Forde Focuses on Future of Early-Stage NSCLC

Patrick M. Forde, MBBCh

Median survival has nearly tripled in patients with early-stage non—small cell lung cancer (NSCLC), a statistic that is largely attributed to immunotherapeutic agents, explained Patrick M. Forde, MBBCh, an assistant professor of oncology at Johns Hopkins Medicine.

“From the first cohorts of patients who were treated with anti—PD-1 therapy 5 or 7 years ago, we're seeing 4- and 5-year survival rates of 15% or even 20% in some cases,” explained Forde. “Many of those patients are still in remission without further progression, suggesting that there is a small but definite group of patients who achieve long-term remission from immunotherapy.”

An influential trial in this setting was the PACIFIC trial, in which the median progression-free survival (PFS) was 16.8 months with durvalumab (Imfinzi) versus 5.6 months with placebo in patients with locally advanced unresectable NSCLC (HR, 0.52; 95% CI, 0.42-0.65; P <.0001).¹ Patients were treated with the PD-L1 inhibitor following standard chemoradiotherapy.

Additional research is now investigating whether neoadjuvant immunotherapy can be adopted into earlier stages of resectable disease. In a pilot study published in the New England Journal of Medicine, 21 treatment-naïve patients with surgically resectable disease were given 2 preoperative doses of nivolumab (Opdivo; NCT02259621). Neoadjuvant nivolumab induced a major pathological response in 9 of 20 patients (45%) whose tumors were completely resected.²

OncLive: How has the PACIFIC trial impacted practice and future research?

Where does neoadjuvant therapy show the most promise?

Is surgery still a mainstay in treatment?

What other approaches are being investigated?

Could adjuvant targeted therapy and immunotherapy be a potential combination worth exploring in patients with driver mutations?

Though physicians have made significant strides with immunotherapy, Forde also noted the reality of patients who progress on or do not respond to immunotherapy in an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer. Forde also discussed the advances in early-stage disease, emphasizing neoadjuvant and adjuvant immunotherapy trials in stage I, II, and III disease.Forde: The PACIFIC study was very promising when it was published just over 1 year ago. Patients received 1 year of durvalumab after definitive chemoradiation for unresectable stage III lung cancer. It had a significant benefit in terms of time to progression from receiving durvalumab with very little additive toxicity. At that time, the OS data from the study were not mature. However, we hope those data will be presented at the 19th World Conference on Lung Cancer. There was a press release suggesting there was an OS advantage from durvalumab. Our hope is that will be confirmed given the three-fold marked improvement in PFS.We've been interested at [the work being done at] Johns Hopkins Medicine and Memorial Sloan Kettering Cancer Center in delivering immunotherapy to patients with even earlier-stage disease—–stage I or II disease that was amenable to surgical resection. We conducted a study across the 2 sites where we gave 2 doses of nivolumab (Opdivo) to those patients prior to surgery. We showed that nearly half the patients had a major pathologic response in which there was minimal or no residual tumor when it was removed. That study and others have led to large phase III trials that are giving neoadjuvant immunotherapy, in most cases with chemotherapy prior to surgery. Those trials are ongoing in that setting, and we await the results of those studies. There are also large adjuvant studies giving immunotherapy after surgery. Those studies are ongoing and are accruing well in the United States and elsewhere.Surgery is still the mainstay for patients with stage I and II disease and some patients with stage IIIa lung cancer. However, almost half of patients who have surgery relapse. I hope immunotherapy will improve that statistic in the future.Broadly speaking, we have 3 categories of therapy for lung cancer: chemotherapy, immunotherapy, and targeted agents. There are several studies looking at giving targeted agents after surgery for lung cancer for patients whose tumors harbor specific mutations such as EGFR or ALK. Those studies are ongoing.In advanced lung cancer, there are very minimal data on using immunotherapy for patients who have EGFR or ALK [mutations]. We have limited data from the IMpower150 study, in which patients who progressed on an EGFR tyrosine kinase inhibitor were eligible. They received carboplatin, paclitaxel, atezolizumab (Tecentriq), and bevacizumab (Avastin). There appeared to be some efficacy for those patients [with the addition of] atezolizumab.

What other clinical trials are you looking forward to reading out?

What will research be able to address in the coming years?

Despite these challenges, how has the outlook on early-stage NSCLC changed?

At the moment, we have no data for patients who have EGFR or ALK alterations in early-stage disease. Until we can show that the targeted therapy has efficacy in patients with those targets and whether immunotherapy has efficacy in the more general population, it will be too early to compare directly.It will be interesting to see some of the studies looking at novel combinations. For example, there are agents targeting the adenosine pathway combined with anti—PD-1 agents. The big area of investigation at the moment is in patients who either don't respond to PD-1 therapy or who develop progression after responding to PD-1 therapy. Much of the clinical trial research at the moment is focused on that population of patients with PD-1-resistant/refractory lung cancer. That will be a big driver for further investigation if we start to see some efficacy from those studies.Despite the advances we have seen with immunotherapy and targeted therapy, there is still a significant population of patients with lung cancer who are not amenable to targeted therapy because they don't have the mutation. Many of those patients also don't respond to immunotherapy. While we're seeing [median] survivals of 2 to 3 years, that is still not curative for most patients. Those who have non-targetable next-generation sequencing profiles and don't respond to immunotherapy are a difficult population. Also, we don't have good drugs for patients who develop resistance or acquired resistance to immunotherapy after responding.There have been very significant advances. With chemotherapy alone, the median survival was about 8 to 12 months. Now, we're seeing median survivals in the range of 24 to 36 months depending on the study.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937.
2. Forde P, Chaft J, Smith K, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378:1976-1986. doi: 10.1056/NEJMoa1716078.