Posted: March 1, 2019
In the following interview, Jamie E. Chaft, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, discusses new data on induction immunotherapy for patients with resectable NSCLC as well as the recently published summary paper on the IASLC–U.S. Food and Drug Administration (FDA) summit on neoadjuvant therapies.1
Q: What are the implications of induction or neoadjuvant immunotherapy in patients with resectable NSCLC?
A: We now have data from multiple earlyphase studies of neoadjuvant immunotherapy that preoperative immunotherapy is both safe and feasible. These studies have helped alleviate the fears of high rates of pneumonitis from thoracic surgery shortly after a dose of anti–PD-1/– PD-L1 therapy. Although these results are useful, the practical implication of these studies comes from the unanticipated efficacy seen after just two doses of single-agent anti–PD-1/–PD-L1 therapy. This observation has spurred tremendous commitment from industry to move drugs and drug combinations into the neoadjuvant space.
Q: What advantages, if any, does induction therapy offer over “conventional” adjuvant treatment?
A: Induction therapy offers practical advantages of improved tolerability/drug delivery, time for preoperative smoking cessation, and the ability to monitor the efficacy of the drug in vivo, both radiographically during treatment and pathologically after treatment. The resection specimen provides a unique opportunity for systemic evaluation of treatment response and the potential for identification of surrogate markers of much later clinical endpoints.
Q: Is major pathologic response (MPR; < 10% residual viable tumor in the surgical specimen) a reasonable surrogate for long-term benefit? Do you think the FDA will allow this endpoint as a conduit to accelerated approval?
A: The FDA’s previously published position, outlined in the joint IASLC–FDA paper in the Journal of Thoracic Oncology,1 considers accelerated approval based on surrogacy in a caseby-case basis. A provisional surrogate must measure response to the intervention and be reasonably likely to predict clinical benefit. MPR was developed to fill a void in NSCLC, as pathologic complete response (pCR) to chemotherapy is too infrequent. MPR measures the effect of neoadjuvant chemotherapy at a more clinically relevant frequency and has been associated with clinical outcomes. Perhaps as our therapies improve, we will have the opportunity to use pCR. Until then, the systematic study of MPR with collection of later clinical outcomes should be a priority of the lung cancer community with the goal of working with regulatory authorities to bring effective drugs to patients sooner.
Q: What are your thoughts on combining platinum-based chemotherapy with immunotherapy in this setting? Do you think this approach might pose an advantage over neoadjuvant immunotherapy alone?
A: The presented data on the combination of neoadjuvant chemotherapy plus immunotherapy have shown unprecedented pCR and MPR rates, without safety concerns.2 These small studies have garnered great enthusiasm for the study of neoadjuvant immunotherapy and the potential to increase cure rates.
Q: What are your thoughts on the NADIM trial in stage IIIA NSCLC,3 where the MPR rate exceeded 70% and the pCR rate exceeded 50% in patients receiving induction nivolumab, paclitaxel, and carboplatin?
A: The NADIM study showed remarkable rates of pathologic regression in high-risk resectable NSCLC with what was a very tolerable regimen. The pathologic response methodology was not presented with the data; therefore, it is unclear how these numbers would shift with external review. Regardless, the regimen was exceptionally effective. I hope these data will fuel enrollment of the ongoing phase III induction trials.
Q: Which biomarkers are most useful in this setting?
A: We are still learning about predictive biomarkers in this setting. The dataset in the neoadjuvant nivolumab study was incomplete, but tumor mutation burden associated well with pathologic regression. The LCMC3 effort4 with neoadjuvant atezolizumab will provide a very large dataset to evaluate the question of predictive biomarkers for single-agent immunotherapy. We will have to wait and see if any of these hold up when chemotherapy is added to immunotherapy.
Q: The IASLC just released a paper on this subject. What are the two most salient points for daily practice in the paper?
A: The IASLC–FDA summit on neoadjuvant therapies produced a summary paper outlining the discussion of many experts in the field.1 To me, the take-home messages are that neoadjuvant therapy should be a consideration for all patients for whom adjuvant therapy would be appropriate. The ability to monitor the effect of the treatment given against the patient’s tumor aides clinical decision making. Research opportunities and the collaborative potential to define a surrogate in this disease further these considerations. ✦
1. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC. J Thorac Oncol. 2018;13(9):1248-1268.
2. Provencio M, Nadal E, Insa A, et al. OA01.05 Phase II Study of Neo-Adjuvant Chemo/ Immunotherapy for Resectable Stages IIIA Non-Small Cell Lung Cancer- Nadim Study-SLCG. J Thorac Oncol. 2018;13(10 Supplement):S320.
3. Provencio-Pulla M, Nadal-Alforja E, Cobo M, et al. Neoadjuvant chemo/immunotherapy for the treatment of stages IIIA resectable non-small cell lung cancer (NSCLC): A phase II multicenter exploratory study—NADIM study-SLCG. J Thorac Oncol. 2018;36(15):8521.
4. Rusch VW, Chaft JE, Johnson B, et al. Neoadjuvant atezolizumab in resectable nonsmall cell lung cancer (NSCLC): Initial results from a multicenter study (LCMC3). J Thorac Oncol. 2018;36(15):8541.