Keytruda: How Merck's Pembrolizumab Became the Best-Selling Cancer Drug of All Time

Keytruda is Merck's $31 billion a year PD-1 inhibitor and the best-selling cancer drug of all time. In Episode 3 of Approved, Alex Kesin and Matthew Pech trace the development of pembrolizumab , featuring interviews the scientists who drove the program forward : co-inventors Gregory Carven and Michel Streuli, and former Merck oncology CMO Roy Baynes.

Topics include preclinical PD1 / CTLA-4 checkpoint biology that brought industry attention to the target (Jim Allison's CTLA-4 work and Tasuku Honjo's PD-1 discovery); how pembro started as a failed rheumatoid arthritis antibody program at a Dutch subsidiary of a paint company; the two mega-mergers that nearly killed the program;  the biomarker enrichment trial design behind KEYNOTE-024 that let Merck break BMS's lead in lung cancer;  the 41-patient Johns Hopkins MSI-H trial behind the first tissue-agnostic FDA approval, and the Jimmy Carter melanoma case that brought pembrolizumab to the public conscious. The episode closes on what comes next for Merck: the 2028 patent cliff, the Keytruda QLEX subcutaneous launch, and efforts to find the next blockbuster checkpoint inhibitor, including Summit/Akeso's PD-1 / VEGF bispecific ivonescimab.

This episode is presented by JLL. Featuring Grant Dettmer on biotech real estate strategy.

CHAPTERS

  00:00:00  —  Introduction: The Best-Selling Cancer Drug of All Time

  00:02:15  —  Part One — A Century of Failed Cancer Immunotherapy

  00:04:17  —  T Cells, CD28, and the Two-Signal Model of Immune Activation

  00:06:25  —  Jim Allison's CTLA-4 Discovery and the Path to Yervoy

  00:12:03  —  Tasuku Honjo Discovers PD-1: A Better Brake on T Cells

  00:14:26  —  Lieping Chen and the PD-L1 Tumor Evasion Hypothesis

  00:16:26  —  Part Two — Organon: The Dutch Paint-Company Subsidiary Behind Keytruda

  00:19:48  —  How Michel Streuli Caught the Solid-Phase Screening Artifact

  00:22:09  —  The Accidental Antagonist: From Rheumatoid Arthritis Drug to Cancer Drug

  00:26:34  —  Sponsor: Grant Detmer (JLL) on Biotech Real Estate Strategy

  00:30:01  —  Russian Nesting-Doll M&A: Schering-Plough Acquires Organon (2007)

  00:31:43  —  The $41 Billion Merck–Schering-Plough Mega-Merger of 2009

  00:34:58  —  Corporate Guerrilla Warfare: Four Scrappy Stunts That Saved Pembrolizumab

  00:39:32  —  BioNovion's Spite-Company Bid to Buy Pembro Back

  00:42:10  —  BMS at ASCO 2010: The Data Print That Revived Merck's PD-1 Program

  00:45:55  —  Part Three — Roger Perlmutter Joins a Bleeding Merck (April 2013)

  00:50:48  —  "Let Me Manage the Tigers": Ken Frazier Backs the All-In Bet on Pembrolizumab

  00:55:22  —  Breakthrough Therapy Designation and Eric Rubin's Adaptive Trial Design

  00:58:25  —  Keytruda's 2014 FDA Approval Erases BMS's Four-Year Lead

  01:00:24  —  The Lung Cancer Battlefield and the PD-L1 Biomarker Bet

  01:02:19  —  BMS vs. Merck: All-Comers vs. Biomarker-Enriched Trial Strategy

  01:08:18  —  KEYNOTE-024 vs. CheckMate-026: The Trial That Decided the Category

  01:12:03  —  Luis Diaz, MSI-H, and the Failed BMS Trial That Made Keytruda Tissue-Agnostic

  01:17:18  —  KEYNOTE-189: Perlmutter's Bet on Combining Keytruda with Chemotherapy

  01:19:21  —  Merck's Clinical Development Playbook: Basket Trials, Backwards March, External Collabs

  01:25:29  —  Part Four — The IO Graveyard: TIGIT, CD47, IDO1, LAG-3 and Tens of Billions Incinerated

  01:30:23  —  Why PD-1 Was the Only Checkpoint That Worked (Lieping Chen Revisited)

  01:33:32  —  Part Five — Inside the Best-Selling Drug of All Time

  01:37:03  —  "Build a Wall, High and Wide": Merck’s Commercial Strategy for Keytruda

  01:43:44  —  Part Six — The Patent Cliff and Loss of Exclusivity in Pharma

  01:45:35  —  Keytruda QLEX (Subcutaneous) and the Lifecycle Management Playbook

  01:50:23  —  PD-1/VEGF Bispecifics: Ivonescimab, Summit Therapeutics, and the Next Threat

  01:55:31  —  The Scorecard: Patient, Academic, and Financial Impact

  02:01:19  —  Who Actually Profited: Merck vs. Organon vs. the Scientists Who Built the Drug

  02:05:54  —  Epilogue: The Jimmy Carter Drug

Sources

Last updated: May 2026

Essential reading

• Shaywitz, David. "The Startling History Behind Merck's New Cancer Blockbuster." Forbes, Jul 26, 2017. The definitive Organon-era origin story.
• Loftus, Peter. "Why Merck Is Betting Big on One Cancer Drug." WSJ, Apr 15, 2018. Source for Perlmutter's "whatever other projects you're working on, you can stop now."
• Lowe, Derek. "The Keytruda Story." In the Pipeline.
• Graeber, Charles. The Breakthrough. Twelve, 2018.

Primary interviews

Greg Carven, Michel Streuli, Roy Baynes — Approved podcast interviews (2026). Quotes attributed to these speakers come from these conversations unless otherwise noted.

Foundational science

• Stutman. "Tumor development in athymic-nude mice." Science (1974). The flawed experiment that killed tumor immunology for two decades.
• Shankaran et al. "IFNγ and lymphocytes prevent primary tumour development." Nature (2001). Schreiber's cancer immunoediting paper.
• Leach, Krummel & Allison. "Antitumor immunity by CTLA-4 blockade." Science (1996). Allison's '100-to-zero' experiment.
• Ishida, Agata, Shibahara & Honjo. "Induced expression of PD-1." EMBO J (1992). Honjo discovers PD-1.
• Dong, Strome et al. "B7-H1 promotes T-cell apoptosis." Nat Med (2002). Lieping Chen's PD-L1 immune-evasion paper.

Pivotal trials

• Topalian et al. "Anti-PD-1 ...