The number of patients exposed to PD -( L) 1 inhibitors in adjuvant, first-line metastatic, second – line metabolic, and refractory treatment settings is rising quickly as a result of the US Food and Drug Administration’s approval of numerous DP – ( L-1 ) 1 inhibitions across dozens of indications. Although some patients will see long-term benefits, many patients either don’t respond clinically or watch their condition worsen after receiving therapy for the first time. Finding therapeutic strategies to overcome resistance and provide clinical benefits for these patients is crucial. The use of PD-1 pathway blockade in melanoma, non-small cell lung cancer( NSCLC ), and renal cell carcinoma( RCC ) has the longest history. As a result, these environments have the broadest clinical experience with resistance. Six non-profit organizations representing patients with these diseases undertook a year-long project in 2021, culminating in an intensive 2-day workshop( involved by academic, industrial, and regulatory participants ) to comprehend the difficulties involved in creating effective treatments for patients who had previously been exposed to anti-PD – ( L ) 1 agents and to provide recommendations for creating clinical trials in this context. With a focus on the subjects 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, this manuscript presents key discussion themes and positions reached through this effort.