Immunotherapy Continues to Evolve Multimodal Stage III NSCLC Treatment

Corey J. Langer, MD, FACP

Checkpoint inhibitors in the neoadjuvant setting, as consolidation post-chemoradiation, or in combination with concurrent chemoradiation, are all strategies actively being pursued in the locally advanced non—small cell lung cancer (NSCLC) setting, said Corey J. Langer, MD, FACP. However, phase III studies and additional subgroup are still needed to determine the optimal placement for such approaches.

Updated data in the locally advanced setting are showing responses and survival benefits with the incorporation of immunotherapy. Yet, it’s not a one-size-fits-all method, Langer stressed in a presentation during the 20th Annual International Lung Cancer Congress.

"Is checkpoint inhibition the standard of care in all patients? Certainly [it is] in fit patients," said Langer, who raised caution about those with autoimmune disease, an ECOG performance status of 2, and those with PD-L1—negative tumors. "Is there a role for concurrent checkpoint inhibition and chemoradiation? It will take phase III trials to determine this."

In a presentation titled, "Interdisciplinary Management of Locally Advanced NSCLC: 25 Years in the Trenches," during the meeting, Langer, director, Thoracic Oncology, Abramson Cancer Center, professor of medicine, University of Pennsylvania, touched upon both early- and late-phase data poised to take multidisciplinary care for this patient population to the next level.

Neoadjuvant Investigations Ongoing With Chemoimmunotherapy

PD-1 inhibition has demonstrated intriguing results in the neoadjuvant setting for patients with locally advanced disease. The combination of nivolumab (Opdivo) and carboplatin/paclitaxel was evaluated in patients with stage IIIA resectable NSCLC in a single-arm, phase II trial (NCT03081689). In the study, 1 nivolumab was given intravenously (IV) at 360 mg for 3 cycles, plus IV carboplatin area under the curve 6 every 3 weeks and paclitaxel at 200 mg/m2, followed by 1 year of adjuvant nivolumab.

Final data showed that the preoperative combination was well tolerated and did not delay surgery, and the major pathological response rate was 85.3% (95% CI, 71%-95%) and the complete pathological response rate was 71.4% (95% CI, 54%-87%); the partial response (PR) rate was 14.6%.¹

“You see a major pathological and complete response [rate of] over 70%,” said Langer. “This far outstretched the data that we’ve seen with either induction chemotherapy historically or single-agent immunotherapy.”

A number of ongoing studies of immunotherapy/chemotherapy regimens are also being explored in the neoadjuvant setting. CheckMate-816 (NCT02998528) is a phase III study evaluating nivolumab plus platinum-doublet chemotherapy versus platinum-doublet therapy and versus nivolumab and ipilimumab (Yervoy) in patients with stage IB to IIIA NSCLC.

The phase III KEYNOTE-617 (NCT03425643) trial is comparing the combination of pembrolizumab (Keytruda) plus platinum-doublet chemotherapy with platinum-based therapy alone in patients with stage IIB to IIIA disease, while the phase III IMpower030 study (NCT03456063) is evaluating the combination of atezolizumab (Tecentriq)/platinum-based therapy compared with platinum-doublet therapy alone in patients with stage II to IIIB NSCLC. Finally, the phase III AEGEAN study (NCT03800134) is comparing durvalumab (Imfinzi) plus platinum-doublet therapy with platinum-doublet alone.

“Are neoadjuvant checkpoint inhibitors or combination chemotherapy and checkpoint inhibitors ready for prime time in resectable NSCLC? We need the phase III data to prove that,” Langer said.

Checkpoint Inhibitors: Standard for All Patients Post-Concurrent CRT?

Treatment for patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemoradiation changed significantly with the FDA approval of durvalumab in February 2018.

The approval was based on findings from the double-blind, placebo controlled, international, phase III PACIFIC trial, in which patients with locally advanced, unresectable stage III NSCLC who did not progress on chemoradiotherapy were randomized to durvalumab or placebo. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS).

In the primary OS analysis, results showed that the PD-L1 inhibitor demonstrated a 32% reduction in the risk of death compared with placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0025).² In July 2019, the FDA updated the label for durvalumab setting to include the OS data. Moreover, the updated median PFS was 17.2 months with durvalumab compared with 5.6 months with placebo (HR, 0.51; 95% CI, 0.41-0.63). The 12-month PFS rates with durvalumab and placebo were 55.7% and 34.4%, respectively; the 18-month PFS rates were 49.5% and 26.7%.

Three-year follow-up results of a post-hoc OS analysis from PACIFIC were presented at the 2019 ASCO Annual Meeting, showcasing the long-term benefit with the PD-L1 inhibitor (HR, 0.69; 95% CI, 0.55-0.86).³ The median OS with durvalumab was not reached compared with 28.7 months with placebo (HR, 0.68; 99.73 CI, 0.47-0.997; two-sided P = .0025), and 57% of patients on durvalumab were alive (95% CI, 52.3%-61.4%) compared with 44% of those who received placebo (95% CI, 37.0%-49.9%) at the 3-year mark.

However, in the preliminary analysis, the survival benefit did not correlate with patients with PD-L1 <1% (HR, 1.36; 95% CI, 0.79-2.34)⁴; the hazard ratio was 1.14 at the 3-year follow-up—a dataset said to be "hypothesis generating," Langer said.

Regarding safety, all-grade pneumonitis or radiation pneumonitis occurred in 33.9% of durvalumab-treated patients compared with 24.8% of those on the placebo arm.

"I have to confess, I embrace durvalumab with enthusiasm," said Langer, who did cite concerns that the study remains blinded to OS and the lack of data on the percentage of patients who received <60 Gy or the nature of subsequent or concurrent chemotherapy.

In comparison, the PD-1 inhibitor pembrolizumab was explored as consolidation therapy with concurrent chemoradiation in this patient population in the phase II LUN14-179 study.⁵ At a median follow-up of 23.9 months, the median PFS was 15 months, the 12-month PFS rate was 60.8%, and the 18-month PFS rate was 46.9%. The median OS, 1-year, and 2-year OS rates were not reached, 81.0%, and 61.9%, respectively.

Role for Concurrent Immunotherapy and Chemoradiation

Early-phase prospective studies have evaluated checkpoint inhibitors during concurrent chemoradiation in patients with locally advanced, unresectable disease. In a phase I, 5-cohort trial, pembrolizumab was given as consolidation therapy or concurrently with chemoradiation at varying dose levels and schedules. Results showed that there were no dose-limiting toxicities in any of the cohorts, and 6 of the 23 patients experienced grade to 2 to 4 pneumonitis.⁶

Additionally, results of the phase II DETERRED trial that were presented during 2019 ASCO Annual Meeting showed that consolidation atezolizumab following chemoradiation (part 1) in patients with locally advanced NSCLC led to 1 grade 5 treatment-emergent fistula; in those who received consolidation atezolizumab with concurrent chemoradiation (part 2) there was 1 grade 3 and 2 grade 2 cases of pneumonitis.⁷ Preliminary data showed that the median PFS in part 1 was 20.1 months and was not reached in part 2.

The role of chemotherapy continues to be essential in this setting, Langer said, though the combination partner of cisplatin is not limited to etoposide. Updated NCCN Guidelines state that cisplatin/vincristine, cisplatin/pemetrexed, carboplatin/vincristine, and carboplatin/paclitaxel are all effective strategies with similar outcomes, he added.

However, "do we need radiation in potentially resectable stage IIIA patients? Maybe not in the checkpoint inhibitor era. That remains to be determined," he explained.

References

1. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): A phase II multicenter exploratory study—Final data of patients who underwent surgical assessment. J Clin Oncol. 2019;37 (suppl; abstr 8509). doi: 10.1200/JCO.2019.37.15_suppl.8509.
2. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.
3. Gray JH, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.
4. Antonia SJ, Villegas A, Daniel D, et al. Supplement to: overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342-2350. doi: 10.1056/NEJMoa1809697.
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). doi: 10.1200/JCO.2018.36.15_suppl.8500.
6. Jabbour SK, Berman AT, Decker RH, et al. Prospective phase I multi-institutional trial of PD-1 blockade with pembrolizumab during concurrent chemoradiation for locally advanced, unresectable non-small cell lung cancer. J Clin Oncol. 2019;37(suppl; abstr 8511).
7. Lin SH, Lin Y, Mok I, et al. Phase II trial combining atezolizumab concurrently with chemoradiation therapy in locally advanced non-small cell lung cancer. J Clin Oncol. 2019;37(suppl; abstr 8512). doi: 10.1200/JCO.2019.37.15_suppl.8512.

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