The Dilemma of New Evidence: When to Shift Gears

Maurie Markman, MD,

When is it appropriate to accept a specific strategy, either formally or informally, as a standard-of-care option in managing the treatment of patients with cancer in a particular clinical setting? That question emerges as an underlying issue in 2 unrelated peer-reviewed articles and an accompanying commentary in a recent issue of the Journal of Clinical Oncology.^1-3

The first article examined outcomes for patients who received nivolumab (Opdivo) as neoadjuvant treatment for high-risk stage IIA to IV resectable Merkel cell carcinoma (MCC), an aggressive skin cancer that predominantly affects an older population (median age at diagnosis, 75-79 years).¹ Previously reported data revealed the utility of this class of immunotherapeutic agents in unresectable or metastatic disease, including impressive objective response rates (40%60%), often with extended durability.1 The report of the multicenter phase 1/2 CheckMate 358 study (NCT02488759) involving 39 patients conducted over a 3-year time frame was a logical extension of previous efforts with this rare malignancy. Of the 36 patients who subsequently underwent surgery, 47.2% achieved a pathologic complete response, and no patient who reached this clinical state experienced a relapse during follow-up at the time of the report.¹

However, in an accompanying commentary, 2 sarcoma specialists maintained that “we do not believe that CheckMate 358 should define the new standard for all stage II-III MCC cases.” They argued that “the approximately 60% event-free rate at 2 years during the trial does not strike us as unequivocally superior to the 48% RFS [relapse-free survival] at 3 years reported in our historical cohort for stage III disease.”² (It should be noted the authors describe certain clinical scenarios where they might consider the neoadjuvant strategy to be appropriate.)

The issue is not the opinion of these authors regarding why or how they might utilize the neoadjuvant delivery of a checkpoint inhibitor in the management of MCC, but rather the concept of “standard of care.”

What exactly defines “standard of care” in a rare tumor type? Surely one would not rationally suggest that a phase 3 randomized trial is required in a setting where a total of 39 patients with MCC stages ranging from II to IV were recruited over a 3-year period into a multicenter study to obtain the current phase 1/2 trial results.¹ Should the oncology community, and most importantly patients with MCC, have to wait for the reported outcome of such an effort (assuming it was ever initiated and subsequently completed) before the neoadjuvant delivery of an FDA-approved agent in this malignancy could be employed outside the confines of an investigative study?

Unless there is some reason to disbelieve the favorable clinically relevant outcomes of such a multicenter study published in a high-impact peer-reviewed medical/oncology journal, with investigators and institutions acknowledged for both their expertise and the quality of their research, why not simply declare that the approach outlined in the publication can serve as an acceptable standard of care in that well-described clinical setting?

Choosing a Less Toxic Approach

The second manuscript deals with whether it is acceptable to employ a reduced-intensity (“de-escalation”) strategy outside the confines of an investigative setting for patients with human papillomavirus (HPV)–related head and neck cancer.³ The authors state: “Implementation into clinical practice before high-level evidence is available should not be undertaken in this context.” The investigators note that previously reported phase 3 trial efforts attempted unsuccessfully to substitute a major component of the standard-of-care management of nonmetastatic head and neck cancer in individuals with HPV-related (as opposed to smoking-related) disease with the goal of improving the tolerability of therapy while maintaining therapeutic efficacy. For example, they highlight findings from a phase 3 trial that substituted cetuximab (Erbitux) for cisplatin delivered concurrently with radiation therapy; inferior overall survival and local regional control were associated with the use of cetuximab.³

The authors go on to discuss several nonrandomized phase 2 trials with a variety of approaches designed to prevent or minimize the serious long-term adverse effects of the established paradigm for the management of head and neck cancer. Further, they specifically comment on the fact that “these are generally smaller studies that do not include a comparator control arm.” Importantly, they conclude that “although hypothesis generating, without additional data, these studies cannot be used to define treatment paradigms at this point.”

But why not? What is wrong with permitting patients diagnosed with HPV-positive head and neck cancer to learn about the details of a well-designed and conducted single- or multi-institution peer-reviewed report from recognized experts in this clinical arena, with appropriate long-term follow-up of the treated patient population, and to decide for themselves if the limitations of the level of evidence justify the conclusion that they receive the existing, more toxic standard-of-care strategy?

To be clear, phase 2 findings, no matter how intriguing their reported outcome concerning efficacy and toxicity, should not be considered the new single standard of care in the local/regional management of HPV-positive head and neck cancer. However, with essential and thorough discussions with the patient, such efforts could be considered an acceptable standard of care for that individual patient, if this is how that patient elects to have their malignancy managed.

References

1. Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkle cell carcinoma in the CheckMate 358 trial. J Clin Oncol. 2020;38(22):2476-2487. doi:10.1200/JCO.20.002012.
2. Brohl AS, Sondak VK. Neoadjuvant checkpoint inhibitor therapy for Merkel cell carcinoma. J Clin Oncol. 2020;38(22):2471-2475. doi:10.1200/JCO.20.007523.
3. Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a Head and Neck Cancer InterGroup framework for future de-escalation studies. J Clin Oncol. 2020;38(22):2552-2557. doi:10.1200/JCO.20.00056