Genomic Testing Expands With Evolving Lung Cancer Treatment Paradigm
November 15, 2019 09:37pm
By Fred R. Hirsch, MD, PhD
Findings from 2 studies of patients with operable early-stage non–small cell lung cancer showed preoperative immunotherapy had positive activity and favorable toxicity, according to a presentation at the 2019 ASCO Annual Meeting, and phase III clinical trials are already testing these stratgies.
David J. Kwiatkowski, MD, PhD
Findings from 2 studies of patients with operable early-stage nonsmall cell lung cancer (NSCLC) showed preoperative immunotherapy had positive activity and favorable toxicity, according to a presentation at the 2019 ASCO Annual Meeting, and phase III clinical trials are already testing these stratgies.
Investigators reported that the PD-L1 inhibitor atezolizumab (Tecentriq) induced a major pathological response (MPR) in 19% of patients and a pathologic complete response (pCR) in 5% of patients in the primary efficacy population who went on to complete surgical resection in the Lung Cancer Mutation Consortium (LCMC3) study.1
In the NEOSTAR study, investigators said the combined MPR and pCR rates in the intention-to-treat (ITT) population were 17% among patients who received nivolumab (Opdivo) and 33% in those who took the PD-1 inhibitor plus the CTLA-4 inhibitor ipilimumab (Yervoy).2
Several pilot studies have demonstrated that preoperative immune checkpoint immunotherapy may be effective in early-stage NSCLC, David J. Kwiatkowski, MD, PhD, lead author of the LCMC3 study who is a senior physician at Dana-Farber/Brigham and Women's Cancer Center, said in presenting the LCMC3 data. "Immune checkpoint therapy is included as a standard of care for patients with advanced (metastatic) lung cancer, and this study suggests that it may also have benefit in early-stage, operable lung cancer," he said in a press release.
More than 50% of patients with stage I to III resectable NSCLC relapse and perioperative chemotherapy has been associated with an absolute 5-year overall survival benefit of only 5% versus surgery alone, noted Tina Cascone, MD, PhD, lead author of the NEOSTAR study, during her presentation. Cascone is an assistant professor in the Department of Thoracic Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.
The advantages of administering immune checkpoint inhibitor therapies in the neoadjuvant setting include an opportunity to address micrometastases earlier in the disease process, the potential for increasing patient compliance with systemic therapy, and the use of pCR as an early surrogate for overall survival, according to Maximilian Diehn, MD, PhD, who served as a discussant during the session where the 2 abstracts were presented.3
Nevertheless, there are disadvantages, including a risk of progression prior to surgery, the potential for increased surgical complications, and the danger of overtreatment, said Diehn, an associate professor of radiation oncology at Stanford University in California.
He said additional research is needed to identify the clinical utility of neoadjuvant immunotherapy, including the identification of biomarkers to personalize treatment. He also said that MPR has not been accepted as a validated surrogate for survival in drug registration trials.
Additionally, Diehn said that although the 2 studies presented at the 2019 ASCO Annual Meeting show an impact for neoadjuvant MPR, the rates have been higher in other small trials that have combined immune checkpoint immunotherapy with chemotherapy in this population. He said several ongoing phase III clinical trials testing immunotherapy in this setting include an arm in which checkpoint blockade agents are combined with chemotherapy.
LCMC3 Study Findings
In the ongoing phase II LCMC3 study (NCT02927301), investigators are seeking to recruit 180 patients with stage IB to IIIB NSCLC, including those with T3N2 or T4 tumors by size criteria. Participants receive 2 cycles of atezolizumab prior to surgery and are eligible to receive up to 12 months of the PD-L1 inhibitor postoperatively. The primary endpoint of the study is MPR, defined as ≤10% viable tumor cells at surgical resection.
In all, 101 patients were enrolled in the study as of the September 2018 data cutoff for the interim efficacy analysis. The participants were a median age of 65 years (range, 37-83) and were diagnosed with stage IB (11%), IIA (16%), IIB (28%), IIIA (39%), and IIIB (7%) disease.
Of this group, 95% completed 2 cycles of atezolizumab and 5% had 1 cycle. Ninety patients (89%) were candidates for surgery; of these, 84 patients (83%) completed surgical resection and underwent MPR assessment. Patients who had either progressive disease and did not receive surgery or were unresectable had stage IIIA or IIIB disease, whereas those with stage I and II disease were able to undergo surgical resection, Kwiatkowski noted.
The primary efficacy population comprised the 77 patients who underwent surgery and had no known molecular drivers of disease. In this population, 15 patients (19%; 95% CI, 11%-30%) achieved MPR, 4 (5%) reached pCR, and 38 (49%) had ≥50% pathological regression. pCR is defined as 0% viable tumor cells and pathological regression as a percentage of viable tumor cells. In terms of biomarkers, neither PD-L1 expression nor tumor mutational burden had an impact on MPR or pathological regression. Additionally, there were no significant associations between gene alterations and MPR.
In the safety population, which comprised all patients enrolled in the study, most participants (97%) experienced adverse events (AEs). The rate of serious AEs was 30%, with 5% of patients withdrawing from the study due to toxicities. There were 2 deaths that were deemed to be unrelated to the study treatment; 1 death was attributable to cardiac causes after resection and the other to disease progression.
All-grade treatment-related AEs (TRAEs) included fatigue (20%), infusion-related reaction (11%), and pyrexia (10%). Grade ≥3 TRAEs consisted of pneumonitis (3%) and 1 occurrence each of nasal congestion, decreased lymphocyte count, and anemia (1% each).
The phase III Impower030 study (NCT03456063) is evaluating atezolizumab combined with platinum-based chemotherapy versus placebo plus chemotherapy. The study, which seeks to enroll 374 participants, has primary endpoints of MPR and investigator-assessed event-free survival (EFS).
The phase II NEOSTAR study (NCT03158129) randomized patients with operable stage I to IIIA NSCLC (excluding N3 surgical candidates) to nivolumab at 3 mg/kg on days 1, 15, and 29 of each cycle or nivolumab plus ipilimumab at 1 mg/kg on day 1. Patients then proceeded to surgery within 3 to 6 weeks after the last immunotherapy dose. The primary endpoint of the study is MPR, with a prespecified efficacy boundary of ≥6 MPRs.
The study, which is no longer recruiting patients, randomized 44 patients to treatment: 23 received nivolumab monotherapy and 21 took the combination. Of these patients, 39 underwent curative surgery, including 2 who received surgery off the trial after additional induction therapy. Five patients did not proceed to surgery: 1 patient who received nivolumab monotherapy had a serious AE (grade 3 hypoxia), and 4 in the combination arm due to lack of resectability, high surgical risk, progressive disease, and refusal of surgery (1 instance each).
The participants were a mean age at randomization of 65.6 years (standard deviation, 8.3) and were diagnosed with stage IA (18%), IB (34%), IIA (16%), IIB (11%), and IIIA (20%) disease.
As of May 8, 2019, the cutoff for data analysis, the combined MPR and pCR rate for the 44 patients in the ITT population was 25%, consisting of 18% pCR and 7% MPR. The combined rate was 17% (95% CI, 5%-39%) in the nivolumab arm (n = 23) and 33% (9d% CI, 15%-57%) in the combination arm (n = 21).
In the 37 patients who underwent resection according to the trial protocols, the combined MPR plus pCR rate was 30%, consisting of 22% pCR and 8% MPR. The combined rate among these patients was 19% among those who received nivolumab monotherapy (n = 21) and 44% among those treated with the combination (n = 16).
Additionally, Cascone noted that the immunotherapy combination was associated with increased T-cell infiltration and increased frequencies of tissue resident and effector memory T cells at surgery.
Most TRAEs were of grade 1 or 2 severity. For the nivolumab and combination therapy arms, these included, respectively, fatigue, 35% and 33%; rash acneiform, 26% and 33%; pruritus, 9% and 10%; and diarrhea, 9% and 29%. Grade 3 to 5 TRAEs in the nivolumab arm comprised 1 grade 3 occurrence each of hypermagnesemia and hypoxia; another patient had both grade 3 pneumonitis and grade 5 pneumonia. In the combination arm, there was 1 occurrence each of diarrhea and hyponatremia.
After a median follow-up of 8.4 months, 1 patient in the nivolumab monotherapy arm died of steroid-treated pneumonitis 4.1 months after randomization and 1 patient in the combination group had progressive disease 2 months after starting treatment and died 17 months after randomization.
The role of neoadjuvant nivolumab as a single agent and in combination with ipilimumab is being investigated in the phase III CheckMate-816 study (NCT02998528). The trial, which aims to enroll 350 participants, randomizes patients to platinum doublet chemotherapy with or without nivolumab; a third arm that combined nivolumab plus ipilimumab closed to accrual in December 2018. The primary endpoints of the trial are pCR and EFS.