Updates in Early-Stage Treatment

Elizabeth Waxman

To put some of these new treatments and studies in the non–small cell lung cancer (NSCLC) space into perspective, it’s important to briefly revisit the impact of currently available NSCLC treatments. Lung cancer has a 5-year overall survival of only about 25% in all comers; for localized disease (stage I-II), it’s about 63%.¹ But even stage I has a recurrence rate of almost 50%, which is much higher than with many other solid tumors. When we consider locally advanced disease, around stage III, the 5-year survival drops to 35%.

With these numbers, it isn’t a stretch of the imagination to understand that lung cancer is the leading cause of cancer-related death in the United States, particularly given that it is the most common cancer worldwide and second most common in the United States.² Any time we can move the needle on survival, it has the potential to make a tremendous impact on hundreds of thousands of patients and their families throughout the world.

Whitney Lewis

Yes, that is so true. One newer study we should highlight is the IMpower010 trial, which looked at maintenance atezolizumab.³ Although it’s an early report without completely mature data and the paper is not yet fully published, I think this study is great news for patients without driver mutations or with squamous cell histology. 

This pre-planned interim analysis of IMpower010—which enrolled patients with stage Ib-IIIa NSCLC with resected disease—was perhaps the splashiest abstract at the 2021 ASCO Annual Meeting.³ The current standard of care for resected stage Ib-IIIa NSCLC is four cycles of adjuvant platinum-based doublet chemotherapy. This has a 5-year overall survival benefit of about 5.4%, which is objectively not great. This phase III trial aims to improve disease-free survival for patients with resected tumors at least 4 cm in size with a good performance status. After four cycles of cisplatin-based chemotherapy, patients—almost 1000 patients, by the way, which is pretty big for an NSCLC trial—were randomized 1:1 to receive either atezolizumab monthly for 12 months or best supportive care, which is the current standard. The analysis for disease-free survival has been conducted looking at the subgroups of PD-L1–positive patients, all randomized patients, and all patients in the intent-to-treat arms.

Atezolizumab showed a more pronounced benefit in disease-free survival in the PD-L1–positive arm but retains benefit in all randomized patients.³ The overall survival data is not yet mature and has not yet been tested. No new safety signals were identified in this population, with ~22% in the atezolizumab arm and ~12% in the supportive care arm having a grade 3 or 4 event. Only 18% of patients discontinued treatment with atezolizumab due to an adverse effect. Median disease-free survival was prolonged from 35.3 months to 42.3 months in all randomized patients, and it has not yet been reached in patients with PD-L1 expression. This is the first trial evaluating adjuvant immunotherapy in early-stage resected lung cancer, and although results are early, it is very clinically meaningful and it has the potential to become practice-changing and the new standard of care in resected early-stage lung cancer.

Elizabeth Waxman

In the ADAURA trial, which looked at adjuvant osimertinib for early-stage resected EGFR-mutant NSCLC, disease-free survival isn't reached yet versus about 20 months in the placebo group, and death or recurrence is only 11% versus 46%.⁴ An update at the 2021 World Conference on Lung Cancer showed that disease-free survival events had occurred in only 11% of patients on the osimertinib arm—both with or without adjuvant chemotherapy—and in 50% and 41% of patients who received chemotherapy/placebo or placebo alone, respectively.⁵ That seems like it would confer an overall survival benefit, but it's not yet clear, and we’re still following this trial.

Even so, both IMpower010 and ADAURA show the importance of mutation testing in early-stage, resectable lung cancer, and that mutation testing should be done if it is not already ordered for patients with early-stage disease. There are many trials opening up across the country looking to enroll patients with other targetable mutations after surgical resection to study the effects of TKIs in the adjuvant setting, similar to the ADAURA trial, so it’s worthwhile to profile patients early and potentially refer to a center with an accruing trial for your patients after definitive treatment.

Now transitioning a little bit from early-stage, resectable disease to those patients with more locally advanced disease not amenable to surgery – Whitney, what is the latest update from the PACIFIC trial? 

Whitney Lewis

So it’s funny you should ask that, Liz! I’m so glad you did because it’s a very timely question. The authors published the 4-year survival update for the PACIFIC trial in January 2021,⁶ but then the 5-year survival update was presented at the 2021 ASCO Annual Meeting in June.⁷

As a reminder, patients with unresectable tumors generally receive concurrent chemotherapy and radiation and now go on to receive an additional year of adjuvant immunotherapy with durvalumab—this treatment regimen is supported by data from the PACIFIC trial, which established a new standard of care for this population. Before the PACIFIC trial, patients would either receive two cycles of consolidative chemotherapy or observation alone after concurrent treatment. In PACIFIC, patients were randomized to receive concurrent chemotherapy radiation and then go on to receive either a year of adjuvant durvalumab or a year of placebo as long as their disease had not progressed after the concurrent phase.^6,7 

The PACIFIC standard of care was originally approved on progression-free survival data, but the longer out we go for this study, honestly the better the data looks. At 5 years, the median overall survival of patients on durvalumab was 48 months versus 29 months, and the progression-free survival was 17 versus 5.5 months.⁷ Adjuvant immunotherapy after chemoradiation is such an important step in patients’ therapy. Originally, with only progression-free survival data, it was a bit more controversial to add on durvalumab after chemoradiation since we didn’t have proof that a “watch-and-wait and then start immunotherapy” regimen in the recurrent/metastatic setting would be inferior, but these outcomes really speak for themselves in terms of setting a new standard of care.

Elizabeth Waxman

What about the safety profile of durvalumab? What is the updated data on that?

Whitney Lewis

Yes, durvalumab continues to be very well tolerated. One worry I had when this trial came out was if rates of pneumonitis would be higher with adjuvant durvalumab since patients would have just undergone curative radiation therapy to the lungs. But pneumonitis rates were relatively similar.⁸ In my experience, the most common adverse effects that patients with lung cancer have from immune checkpoint inhibitors such as durvalumab, other than changes in electrolytes and potentially transient changes in the CBC, are fatigue and arthralgias/myalgias, both of which are manageable.

The benefit of durvalumab has also been seen across all subgroups—PD-L1–positive and–negative, former and never smokers, and by age. The authors estimate about 43% of patients on durvalumab are still alive at 5 years, and almost one in three are alive and without progression.⁷ Take a moment and compare that to the 5.6 months of progression-free survival on the placebo arm. That’s a massive number of patients we may have cured with adjuvant immunotherapy. And hopefully in the future we can see this same impact on patients who receive immunotherapy after surgical resection as well as in some of the neoadjuvant immunotherapy or chemoimmunotherapy papers that are coming out.