Vanderbilt-Ingram Cancer Center Nashville, TN

Current Standard of Care: Are Outcomes Satisfactory?

Neoadjuvant chemotherapy with or without radiation has become the preferred treatment in patients with resectable stage IIIA non—small cell lung cancer (NSCLC).

 However, results from studies have not shown a similar survival benefit for patients with early-stage (I or II) NSCLC who are candidates for upfront resection.

This may be changing with the introduction of neoadjuvant immunotherapy, as described in the plenary presentation “Immunotherapy Combinations: The New Frontline in Lung Cancer” at the 2018 American Association for Cancer Research meeting and in a study by Forde et al published in the 

Neoadjuvant Nivolumab Improves Major Pathologic Response Rate

The multidisciplinary interest in improving the standard of care for patients with surgically resectable NSCLC stems from higher-than-desired local and systemic recurrence rates after resection1 and low 5-year survival.3 Improvement in outcomes for these patients is a major need.

In their recent publication, Forde et al demonstrated an impressive major pathologic response in 45% (9 of 20) of patients treated with 2 preoperative doses of nivolumab (Opdivo) with no delays in surgical resection.4 Major pathologic response is defined as <10% viable residual tumor at the time of resection. In the study, a major pathologic response was identified in 6 patients with adenocarcinoma, 2 patients with squamous cell carcinoma, and 1 patient with pleomorphic carcinoma. By stage, these were 2 patients with stage I disease, 5 patients with stage II disease, and 2 patients with stage IIIA disease.

Does Major Pathologic Response Really Matter?

Interestingly, of the 9 patients with a major pathologic response, only 2 had a partial response on preoperative imaging, which calls into question the reliability of imaging as a marker for pathologic response to neoadjuvant nivolumab.

Many studies use “major pathologic response” as a surrogate endpoint. But is this clinically meaningful?

Although this endpoint has not been fully evaluated in the context of neoadjuvant immunotherapy, it has been well defined for neoadjuvant chemotherapy administered to patients with resectable NSCLC.

 Results from neoadjuvant chemotherapy clinical trials with populations analogous to those in the pilot trial by Forde et al have shown that rates of major pathologic response correlate strongly with overall survival (OS).

 This finding is not unique to NSCLC, as rates of pathologic response correlate with OS in other malignancies, such as neoadjuvant chemotherapy in patients with breast cancer.

Putting the pilot trial results in the context of resectable cancer, major pathologic response seems to be establishing itself as a good surrogate and predictor of survival in patients with NSCLC.

Most studies evaluating the efficacy of neoadjuvant chemotherapy in patients with resectable NSCLC reported a pathologic complete response rate of 0% to 20%,

 with the highest reported response rate in the literature being 27% (in 11 of 41 patients) after 3 doses of neoadjuvant bevacizumab.

In the historical context of neoadjuvant chemotherapy, the major pathologic response rate of 45% achieved by Forde et al is impressive.

Who Benefits Most From Neoadjuvant Immunotherapy?

But many questions remain: Will this continue to be well tolerated? Will it remain as effective in larger groups of patients? Will neoadjuvant nivolumab decrease recurrence rates, and will it decrease the efficacy of immunotherapy in the relapse setting? Will it translate to improved long-term survival?

Although 45% of patients had a major pathologic response, the majority did not. Can response to neoadjuvant immunotherapy be predicted? Forde et al found that there was a positive correlation between pretreatment tumor mutational burden (TMB) and major pathologic response to nivolumab. In addition, TMB performed better than tumor PD-L1 expression as a predictive biomarker in this setting.

 If adjuvant therapy options being studied in patients with resectable NSCLC succeed, initial biopsy TMB may help determine the ideal perioperative timing (preoperative vs postoperative vs both) for immunotherapy treatment.

Biomarkers predictive of treatment efficacy are an essential companion to new therapies; equally important is predicting which patients are likely to suffer adverse events. In this small pilot study, there were few adverse events—the only grade >2 adverse event was 1 instance of grade 3 pneumonia.

The long-term sequelae of patients receiving neoadjuvant immunotherapy are unknown, and although patients who achieve a major pathologic response are likely to fare better than those in historical controls, the prognosis of patients who did not respond to neoadjuvant immunotherapy is not defined.

Does the FDA consider major pathologic response a valid surrogate endpoint? The FDA defines an acceptable surrogate endpoint as one that is “reasonably likely to predict clinical benefit.”

 In the context of neoadjuvant systemic therapy for resectable cancer, pertuzumab (Perjeta) in HER2-positive breast cancer provided a precedent. In 2013, pertuzumab was granted accelerated FDA approval as neoadjuvant therapy in patients with HER2-amplified breast cancer based on pathologic response and the documented correlation between pathologic response and OS in patients with breast cancer.

 This precedent suggests that there is a promising regulatory future for neoadjuvant immunotherapy in patients with resectable NSCLC based on improvements in major pathologic response rates. Whether nivolumab will be the first agent approved in this setting remains unsettled.

Nivolumab monotherapy is not the only immune checkpoint inhibitor being applied in the neoadjuvant setting in patients with resectable NSCLC. Both atezolizumab (Tecentriq) (LCMC3; NCT02927301) and combination nivolumab and ipilimumab (Yervoy) (CheckMate 816; NCT02998528) are in clinical trials as neoadjuvant therapy in patients with resectable NSCLC. The phase II atezolizumab trial began in April 2017, and it will also evaluate TMB as a predictor of response to neoadjuvant immunotherapy. The phase III CheckMate 816 trial started in January 2017 and will enroll 642 patients from North America, South America, Europe, and Asia. Neither of these trials has reported results, but it will be important to compare both efficacy and toxicity among the various emerging neoadjuvant immunotherapy treatment strategies.

The field of neoadjuvant systemic therapy in patients with resectable NSCLC has received a breath of hope for improvement with the publication of the initial data in patients treated with 2 doses of neoadjuvant nivolumab.4 These results will need to be validated in a larger cohort of patients with special attention to perioperative toxicity profiles.

Head-to-head trials comparing neoadjuvant chemotherapy, immunotherapy, and combination chemotherapy plus immunotherapy will be essential in helping to establish neoadjuvant treatment protocols. Despite the research that still needs to be done, the future looks promising for neoadjuvant immunotherapy.

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