Maximilian Diehn, MD, PhD

Neoadjuvant immunotherapy is potentially attractive because it addresses micrometastases early in the course of treatment and may improve compliance with systemic therapy, said formal discussant Maximilian Diehn, MD, PhD, of Stanford Cancer Institute, Stanford University School of Medicine, Palo Alto, California. Potential disadvantages of neoadjuvant therapy include delays in surgery, risk of disease progression prior to surgery, potential for increased surgical complications, and overtreatment of patients without micrometastatic disease.

“Major pathologic response after neoadjuvant therapy may be a useful surrogate for survival, but challenges remain. Importantly, it is currently not a validated surrogate endpoint for regulatory approval,” Dr. Diehn said.

“Results of neoadjuvant immunotherapy studies to date, including the two reported at the 2019 ASCO Annual Meeting, show encouraging rates of major pathologic response. The response rates are in line with what we have previously seen with neoadjuvant chemotherapy.Based on this, combining chemotherapy and immunotherapy in the neoadjuvant setting is a natural next step, and some investigators have already reported early results with promising response rates. As in the advanced disease setting, the combination of chemotherapy and immunotherapy may therefore be the approach with the most activity,” he stated.

Further Considerations

“Longer follow-up of these trials and larger studies are needed to fully evaluate this approach as well as whether major pathologic response could be a validated surrogate endpoint for survival. We eagerly await the results of four large randomized studies testing neoadjuvant chemotherapy plus immunotherapy vs chemotherapy alone. However, an important shortcoming is that none of these studies are based on selection of patients using molecular biomarkers. We therefore urgently need more research to identify biomarkers for personalizing neoadjuvant immunotherapy,” Dr. Diehn noted.

In the studies presented at the Annual Meeting, programmed cell death ligand 1 (PD-L1) appears to be associated with major pathologic response, but some patients with PD-L1–negative tumors also had responses. Tumor mutational burden was not correlated with major pathologic response in LCMC3.

“A third biomarker that appears to hold promise is circulating tumor DNA (ctDNA). Data from other studies show that ctDNA after surgery can predict which patients are likely to develop recurrence. Thus, in the future we might be able to use ctDNA to assess response during neoadjuvant therapy; after surgery, ctDNA analysis might identify which patients need adjuvant therapy,” he suggested. ■

DISCLOSURE: Dr. Diehn is a consultant/advisor for AstraZeneca and BioNTech AG; has received research funding from Varian Medical Systems; has patent filings on ctDNA detection and treatment resistance mechanisms assigned to Stanford University; and has received travel expenses from Roche, Varian Medical Systems, and AstraZeneca.