Swinging for the Fences in the Curative Setting for NSCLC

Over the past 20 years, we have witnessed a remarkable transformation for patients with advanced lung cancer, thanks in large part to progress in molecular oncology and immunotherapy.

Now, as we turn the page on another year, it's customary to offer some predictions moving forward.

I predict that over the next few years we will see similar positive trials in early-stage non–small cell lung cancer (NSCLC) and competing treatment alternatives emerge, as we have seen in the stage IV setting.

For example, in 15 years, treatment for advanced NSCLC has gone from the same platinum doublet chemotherapy regimen for everyone to an array of immunotherapy and chemotherapy combinations based on PD-L1 expression and other features of a patient's cancer. And overall survival has gone from being measured in months to years for many more patients.

A growing body of recent evidence supports a similar transformation in earlier-stage disease, where the stakes are higher and cure may be possible. Already in the past few years, promising data have emerged and led to new FDA approvals in potentially curative settings.

For instance, we found that adding consolidation durvalumab after chemoradiation in patients with stage III unresectable NSCLC resulted in highly significant improvements in disease-free survival and overall survival, sustained over 5 years. This represents the greatest advance in this clinical setting in the past two decades, and in 2018, the FDA approved durvalumab in this setting.

In December 2020, the FDA approved osimertinib in the adjuvant setting after a phase 3 trial that year reported tremendous gains in disease-free survival in patients with stage IB-IIIA EGFR mutation–positive NSCLC on this regimen.

This past year, the biggest story in thoracic oncology was the striking clinically significant improvement in disease-free survival with a year of adjuvant atezolizumab after postoperative chemotherapy for patients with stage II-IIIA resected NSCLC whose cancer expresses PD-L1. This finding also led to an FDA approval in this setting as well as a change in routine practice.

And, as it turns out, this regimen is not the only good option for these patients with stage II-IIIA resected NSCLC: Neoadjuvant chemotherapy plus immunotherapy represents another promising strategy. In 2021, the CheckMate-816 trial reported a fourfold improvement in response rate on imaging and a more than 10-fold increase in the rate of pathologic complete response when nivolumab was added to three cycles of neoadjuvant chemotherapy in patients with stage IB-IIIA NSCLC, regardless of PD-L1 expression. The addition of immunotherapy also allowed more patients with stage IIIA disease to undergo minimally invasive surgery and lobectomy rather than pneumonectomy.

These studies represent initial progress in the treatment of earlier-stage NSCLC. Despite this momentum, there are still big gains to be realized and challenges to overcome — namely, in many instance we are still awaiting overall survival data in these trials of earlier-stage NSCLC. We must then ask ourselves how reliably surrogate endpoints like pathologic complete response and disease- or event-free survival translate to improvements in overall survival.

My personal view is that when the improvements in these surrogate endpoints are striking, we should favor following that treatment path, but also revisit that decision if we find that overall survival does not ultimately improve.

Another challenge that arises: How do we extrapolate principles from one driver mutation to another? We have frequently borrowed principles in the stage IV setting about acquired resistance or intracranial efficacy of systemic therapy for driver mutations and applied our observations to earlier disease stages. In such instances, we recognize that the guiding principles and common themes have generally worked well in settings where we can't expect to replicate every question for patients with every mutation.

We also can't rely on FDA approvals to dictate our decisions. The agency follows a principle of offering broad approvals for cancer drugs and defers to the clinician for decision-making on an individual level. In some instances, patients may be better served by not receiving an approved option.

Take the phase 3 ADAURA trial in patients with stage IB to IIIA EGFR mutation–positive NSCLC. Should we also extend treatment with osimertinib in the adjuvant setting to patients with an ALK rearrangement or RET fusion?

Conversely, should we carve out subgroups that appear to not benefit but were eligible and enrolled as part of a largely positive trial? Giving a year of consolidation durvalumab to patients with PD-L1-negative NSCLC or adjuvant atezolizumab to patients with low tumor PD-L1 expression will affect a broad subpopulation, and thus, interpreting the subgroup analysis requires careful reflection.

I believe that the biggest limitation will be applying appropriate molecular selection in the early-stage setting. Emerging patterns for improving management of stage I-III NSCLC are predicated on molecular testing for PD-L1 and driver mutations, yet the latest data demonstrate that testing rates for molecular markers and PD-L1 in NSCLC are far lower than clinical guidelines would indicate. In fact, substandard molecular testing represents a critical bottleneck, not only limiting optimal clinical outcomes for advanced NSCLC but creating a new source of disparities in quality depending on where patients receive care.

So, while I am confident that we will see an array of positive molecularly selected and immunotherapy-powered trials of earlier-stage patients with NSCLC in the curative setting, I'm also aware of the difficulties we face in making treatment decisions in certain subgroups with limited data.

Am I too optimistic about the probability of new positive trials in this space, or perhaps too negative about the challenges we face?

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape. Dr West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing education programs and other educational programs, including hosting the audio podcast West Wind.

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