NEW YORK – Investigators from the Targeted Agent and Profiling Utilization Registry (TAPUR) study have shown that palbociclib (Pfizer's Ibrance) shows activity in some non-small cell lung cancer patients with alterations in CDKN2A.
In a paper published in JCO Precision Oncology last week, researchers led by Pam Mangat, associate director of TAPUR at the American Society of Clinical Oncology, wrote that although CDK4/6 inhibitors like palbociclib appear to have "modest antitumor activity" in advanced NSCLC patients, CDKN2A alterations may not be the best predictive marker for identifying those most likely to respond.
The NSCLC cohort Mangat and colleagues discussed in the paper was one of the first TAPUR arms to meet the trial's predefined criteria for clinical activity. Preliminary responses were shared last year at ASCO's annual meeting. TAPUR is a Phase II basket trial launched by ASCO a few years ago to identify new antitumor activity signals of already marketed targeted drugs in molecularly defined subgroups of advanced cancer patients.
Palbociclib is a US Food and Drug Administration-approved CDK inhibitor indicated for HR-positive, HER2-negative breast cancer patients in combination with antihormonal therapy.
TAPUR considered the activity of this drug in NSCLC patients who commonly have either mutations in or loss of CDKN2A. Additionally, CDKN2A alterations are found in 24.5 percent of EGFR-mutated NSCLC.
The CDKN2A-altered NSCLC cohort in TAPUR included 27 heavily pretreated NSCLC patients who were evaluable for response. The disease control rate was 31 percent on palbociclib monotherapy. One patient had a partial response to treatment and six patients had stable disease. The median progression-free survival was 8.1 weeks and the median overall survival was 21.6 weeks.
In the study, next-generation sequencing tests were used to profile patients' tumors and peripheral blood for CDKN2A alterations. The most commonly used test was Foundation Medicine's FoundationOne CDx, followed by Caris Life Sciences' Caris Mi Profile, Guardant Health's Guardant 360, and tests conducted locally at Intermountain Healthcare and the University of Nebraska.
In this cohort, 70 percent of patients had received three or more prior therapies. Of the 21 patients who did not respond to palbociclib, 10 received an immune checkpoint inhibitor immediately before starting palbociclib.
The one patient who had a partial response had a CDKN2A p16INK4a A17fs*26 mutation and no reported alterations in ALK, EGFR, KRAS, and ROS1. This patient received two prior lines of therapy after a right upper lung lobectomy. The most recent treatment the patient progressed on was nivolumab (Bristol Myers Squibb's Opdivo), administered 27 days before starting palbociclib.
Also, three of the six patients with stable disease for more than 16 weeks had received an immune checkpoint inhibitor as their most recent therapy. "Even though each patient had documented disease progression before initiation of palbociclib treatment, a possible delayed antitumor effect of these agents cannot be ruled out," the authors noted.
Mangat and colleagues wrote that while this cohort of CDKN2A-altered NSCLC patients met TAPUR's predefined criteria for clinical activity, another cohort within this same study involving pancreatic and biliary cancer patients with CDKN2A alterations did not.
This raises "the possibility that CDKN2A loss or mutation is not a relevant predictive biomarker for palbociclib activity or that other features of the genomic milieu of the tumor affect the activity of palbociclib in the presence of CDKN2A loss or mutation," the authors wrote. "It is also possible that the genomic profiling results did not reflect the mutational status of the tumor at the time of treatment because archived specimens could have been selected by the treating physicians instead of performing new tumor biopsies."
The authors acknowledged the need for additional research to see if there were other potential biomarkers of drug sensitivity in these patients, such as analyses of whether different types of CDKN2A alterations and coexisting mutations are better predictors of response.
The researchers also noticed that patients with a signal of activity tended to have KRAS-wildtype tumors and argued that studies of palbociclib in patients with KRAS-wildtype NSCLC with CDKN2A alterations might be warranted.
Further, they suggested that the activity of palbociclib and other CDK inhibitors could be boosted by combining them with chemotherapy, radiation, immunotherapy, or tyrosine kinase inhibitors.