TY - JOUR
T1 - Addressing resistance to PD-1/PD-(L)1 pathway inhibition
T2 - Considerations for combinatorial clinical trial designs
AU - Zhang, Tian
AU - Forde, Patrick M.
AU - Sullivan, Ryan J.
AU - Sharon, Elad
AU - Barksdale, Elizabeth
AU - Selig, Wendy
AU - Ebbinghaus, Scot
AU - Fusaro, Gina
AU - Gunenc, Damla
AU - Battle, Dena
AU - Burns, Robyn
AU - Hurlbert, Marc S.
AU - Stewart, Mark
AU - Atkins, Michael B.
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023/5/3
Y1 - 2023/5/3
N2 - With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.
AB - With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.
KW - immunotherapy
KW - kidney neoplasms
KW - lung neoplasms
KW - melanoma
KW - tumor escape
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U2 - 10.1136/jitc-2022-006555
DO - 10.1136/jitc-2022-006555
M3 - Article
C2 - 37137552
AN - SCOPUS:85159395181
SN - 2051-1426
VL - 11
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 5
M1 - e006555
ER -