Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.

Sunitinib in Patients with Metastatic Colorectal Cancer (mCRC) with FLT-3 Amplification: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

BACKGROUND: TAPUR is a pragmatic, phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Sunitinib is an oral multikinase inhibitor of FMS-like tyrosine kinase-3 (FLT-3), among other targets. Results from a cohort of patients with metastatic colorectal cancer (mCRC) with FLT-3 amplification treated with sunitinib are reported. OBJECTIVE: This study aimed to investigate whether patients with mCRC with FLT-3 amplification would be responsive to sunitinib, an oral multikinase inhibitor. METHODS: Eligible patients received a standard sunitinib dose of 50 mg orally for 4 weeks followed by 2 weeks off. Simon's two-stage design was used with the primary study endpoint of objective response (OR) or stable disease (SD) at 16 weeks based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints were progression-free survival, overall survival, and safety. RESULTS: Ten patients were enrolled from November 2016 to April 2018. All patients had mCRC with FLT-3 amplification. No ORs were observed. Although two patients had SD at 16 weeks, one died because of disease progression shortly thereafter and the cohort was closed. A single grade 3 adverse event of diarrhea was reported as possibly related to sunitinib. CONCLUSIONS: Monotherapy with sunitinib does not have clinical activity in patients with mCRC with FLT-3 amplification and should not be prescribed for off-label use. Other treatments should be considered for these patients, including treatments offered in clinical trials. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February 2016).

Palbociclib in Patients With Non-Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non-small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS: Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon's two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION: Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.

Palbociclib in Patients With Pancreatic and Biliary Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study identifies signals of antitumor activity of commercially available targeted agents in patients with advanced cancers that harbor genomic alterations known as drug targets. In this article, data from two cohorts of patients with pancreatic and biliary cancers with CDKN2A loss or mutation treated with palbociclib are reported. METHODS: Eligible patients age 12 years and older with advanced measurable or evaluable solid tumors are provided treatment according to protocol-specified genomic matching rules. The primary study end point is objective response or stable disease of at least 16 weeks duration. For each cohort, a Simon two-stage design was used with a futility evaluation after 10 patients. Secondary end points include safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Between July 2016 and November 2017, 12 and 10 patients with pancreatic and biliary cancer, respectively, with CDKN2A loss or mutation were treated with palbociclib. Twenty evaluable patients (10 per cohort) were included in the analysis. No patients had objective response or stable disease at 16 weeks, and both cohorts were closed. Two patients, neither with response, were determined to be ineligible. All patients were evaluated for safety, PFS, and OS. A median PFS of 7.2 weeks (90% CI, 4.0 to 8.0 weeks) and median OS of 12.4 weeks (90% CI, 4.7 to 23.1 weeks) were observed in the pancreatic cohort. A median PFS of 7.3 weeks (90% CI, 3.9 to 7.9 weeks) and median OS of 11.1 weeks (90% CI, 5.1 to 14.0 weeks) were observed in the biliary cohort. No unexpected toxicities were observed. CONCLUSION: Palbociclib monotherapy does not have clinical activity in patients with advanced pancreatic or biliary cancers with CDKN2A loss or mutation. Toxicity is similar to reported experience with palbociclib in other tumor types.

Insurance denials for cancer clinical trial participation after the Affordable Care Act mandate.

BACKGROUND: The Affordable Care Act (ACA) includes a mandate requiring most private health insurers to cover routine patient care costs for cancer clinical trial participation; however, the impact of this provision on cancer centers' efforts to accrue patients to clinical trials has not been well described. METHODS: First, members of cancer research centers and community-based institutions (n = 252) were surveyed to assess the status of insurance denials, and then, a focused survey (n = 77) collected denial details. Univariate and multivariate analyses were used to examine associations between the receipt of denials and site characteristics. RESULTS: Overall, 62.7% of the initial survey respondents reported at least 1 insurance denial during 2014. Sites using a precertification process were 3.04 times more likely to experience denials (95% confidence interval, 1.55-5.99; P ≤ .001), and similar rates of denials were reported from sites located in states with preexisting clinical trial coverage laws versus states without them (82.3% vs 85.1%; χ = 50.7; P ≤ .001). Among the focused survey sites, academic centers reported denials more often than community sites (71.4% vs 46.4%). The failure of plans to cover trial participation was cited as the most common reason provided for denials (n = 33 [80.5%]), with nearly 80% of sites (n = 61) not receiving a coverage response from the insurer within 72 hours. CONCLUSIONS: Despite the ACA's mandate for most insurers to cover routine care costs for cancer clinical trial participation, denials and delays continue. Denials may continue because some insurers remain exempt from the law, or they may signal an implementation failure. Delays in coverage may affect patient participation in trials. Additional efforts to eliminate this barrier will be needed to achieve federal initiatives to double the pace of cancer research over the next 5 years. Future work should assess the law's effectiveness at the patient level to inform these efforts. Cancer 2017;123:2893-900. © 2017 American Cancer Society.