Assessment of Cancer Therapy Evaluation Program Advocacy and Inclusion Rates of People Living With HIV in Anti-PD1/PDL1 Clinical Trials

Abstract

Importance: Anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD1/PDL1) immune checkpoint blockade (ICB) constitutes the therapeutic backbone for multiple malignant neoplasms. People living with HIV (PLWH) have routinely been excluded from ICB clinical trials, thus inhibiting broad implementation of ICB to PLWH with cancer.

Objective: To evaluate trends in the inclusion of PLWH in ICB cancer clinical trials that have occurred in association with ongoing efforts by the Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, to promote inclusion of PLWH.

Design, setting, and participants: This quality improvement study of ICB letters of intent (LOIs) included anti-PD1/PDL1 agents (nivolumab, pembrolizumab, atezolizumab, and durvalumab) submitted to CTEP that proceeded to approved protocols between January 2014 to May 2019. The setting was ICB clinical trial development and inclusion of underrepresented populations, specifically PLWH. All 97 submitted cancer clinical trial LOIs that included the aforementioned ICB agents were eligible for inclusion. Ten proposals were excluded, of which 3 were designed specifically for PLWH and 7 were LOIs that did not advance to approved protocols within the study period. Statistical analysis was performed from April to September 2020.

Exposures: CTEP advocacy included the requirement for justification of exclusion of PLWH and formal discussion of inclusion criteria during conference calls between CTEP and trial investigators.

Main outcomes and measures: The frequency of inclusion of PLWH in initially submitted LOIs was compared with final approved protocols using descriptive statistics. The probability of inclusion of PLWH in submitted LOIs and approved protocols over time was assessed using logistic regression.

Results: Eighty-seven studies were included, of which 68 (78%) were pilot, phase 1, phase 1/2, or phase 2 studies and 19 (22%) were phase 2/3 or phase 3 studies. Thirty-nine studies (45%) included nivolumab, 23 (26%) included pembrolizumab, 19 (22%) included atezolizumab, and 6 (7%) included durvalumab. At initial LOI stage, 14 of 87 (16%) included PLWH. Following CTEP advocacy efforts, 61 of 87 protocols (70%) included PLWH. Of 36 LOIs to initially exclude PLWH, 24 (67%) included PLWH in final protocols. Among the 25 protocols to exclude PLWH, 21 (84%) were earlier phase studies (pilot to phase 2) and 4 (16%) were later phase studies (phase 2/3 to phase 3). Only 13 of 25 protocols (52%) provided justification for exclusion of PLWH, with safety being the most frequently cited concern (9 of 13 studies). The inclusion of PLWH on submitted LOIs increased over time (odds ratio, 3.38; 95% CI, 1.14-3.91), whereas inclusion on final protocols did not increase over time (odds ratio, 1.80; 95% CI, 0.81-1.59).

Conclusions and relevance: This study identified encouraging trends in the inclusion of PLWH in anti-PD1/PDL1 cancer trials that occurred in the period following the initiation of CTEP advocacy. Work is needed to examine what impact this will have on enrollment of PLWH in such trials. Similar advocacy may help to promote inclusion of other underrepresented populations in cancer clinical trials, including those with organ dysfunction and chronic infections.

Figure.. Inclusion of People Living With HIV (PLWH) in Submitted Anti–Programmed Death 1 and Anti–Programmed Death Ligand 1 (Anti–PD1/PDL1) Letter of Intent (LOI) Proposals and Final Protocols

Panel A shows raw number of studies that included, excluded, or did not specify inclusion of PLWH delineated by LOI and final protocol. Eighty-seven studies were included. Comparison of inclusion of PLWH in submitted LOI and final protocol is delineated by study phase (B) and anti–PD1/PDL1 agent (C). Panel D shows estimated probabilities of explicit inclusion of PLWH in submitted LOIs (obtained using logistic regression modeling) plotted against corresponding dates of LOI submission.