= .032).

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.³Median 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= .123).

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.

The randomized, double-blind, placebo-controlled, multicenter PACIFIC trial enrolled patients with stage III locally advanced unresectable NSCLC who had not progressed on platinum-based chemoradiation therapy. Patients were randomized 2:1 to either 10 mg/kg every 2 weeks of durvalumab for up to a year or matched placebo.⁴Patients had to have an ECOG performance status of 0 or 1 and have received a minimum of 2 doses of chemotherapy and a minimum radiation dose of 60 Gy. Langer said that this was one of the largest immunotherapy trials in locally advanced NSCLC, with 709 patients receiving treatment.

The median progression-free survival with durvalumab was 16.8 months (95% CI, 13.0-18.1) compared with 5.6 months (95% CI, 4.6-7.8) with placebo (HR, 0.52; 95% CI, 0.42-0.65;P<.001). At 12 months, the PFS rate was 55.9% versus 35.3% and 44.2% versus 27.0% at 18 months, respectively.

In May 2018, AstraZeneca, the company developing durvalumab, announced that OS data were positive for the study. OS results have not yet been released but are expected to be presented at an upcoming conference.

Langer said that the PFS results were unprecedented and very impressive, although he did question why patients in the placebo arm performed so poorly.

He added that augmented responses were seen with durvalumab, with many patients responding to the anti—PD-L1 therapy after chemoradiotherapy. The objective response rate with durvalumab was 28.4% compared with 16.0% with placebo.

In subgroup analyses, younger patients and patients with higher PD-L1 expression especially showed better hazard ratios. Patients under 65 years had an unstratified hazard ratio of 0.43 compared with 0.74 in older patients and patients with PD-L1 expression &ge;25% had a hazard ratio of 0.41 compared with 0.59 in patients with PD-L1 <25% or unknown status.

Grade 3/4 adverse events occurred slightly more frequently in the durvalumab arm compared with the placebo arm (29.9% vs 26.1%) and more frequently led to treatment discontinuation (15.4% vs 9.8%). Langer noted that there was an increased rate of any-grade pneumonia (13.1% vs 7.7%), rash (12.2% vs 7.3%), hypothyroidism (11.5% vs 1.7%), and pneumonitis (33.9% vs 24.8%) with durvalumab, however there were few deaths due to pneumonitis or radiation pneumonitis on either arm.

&ldquo;[It&rsquo;s an] astoundingly positive trial, every endpoint showing a benefit—significant PFS improvement, clinically meaningful benefit and response rate, acceptable toxicity, lower than anticipated pneumonitis,&rdquo; Langer said. &ldquo;So it&rsquo;s not a promising new therapeutic option, it&rsquo;s the new standard option in this setting.&rdquo;

However, Langer noted that a few questions remained regarding the PACIFIC data, for instance, he noted that most patients did not undergo pretreatment PET scans and that more patients in the durvalumab arm had higher PD-L1 expression levels compared with placebo. He is eagerly anticipating further data from the PACIFIC trial.

Other Checkpoint Immunotherapies Explored as Consolidation

The single-arm, multicenter phase II LUN 14-179 trial similarly looked at concurrent chemoradiation with consolidation immunotherapy in patients with unresectable stage III NSCLC. Results from the trial were recently presented at the 2018 ASCO Annual Meeting.⁵

Unlike the PACIFIC trial, the LUN 14-179 trial offered different chemotherapy options as physician&rsquo;s choice of concurrent chemoradiation, which Langer noted was &ldquo;the right way to go for these trials.&rdquo; Patients who achieved stable disease or a response to chemoradiotherapy went on to receive pembrolizumab (Keytruda) at 200 mg intravenously every 3 weeks for up to 12 months (n = 92). The trial had the same duration of treatment and a similar patient population to the PACIFIC trial.

With pembrolizumab, the median time to metastatic disease or death was 22.4 months (95% CI, 17.9-not reached). Median PFS was 17.0 months (95% CI, 11.9-not reached); at 1 year, the PFS rate was 60.2% and at 2 years the PFS rate was 44.6%. Preliminary OS results showed that the median OS was not yet reached with pembrolizumab (95% CI, 22.4-not reached), but at 12 months the OS rate was 81.0% and the 24-month OS rate was 61.9%.

Forty patients completed 1 year of treatment, which was also comparable with the PACIFIC trial, Langer said. Twenty-five percent discontinued due to disease progression and 19.6% due to adverse events. Fatigue was seen most commonly with pembrolizumab (any-grade, 46.2%; grade 3, 4.3%). Grade 3 dyspnea was seen in 5.4% of patients and grade 3 diarrhea in 4.3%.

Of note, grade 2 hypothyroidism was seen in 6.5% of patients and grade &ge;2 pneumonitis was seen in 17.2%, including 1 event that was grade 4 and 1 that was grade 5. Seventy-five percent of grade &ge;2 pneumonitis cases occurred within the first 12 weeks of treatment with pembrolizumab.

Langer noted that he was looking forward to seeing similar OS rates in the PACIFIC trial when further data were released.

References

1. Auperin A, Rolland E, Curran WJ, et al. Concomitant radio-chemotherapy (RT-CT) versus sequential RT-CT in locally advanced non-small cell lung cancer (NSCLC): a meta-analysis using individual patient data (IPD) from randomised clinical trials (RCTs).J Thorac Oncol.2007;2(8):S310. doi: 10.1097/JTO.0000283094.86594.8f.
2. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.Lancet Oncol.2015;16:187-199. doi: 10.1016/S1470-2045(14)71207-0.
3. Butts C, Socinski MA, Mitchell PL, et al; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.Lancet Oncol.2014;15(1):59-68. doi: 10.1016/S1470-2045(170510-2.
4. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer.N Engl J Med.2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.
5. Durm GA, Althouse SK, Sadiq AA, et al. Phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.J Clin Oncol.2018;36(suppl; abstr 8500).