Role of MPR as an Early Signal for Efficacy in Neoadjuvant Studies

In this issue of Clinical Cancer Research, Cascone and colleagues assess the efficacy and safety of nintedanib with neoadjuvant chemotherapy in patients with resectable non–small cell lung cancer (NSCLC) and use major pathologic response (MPR) as their surrogate endpoint of clinical efficacy (1). Clinical trials for early-stage lung cancer have largely been dominated by adjuvant therapy trials; however, these trials can take years to accrue and for data to mature. The rapid pace at which new drugs are developed and in which the standard of care for treatment of NSCLC is changing makes the results of many of these trials obsolete by the time they are published. Neoadjuvant clinical trials offer the advantage of being able to assess the immediate impact of novel therapeutic approaches on the tumor; however, overall survival and disease-free survival have remained the gold standard endpoints for determining efficacy. The challenge of these endpoints is the prolonged time to read-out in early-stage patients, which leads to significant delays in efficacy assessment and thus delays in development of new treatment approaches (Fig. 1). Trials that utilize traditional endpoints can take upwards of 10 years for the data to mature, while trials that specify MPR as the primary endpoint can provide efficacy data within a few weeks to months of completion of enrollment. This has become particularly relevant with the development of effective targeted and immunotherapies, which have led to significant increases in survival for patients with metastatic NSCLC (2). Despite the significant advances in systemic therapies in the metastatic setting, and resulting survival benefit, utilization of these therapies in early-stage disease is lagging. This has left us with minimal improvement in recurrence-free survival for early-stage patients. Fortunately, multiple clinical trials are underway to utilize these newer therapeutic approaches in early-stage, resectable disease.

Cascone and colleagues evaluated the efficacy and safety of nintedanib, a triple angiokinase inhibitor targeting VEGF, PDGF, and FGF pathways, in combination with platinum doublet by incorporating MPR as the primary endpoint of response assessment and performed an exploratory analysis of immune markers and their correlation to outcomes (1). They used a standard 3+3 run-in in combination with cisplatin and docetaxel infusions every 21 days for up to 3 cycles in patients with early-stage surgically resectable NSCLC. The expansion phase included an additional priming phase of nintedanib with the goal of priming the tumor vasculature to improve cancer cell exposure to chemotherapy. Across all patients, they observed an MPR rate of 9.5% (2/21). This MPR rate was lower than the historical rate of approximately 15%–22% with chemotherapy and 17%–83% in trials of immunotherapy monotherapy or combination therapy (1, 3). At the interim analysis, the trial was closed due to lack of efficacy.

Although this was a negative study, it is important in that it demonstrates the value of utilizing MPR to determine efficacy early in the development of new therapies. In addition, it speaks to the need to develop metrics for evaluating efficacy in a real-world timeline that will help improve patient care on a timeline that is more in line with the pace of scientific discovery.

Prior studies of neoadjuvant chemotherapy in unselected, but resectable, NSCLC have demonstrated that patients whose tumors showed 10% or less viable tumor have significantly improved survival (3). The use of 10% as the cutoff has become standard based on evaluation of the resection specimens of 192 patients in which the percentage of viable tumor cells was a significant predictor of survival in patients with NSCLC who received neoadjuvant chemotherapy and demonstrated that for every 1% increase in viable tumor, the HR for long-term survival increased by 0.01 (4). The study also evaluated survival based on grouped categories and determined that compared with patients with ≤10% viable tumors that all other groups had an increased HR. Given these findings, 10% has become a standard value of comparison. One of the significant challenges of this measure is that it is both subject to variation in tumor bed as well as variation in pathologic interpretation, thus it is unlikely that additional granularity will be feasible. Many clinical trials have begun to incorporate MPR into determination of efficacy in the neoadjuvant setting (3). In breast cancer, there has been strong adoption of this approach. In 2013, pertuzumab became the first drug to receive FDA approval in breast cancer based on its pathologic compete response rate (5). In lung cancer, there are several trial utilizing immunotherapies such as IMpower030 (NCT03456063) and CANOPY-N (NCT03968419) that are utilizing MPR as their primary endpoint. Cascone and colleagues describe, in detail, several additional recent studies (1, 6).

In addition to assessing MPR, the authors also explore immune biomarkers of response. Although the authors acknowledge the small numbers and limited interpretations that can be drawn from this data, they showed compelling data that increases in the immune cell are associated with improved patient outcomes. this is a critically important area for continued development. Many groups have demonstrated significant changes in the TME in response to systemic treatment. Development of strategies for how to utilize this information in clinical decision making will be paramount to improve patient care.

Neoadjuavant trials with targeted therapies are also incorporating surrogate endpoints, such as MPR, to facilitate earlier determination of effective therapy. Tissue obtained from surgical specimens after targeted therapy treatment can serve as an invaluable resource to better understand mechanisms of disease persistence and resistance, which can drive the development of additional neoadjuvant therapy trials that can quickly assess the potential of novel combination therapy approaches. Two such trials are underway: (i) neoadjuvant osimertinib in patients with early-stage EGFR-mutated NSCLC (NCT03433469) and (ii) neoadjuvant crizotinib in patients with early-stage NSCLC with ALK, ROS1, or MET exon 14 alterations (NCT03088930). We predict that these studies will serve as the foundation for future combination therapy trials aimed at increasing the efficacy of these therapies, leading to improved MPR and potentially complete pathologic responses. Highly effective combination therapies identified through this approach could then be tested as novel first-line therapies for patients with advanced stage disease. These studies demonstrate a sea change in the approach to clinical trials for early-stage NSCLC, which may allow for more rapid testing of new therapeutic approaches analogous to the I-SPY trial series for breast cancer (7).

C.M. Blakely is a paid consultant for Revolution Medicines and Foundation Medicine, and reports receiving commercial research grants from Novartis, AstraZeneca, Takeda, Mirati, Spectrum, and MedImmune. C. E. McCoach is a paid consultant for Genentech and Guardant Health, reports receiving commercial research grants from Revolution Medicines, speakers bureau honoraria from Novartis, and is an unpaid consultant/advisory board member for Takeda and Eli Lilly. No other potential conflicts of interest were disclosed.

This work was funded by grants from AstraZeneca, Novartis, Takeda, Mirati, Spectrum, MedImmune, and Roche.