When Practice-Changing Results Don't Change Practice

H. Jack West, MD


March 30, 2023

The highly favorable results of the CheckMate 816 trial of neoadjuvant chemotherapy plus nivolumab for resectable stage IB to IIIA non–small cell lung cancer (NSCLC) were impressive enough to prompt a US Food and Drug Administration approval of this combination in March 2022.

For many, this led to a marked shift in how we approached these patients. But in my conversations with many care teams, they have expressed ambivalence about using the chemoimmunotherapy regimen. Some have conveyed to me that the lack of statistically significant improvement in overall survival is a sticking point. Others have expressed uncertainty about the true benefit of neoadjuvant chemotherapy alongside nivolumab for patients with earlier-stage disease, given that 64% of patients in the trial had stage IIIA disease. The benefit of the neoadjuvant combination in patients with low or negative tumor programmed death–ligand 1 (PD-L1) expression also remains a question mark, though the trial found no significant differences in outcomes by PD-L1 subset.

But among many of my colleagues who favor adjuvant over neoadjuvant therapy, it isn't necessarily the fine points of the data that present the real barrier: it's the sentiment that "we just don't favor a neoadjuvant approach at my place."

If the worry is that a subset of patients who are eligible for upfront surgery may be derailed from the operating room if they experience significant disease progression or a complication during preoperative therapy or that surgery will more difficult after chemoimmunotherapy, those concerns are not supported by evidence. In fact, data on surgical outcomes from CheckMate 816 assessing these issues found that surgery after chemoimmunotherapy was approximately 30 minutes faster than it was after chemotherapy alone. In addition, the combination neoadjuvant chemoimmunotherapy approach was associated with less extensive surgeries, particularly for patients with stage IIIA NSCLC, and patients experienced measurably lower reports of pain and dyspnea as well.

Though postoperative systemic therapy has been our general approach for resectable NSCLC for nearly two decades, there are several reasons to focus on neoadjuvant therapy.

First, immunotherapy may work more effectively when the tumor antigens as well as lymph nodes and lymphatic system are present in situ at the time.

Second, patients may be eager to complete their treatment within a 3-month period of just three cycles of systemic therapy followed by surgery rather than receiving their treatment over a prolonged chapter of their lives, starting with surgery followed by four cycles of chemotherapy and 1 year of immunotherapy. 

Finally, we can't ignore the fact that most neoadjuvant therapy is delivered exactly as intended, whereas planned adjuvant therapy is often not started or rarely completed as designed. At most, only about one half of appropriate patients for adjuvant chemotherapy even start it, and far less complete a full four cycles or go on to complete prolonged adjuvant immunotherapy.

We also can't underestimate the value of imaging and pathology findings after patients have completed neoadjuvant therapy. The pathologic complete response rate in CheckMate 816 is predictive of improved event-free survival over time.

And that isn't just a binary variable of achieving a pathologic complete response or not. The degree of residual, viable tumor after surgery is a continuous variable associated along a spectrum with event-free survival. Our colleagues who treat breast cancer have been able to customize postoperative therapy to improve outcomes on the basis of the results achieved with neoadjuvant therapy. Multidisciplinary gastrointestinal oncology teams have revolutionized outcomes with rectal cancer by transitioning to total neoadjuvant therapy that makes it possible to deliver treatment more reliably and pursue organ-sparing approaches while achieving better survival.

Putting all of this together, I appreciate arguments against the generalizability or the maturity of the data supporting neoadjuvant chemoimmunotherapy for resectable NSCLC. However, sidestepping our most promising advances will harm our patients. Plus, what's the point of generating practice-changing results if we don't accept and implement them?

We owe it to our patients to follow the evolving evidence and not just stick to what we've always done.

H. Jack West, MD, is an associate professor at City of Hope Comprehensive Cancer Center in Duarte, California, and vice president of network strategy at AccessHope in Los Angeles. 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 medical education and other educational programs.

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