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Neoadjuvant chemoimmunotherapy induces high rate of pathologic response in lung cancer subset
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BARCELONA — Neoadjuvant chemoimmunotherapy with nivolumab induced complete pathologic response at an unprecedented rate among patients with resectable, stage IIIA non-small cell lung cancer, according to findings from the phase 2 NADIM study presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
“At diagnosis, at least 40% of patients [with NSCLC] are diagnosed at an advanced stage, and a third with locally advanced disease,” Mariano Provencio, MD, PhD, head of the medical oncology department at Hospital Universitario Puerta de Hierro-Majadahonda in Madrid, said during an interview with HemOnc Today. “Only 25% to 30% of the NSCLC cases are candidates for curative-intent surgery.”
In his presentation, Provencio noted the strong association between less than 10% residual tumor tissue after neoadjuvant chemotherapy and survival. Patients with between 1% and 10% of residual viable tumor demonstrated an HR for death of 1, which increased to 4.78 (95% CI, 2.06-11.11) for patients with between 71% and 100% of residual tumor.
The single-arm, multicenter exploratory study by Provencio and colleagues included 46 adults (median age, 63 years; 74% men; 54% ECOG performance score of 0) with stage IIIA NSCLC. All participants were current or former smokers, 61% had adenocarcinoma, 83.5% had comorbid conditions, 89.3% had N2 disease and 75.8% had multiple stations.
Researchers assigned patients to receive three cycles of neoadjuvant treatment with nivolumab (Opdivo, Bristol-Myers Squibb), at a dose of 360 mg IV once every 3 weeks, plus chemotherapy with paclitaxel 200 mg/m2 and carboplatin area under the curve 6 via IV every 3 weeks, followed by adjuvant nivolumab for 1 year.
The researchers evaluated the tumors of all patients after completion of neoadjuvant therapy and prior to surgery. Patients underwent surgery during the third or fourth week after day 21 of the third neoadjuvant treatment cycle.
PFS at 24 months served as the study’s primary endpoint. Researchers used objective pathologic response criteria to assess efficacy and the Kaplan-Meier method to approximate PFS and OS curves.
Median follow-up among the intent-to-treat population was 17.1 months.
None of patients withdrew from the study prior to surgery due to progression or toxicity. Forty-one patients underwent surgical resection, and 37 received adjuvant treatment.
Among the 41 patients who underwent resection, 34 (83%; 95% CI, 68-93) achieved major pathologic response, including 24 (59%; 95% CI, 42-74) complete pathologic responses, and seven (17%; 95% CI, 7-32) had residual viable tumor tissue less than 10%.
Among the intent-to-treat population, researchers observed a PFS of 96% (95% CI, 84-99) at 12 months and 81% (95% CI, 61-91) at 18 months. OS in the intent-to-treat population was 98% (95% CI, 85-100) at 12 months and 91% (95% CI, 73-97) at 18 months.
Most treatment-related adverse events during neoadjuvant therapy were grade 1 or grade 2, including fatigue (45.6%), alopecia (34.8%) and nausea (32.6%). Researchers observed three cases of grade 3 to grade 5 treatment-related neutropenia and two cases each of grade 3 to grade 5 febrile neutropenia and peripheral sensory neuropathy.
Twelve patients experienced postsurgical complications, including respiratory infection (n = 5), cardiac arrythmia (n = 4) and air leakage (n = 2).
“The results of treating stage IIIA NSCLC with induction treatment in clinical practice outside the clinical trial show a median survival of 22 months and a 3-year survival rate of 34%,” Provencio told HemOnc Today. “Patients with stage IIIA disease with clinically evident N2 nodal spread have an overall 5-year survival rate of only 10% to 15%. With this treatment, we have 81% PFS at 18 months and 83% major pathologic response and a reduced hazard ratio of death. I think it will be the standard treatment in a few years.” – by Jennifer Byrne
Reference:
Provencio M, et al. Abstract OA13.05. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosures: Provencio reports research grants from and/or consultant roles with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Roche, Takeda and Thermo-Fisher. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Harvey Pass, MD
This is the first mature, phase 2 surgical study of induction checkpoint inhibition with chemotherapy for stage III lung cancer. It’s a very homogenous cohort and immunochemotherapy had response rates approaching 74% in the intent-to-treat population. We had a hint of this from a pilot trial of combination therapy in 27 patients from Columbia University in New York, which showed response rates of approximately 55%, but that included some earlier stage patients. The thoracic surgical community expected the response rates to be higher than usual given the data from previous studies in stage IV disease; however, it is surprising how great the responses in NADIM have been. Now we will await to see if the tail of the curve stays elevated as seen with the nonsurgical checkpoint inhibition trials.
We also need to see the results of ongoing phase 3 neoadjuvant induction immunotherapy trials, including CheckMate and IMpower030. The only problem with these trials is that they’re not confined to stage III, and stage III — especially with mediastinal disease — has been a real problem. Therefore, it’s important to have trials that specifically address this in a randomized situation, ie, checkpoint inhibitors plus chemotherapy induction vs. induction chemotherapy alone. If the NADIM data are validated in those trials, it will truly be practice changing.
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