Forde Forecasts Future Use of Immunotherapy in Early-Stage NSCLC

Patrick M. Forde, MBBCh

Immunotherapy has demonstrated significant activity in patients with metastatic non—small cell lung cancer (NSCLC), noted Patrick M. Forde, MBBCh, with a slow transition to its use in the early-stage setting for those with resectable and unresectable lung disease.

“Huge advances in earlier-stage disease have really exploded in the last year, starting with the PACIFIC study in stage III disease,” said Forde. “Trying to show that we can reduce relapse and improve survival for patients with surgically resectable disease is the ultimate goal.”

In PACIFIC, the PD-L1 inhibitor durvalumab (Imfinzi) had a median progression-free survival by blinded independent central review of 17.2 months versus 5.6 months with placebo (HR, 0.51; 95% CI, 0.41-0.63) in patients with stage III unresectable NSCLC who had stable disease following chemoradiotherapy.^1,2

The clinical benefit of immunotherapy has also been observed in patients with resectable disease, said Forde. In a small phase II study, neoadjuvant nivolumab (Opdivo) demonstrated a pathological response in 45% of patients whose tumors were completely resected in surgery (NCT02259621).^3,4

Investigators believe that research with established and emerging biomarkers such as PD-L1, tumor mutational burden (TMB), and gene signatures will help identify patients with the highest chance of response to treatment. However, Forde explained that challenges remain in making immunotherapy available to those with early-stage disease.

OncLive: Can immunotherapy be effective in early- stage lung cancer?

What are some key trials in early-stage disease that clinicians should be aware of?

Reflecting on recent data, what are the most exciting findings?

How is the use of immunotherapy being explored for patients with EGFR mutations?

What biomarker work is going on to help clarify proper patient selection?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Forde, an assistant professor of oncology at Johns Hopkins Medicine, discussed the future of immunotherapy in early-stage NSCLC.Forde: We’re investigating drugs, such as PD-1 antibodies, in stage I to III lung cancer. We know these drugs have significant efficacy for patients with metastatic cancer in which the disease has spread outside the lung. Now, there’s an increasing push among clinicians and patients to investigate these drugs for patients with early-stage disease to shrink tumors and try to prevent relapse.In collaboration with colleagues at Memorial Sloan Kettering Cancer Center, we at Johns Hopkins conducted a study where we gave nivolumab, a PD-1 antibody, to patients with stage I to stage III lung cancer prior to surgery. We showed that about half of the patients experienced a significant shrinkage or regression in their tumors. That study has led to other international studies that are comparing combinations of chemotherapy with immunotherapy versus chemotherapy alone prior to surgery. There’s also a whole host of studies looking at giving immunotherapy on its own after surgery. Worldwide, there are at least 5 or 6 ongoing phase III trials.Data was presented at the 19th World Conference on Lung Cancer regarding patients with stage III disease in tumors that are not amenable to surgery. These data showed that 1 year of durvalumab given after 6 weeks of chemoradiation prolongs both time to tumor progression and OS. [Durvalumab] is also generally well tolerated, so it has become a new standard of care for this patient population.We’re seeing some interesting data. We saw data with atezolizumab (Tecentriq) given in combination with bevacizumab (Avastin), an antibody targeting VEGF, plus chemotherapy. That study enrolled patients who had received drugs such as erlotinib (Tarceva) or afatinib (Gilotrif) as first-line treatment. The addition of atezolizumab appeared to show benefit for patients. That was really the first large study for patients with EGFR mutations that suggested a benefit with immunotherapy. Ongoing studies are exploring that further. [This approach] has yet to be fully defined, but it appears promising.A huge focus for most investigators and pharmaceutical companies is trying to select patients more precisely for treatments. PD-L1 is an approved biomarker in NSCLC, and it does appear to predict response to single-agent PD-1 or PD-L1 antibodies. Investigators are also looking at TMB as a potential predictor, although the most recent data are not as supportive of that. We have some press releases suggesting that TMB is perhaps not as predictive of response as we had hoped for with the combination of ipilimumab (Yervoy) and nivolumab.

What are the foreseeable challenges to bringing immunotherapy into earlier-stage settings?

There are a whole host of other markers, such as gene signatures, [that are looking at] predicting immune response as well as other potential immunohistochemical markers. This is definitely a hot topic at the moment, and we’re all working hard to try and find new predictive markers of response.Close to 50% of patients who undergo surgery for lung cancer experience an eventual relapse; this is an area of huge unmet need. Traditionally, in most countries, we’ve given systemic therapy after surgery. With many of the immunotherapy trials, we’re looking at administering these drugs prior to surgery, which changes the kind of approach we take for these patients. A medical oncologist who delivers immunotherapy may need to be involved at the very start, when a patient presents to a surgeon. Working very closely with our surgical colleagues will be important going forward.

References

1. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalum- ab versus placebo after chemoradiotherapy in stage III NSCLC: updated results from PACIFIC. In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, ON. Abstract PL02.01.
2. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online ahead of print September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1809697.
3. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT079. doi: 10.1158/1538-7445.AM2018-CT079.
4. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer [published online ahead of print April 16, 2018]. N Engl J Med. 2018;378(21):1976-1986. doi: 10.1056/ NEJMa1716078.

&nbsp

Additionally, 66.3% (95% CI, 61.7%-70.4%) of those treated with durvalumab following chemoradiotherapy experienced a 24-month overall survival (OS) rate compared with 55.6% (95% CI, 48.9%-61.8%) of those who received placebo (2-sided P = .005). Median OS was 28.7 months with placebo and had not yet been reached with durvalumab. However, these findings showed a clear extension in OS with durvalumab (HR, 0.68; 99.73% CI, 0.469-0.997; P = .00251).