Immunotherapy Success in Lung Cancer Sets Stage for Future Research

Antoinette Wozniak, MD, FACP, FASCO

The emergence of immunotherapy agents in stage III non—small cell lung cancer (NSCLC) as well as small cell lung cancer (SCLC) treatment has led to improved survival outcomes, notes Antoinette Wozniak, MD, FACP, FASCO.

For example, the PD-1 inhibitor durvalumab (Imfinzi) has become the standard of care for patients with unresectable stage III NSCLC who do not progress following platinum-based chemoradiation, based on data from the pivotal phase III PACIFIC trial.

Findings from the initial analysis of the trial demonstrated a 32% reduction in the risk of death compared with placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0025), which led to the FDA’s decision to approve the agent for use in this patient population.¹

Three-year follow-up data from a posthoc overall survival (OS) analysis continued to show a benefit with durvalumab (HR, 0.69; 95% CI, 0.55-0.86).² Furthermore, 57% of patients who received durvalumab were alive (95% CI, 52.3%-61.4%) versus 44% of those who were on placebo (95% CI, 37.0%-49.9%) at the 3-year mark.

In SCLC, the phase III CASPIAN trial evaluated chemotherapy versus chemotherapy combined with durvalumab in patients with extensive-stage disease. Results showed that the addition of the PD-L1 inhibitor to chemotherapy resulted in a statistically significant improvement in OS. Specifically, the median OS increased from 10.3 months with chemotherapy alone to 13.0 months from adding durvalumab, representing a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).³ Updated data presented at the 2019 ESMO Congress showed that the durvalumab combination also delays the development of new lesions and improves patient-reported outcomes.⁴

“The key takeaway is that immunotherapy has actually improved survival in both SCLC and in stage III NSCLC,” said Wozniak, adding that these drugs have opened the door for more trials exploring their optimal use.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Wozniak, associate director of clinical research, and medical oncologist, at University of Pittsburgh Medical Center Hillman Cancer Center, discussed the promise of immunotherapy in lung cancer and shared ongoing research efforts further exploring this approach.

OncLive: What are some of the key advances that have been made with immunotherapy in stage III lung cancer?

Wozniak: Stage III NSCLC is a difficult stage to treat because of the heterogeneity of the disease. Many questions still need to be answered with regard to the best treatment and what will advance survival in this disease. The OS data [of the PACIFIC trial] were presented at the 2018 World Conference on Lung Cancer in Toronto. [Two articles on the trial] have also been published in the New England Journal of Medicine. It was a study in which patients with unresectable stage III lung cancer received chemotherapy and radiation and then were randomized on a 2:1 basis to receive durvalumab, a PD-L1 inhibitor, for 1 year versus placebo. Basically, the patients who did receive durvalumab had a significant improvement in survival as a result of the treatment.

Could you expand on the pivotal data from PACIFIC and remaining questions?

The pivotal data were that the PFS was improved [with durvalumab]. Also, the toxicities were acceptable, including incidence of pneumonitis, which would be of concern in patients who receive immunotherapy after radiation.

A retrospective look at the PD-L1 marker was also done and it appears that the patients who were PD-L1 negative did not benefit as well [with durvalumab]. However, [it’s important to remember that] this was a retrospective look; not all the patients provided tissue for PD-L1 analysis, so it's a little unclear what this means. The results of this trial led to the FDA approval of durvalumab for use after chemoradiation in stage III disease.

How does immunotherapy fit into sequencing with regard to chemoradiotherapy?

Right now, immunotherapy is given after chemoradiation, usually when the patients recover from chemotherapy and radiation and are able to take it. Actually, the patients on the trial who were able to start it sooner tended to do a little bit better, but that could be selecting for a group of patients who were doing better and were in better shape. I'm not sure what that means yet.

For the future, ongoing studies are looking at giving immunotherapy with chemoradiation to see if that might be a better approach. Some neoadjuvant studies are also ongoing, where patients who are potentially resectable will receive either immunotherapy or immunotherapy plus chemotherapy prior to surgery.

What developments have been made with this approach in SCLC?

At the 2019 World Conference on Lung Cancer which was held in Barcelona, data from another trial in small cell lung cancer was presented: the CASPIAN trial. What we know about immunotherapy in SCLC came from the IMpower133 trial, where patients received 4 cycles of chemotherapy with or without atezolizumab (Tecentriq). Results showed a 2-month improvement in median OS for the patients who received immunotherapy. Although that might sound like a modest improvement, we have not had a positive trial in SCLC in probably 25 years. These results indicated that there was, indeed, a role for immunotherapy in this disease.

The CASPIAN trial was a 3-arm trial exploring chemotherapy versus chemotherapy plus durvalumab versus chemotherapy plus durvalumab and tremelimumab. Only the first 2 arms of the trial were reported: the chemotherapy arm versus the chemotherapy/durvalumab arm. Results showed a similar improvement in survival—this time, by close to 3 months; survival curves looked similar. Therefore, we now have another confirming study that immunotherapy does add some benefit for patients with SCLC.

What impact do these data have on the treatment paradigm?

It is likely that durvalumab will get approved for use in this particular situation. What both trials have done is open the door to more investigations using immunotherapy in SCLC, either in combination with chemotherapy or in limited-stage disease, where we are not using it routinely yet.

References

1. 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.
2. Gray JH, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(15 suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.
3. Paz-Ares L, Chen Y, Reinmuth N, et al. Overall survival with durvalumab plus etoposide-platinum in first-line extensive-stage SCLC: results from the CASPIAN study. Presented at: International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02. 
4. Paz-Ares L, Goldman JW, Garassino MC, et al. PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: results from CASPIAN. Ann Oncol. 2019;30(5 suppl, abstr LBA89). doi: 10.1093/annonc/mdz394.089.