The recent approval of pembrolizumab as second-line treatment for any solid tumor with high-level microsatellite instability or mismatch repair deficiency agnostic of tissue and origin1 has shattered a glass ceiling for immune checkpoint inhibitors. No longer bound to a specific cancer diagnosis but rather a biomarker, pembrolizumab has heightened a burgeoning optimism towards the drug class. Yet how these agents should carve out additional indications is subject to fierce debate. While we know immune checkpoint inhibitors may not be A-list actors ready to carry first-line treatment plans on their own across all tumor types, can we enable these agents by carefully crafting a supporting cast and distribution strategy? Should they be reserved for leading roles only in certain niche markets defined by biomarkers? Or are they most successful as back-up when the show must go on and the best option is not available?