When Phase 3 Data Can't Guide Clinical Decision-Making in the Real-World--Lumpers vs Splitters

H. Jack West, MD


October 14, 2021

In a perfect world, we would have phase 3 data to guide all of our clinical recommendations. But even if that were possible, phase 3 trials are not able to provide the full range of answers we need in a real-world setting. Do, for instance, the results from a trial of the most fit patients with great organ function apply to our older and somewhat frail patient with poor kidney function?

In a world of precision oncology, oncologists face decisions every day about whether our data from idealized patients apply to the patient with a comorbidity or other complicating clinical feature. It's important to acknowledge the uncertainty when extrapolating data from even the most definitive trials.

Currently, for example, we struggle with the question of whether or not patients with unresectable stage III non–small cell lung cancer (NSCLC) harboring an EGFR mutation or ALK rearrangement should pursue consolidation durvalumab for a year. These patients were included in the PACIFIC trial, but most of what we've seen of patients with driver mutations, at least EGFR and ALK, indicates that they derive little benefit from immunotherapy. Beyond that, there is a real risk for toxicity from the interaction of recent immune checkpoint inhibitor therapy with a newly initiated tyrosine kinase inhibitor.

Similarly, we struggle over whether patients with locally advanced NSCLC and tumor programmed death ligand 1 (PD-L1) expression below 1% benefit from adjuvant durvalumab. A post hoc analysis of the PACIFIC trial indicates they appear not to. However, the recently reported IMpower010 trial of 1 year of adjuvant atezolizumab after chemotherapy for patients with resected stage IB-IIIA NSCLC shows an impressive benefit in disease-free survival. Still, if we look at subsets of patients, we see the benefit is overwhelmingly driven by the minority of patients with tumor PD-L1 expression of 50% or more, even though the trial enrolled far more broadly.

In the absence of more definitive evidence, it's difficult to come to a consensus about whether or not these subgroups should follow the broader standard of care. In other words, we are left to adjudicate the clinical significance of surrogate endpoints and whether we should be "lumpers" or "splitters" when applying results from broad populations to narrow, molecularly defined subgroups. I don't think we will arrive at any kind of consensus, but rather will be left to make our own judgments with our patients.

For me, I will be inclined to present the options to each patient. I am quite dubious about the benefit of adjuvant immunotherapy for patients with low or negative tumor PD-L1 and think the risk may well exceed the benefit, especially with overall survival still pending. Similarly, for patients with stage III unresectable NSCLC, I would be wary of prescribing durvalumab for patients with a driver mutation, in whom immunotherapy may be both unhelpful and pose a real risk for future drug interactions. The risk would be only slightly less for patients with PD-L1 below 1% and no driver mutation. These patients appear not to benefit from durvalumab and may experience pneumonitis or other adverse effects from immunotherapy. Still, I would consider it appropriate to treat an informed patient who understood the data, was eligible on the basis of the data and indication, and wished to pursue this therapeutic option.

Overall, I think the new era of increasingly narrow molecular definition of cancer classification should lead us to acknowledge that we may need to revise our expectations, or at least hope, that phase 3 data can guide most of our clinical decisions. Of note, an FDA approval shouldn't be interpreted as a mandate for clinical use, but rather as a potential option for clinicians.

What do you think? Do you favor a "lumper" or "splitter" approach?

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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