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: April 2026
I. Primary Interviews
Original interviews conducted for this episode. Quotes attributed to these speakers throughout the script come from these conversations unless otherwise noted.
Greg Carven — Approved podcast interview (2026). Named inventor on the pembrolizumab patent; ran the antibody campaign at Organon Cambridge that produced MK-3475.
Michel Streuli — Approved podcast interview (2026). Head of research at Organon Cambridge after 15 years in tumor immunology at Dana-Farber; the scientist who insisted on running the screening assay in solution.
Roy Baynes — Approved podcast interview (2026). Senior Vice President & Head of Global Clinical Development at Merck Research Laboratories; led Keytruda’s clinical program from 2013 onward.
II. Books
Graeber, Charles. The Breakthrough: Immunotherapy and the Race to Cure Cancer. Twelve, 2018.
III. Key Scientific Publications
Foundational immune-surveillance & checkpoint biology
Stutman, O. “Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice.” Science 183 (1974): 534–536. The flawed nude-mouse experiment that effectively killed the tumor immunology field for two decades.
Shankaran, V. et al. “IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity.” Nature 410 (2001): 1107–1111. Bob Schreiber’s RAG2-knockout experiment — the cancer immunoediting paper that re-opened the field.
Leach, D.R., Krummel, M.F., & Allison, J.P. “Enhancement of antitumor immunity by CTLA-4 blockade.” Science 271 (1996): 1734–1736. Jim Allison’s ‘100-to-zero’ mouse experiment that founded the modern checkpoint-inhibitor era.
Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T. “Induced expression of PD-1 upon programmed cell death.” EMBO Journal 11 (1992): 3887–3895. Tasuku Honjo’s lab discovers PD-1.
Dong, H., Strome, S.E., et al. “Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.” Nature Medicine 8 (2002): 793–800. Lieping Chen’s lab establishes that PD-L1 is upregulated on tumors and shuts down T-cells.
Pivotal pembrolizumab & nivolumab trials
Topalian, S.L., Hodi, F.S., Brahmer, J.R., et al. “Safety, activity, and immune correlates of anti–PD-1 antibody in cancer.” NEJM 366 (2012): 2443–2454. BMS’s landmark Phase 1 readout for nivolumab — the data print that woke Merck up to PD-1.
Brahmer, J.R., Tykodi, S.S., Chow, L.Q., et al. “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.” NEJM 366 (2012): 2455–2465.
Hamid, O., Robert, C., Daud, A., et al. “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.” NEJM 369 (2013): 134–144. First major pembrolizumab clinical readout (KEYNOTE-001 expansion).
Le, D.T., Uram, J.N., Wang, H., et al. “PD-1 blockade in tumors with mismatch-repair deficiency.” NEJM 372 (2015): 2509–2520. The Diaz/Le 41-patient MSI-H trial that produced the first tissue-agnostic FDA approval.
Reck, M., Rodríguez-Abreu, D., Robinson, A.G., et al. “Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.” NEJM 375 (2016): 1823–1833. KEYNOTE-024. The biomarker-enriched first-line lung trial that decided the BMS/Merck war.
Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., et al. “Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.” NEJM 378 (2018): 2078–2092. KEYNOTE-189 — the chemo-combination trial that captured the all-comers first-line market.
Reck, M. et al. “Five-year outcomes with pembrolizumab versus chemotherapy for metastatic NSCLC with PD-L1 TPS ≥50%.” JCO (2021). Long-term KEYNOTE-024 follow-up: 31.9% vs 16.3% five-year OS.
Mechanism of action & checkpoint biology reviews
Chen, L. & Han, X. “Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future.” (review). Lieping Chen’s history-of-the-target review.
Chen, L. “PD-L1 and the dawn of modern cancer immunotherapy.” Nature Medicine (2025). Chen’s retrospective on the discovery and translation of PD-L1.
Chen, L. “Why has immune checkpoint therapy failed in most clinical trials?” (2025). Chen’s argument for why TIGIT, TIM-3, CD47 and the rest of the post-PD-1 graveyard didn’t work.
Sharma, P. & Allison, J.P. “Dissecting the mechanisms of immune checkpoint therapy.” Annual Review of Cancer Biology.
Pardoll, D. “The blockade of immune checkpoints in cancer immunotherapy.” Nature Reviews Cancer. Foundational review of the checkpoint-blockade mechanism.
IV. First-Person Accounts & Executive Interviews
Roger Perlmutter
Nature Reviews Drug Discovery. “An interview with Roger Perlmutter.” (2019). Source for Perlmutter’s “12 axes” comment and the γ-interferon/PD-L1 inflammation insight.
Reed Magazine. “The Discovery: Roger Perlmutter & Eikon.” (2024). Long-form profile covering Merck tenure and post-Merck second act.
Wall Street Journal. “Why Merck Is Betting Big on One Cancer Drug.” (April 15, 2018). Source for the “Whatever other projects you’re working on, you can stop now” quote.
BioPharma Dive. “Merck’s Roger Perlmutter to retire; Dean Li to take over.” (2020).
Roy Baynes
The Conference Forum. “Dr. Roy Baynes on Strategy Development for Keytruda.” (editorial). Background reading for Baynes’s clinical-development philosophy.
Lieping Chen
Chen, L. “PD-L1 and the dawn of modern cancer immunotherapy.” Nature Medicine (2025).
Chen, L. “Why has immune ‘checkpoint’ therapy failed in most clinical trials?” (2025).
Luis Diaz
Ludwig Cancer Research. “The Tumor Targeter — interview with Luis Diaz.” (2019). Source for the Hopkins/Vogelstein hallway-conversation origin story.
Other inventor interviews
V. Regulatory & Clinical
FDA. KEYTRUDA (pembrolizumab) — full prescribing information.
FDA. Approval of pembrolizumab for tissue-agnostic MSI-H/dMMR solid tumors. (May 23, 2017). The first tissue-agnostic FDA approval.
FDA Oncologic Drugs Advisory Committee. PD-L1 cutoffs in upper-GI cancers (full meeting, YouTube). BMS’s argument against narrowing labels; the “0.55 inter-pathologist correlation” data point.
FDA. “FDA Approves Pembrolizumab Subcutaneous Formulation (Keytruda Qlex).”
VI. Corporate Documents & Press Releases
Fierce Pharma. “Keytruda taught Merck how to build a blockbuster — manufacturing the second lightning bolt is easier said than done.” (2024). Manufacturing scale-up and post-Keytruda strategy.
PharmaVoice. “Inside Merck’s oncology cancer drug Keytruda + Daiichi ADC.”
HARMONi-2 — Summit/Akeso ivonescimab data (WCLC 2024 presentation, PDF).
VII. News & Trade Press
[2014] First approval & launch
[2014] Forbes (Matthew Herper). “Cancer Drug Approval Is a Triumph for Merck — What’s Next?” (September 5, 2014). Same-day coverage of the FDA accelerated approval.
[2014] Fierce Pharma. “Merck’s melanoma game-changer Keytruda likely to bolster drug-pricing debate.” Source for the analyst projection that Keytruda would do $1.5B by 2017 (it actually did $5B).
[2015] First commercial year
[2016] The lung cancer fork
[2016] Fierce Pharma. “Opdivo in its sights, Merck’s Keytruda nabs breakthrough tag in 1L lung cancer.” Real-time coverage of the KEYNOTE-024 / CheckMate-026 inflection point.
[2017] Tissue-agnostic approval
[2017] Forbes (David Shaywitz). “The Startling History Behind Merck’s New Cancer Blockbuster.” (July 26, 2017). The single most important secondary source on the Organon-era origin story.
[2017] New York Times. “How Cancer Drug Keytruda Shrinks Tumors.” (June 8, 2017). Coverage of the tissue-agnostic MSI-H approval.
[2018] All-in lung & the IDO graveyard
[2018] Wall Street Journal. “Why Merck Is Betting Big on One Cancer Drug.” (April 15, 2018).
[2018] STAT News (Adam Feuerstein). “Incyte trial failure deals serious blow to immuno-oncology hopes.” (April 6, 2018). Real-time coverage of the epacadostat/Keytruda IDO trial failure.
[2018] Chemical & Engineering News. “Merck, Incyte IDO inhibitor fails in Phase 3.”
[2018] Cancer Discovery (AACR). “Companies Scaling Back IDO1 Inhibitor.”
[2018] BioPharma Dive. “Incyte IDO drug development scaled back.”
[2018] GEN. “Incyte/Merck halt Phase III trial after epacadostat/Keytruda combination fails in melanoma.”
[2020–2022] TIGIT and the post-PD-1 graveyard
[2022] BioPharma Dive. “Roche tiragolumab TIGIT lung cancer trial.”
[2022] Fierce Biotech. “Roche’s TIGIT prospect fails another Phase 3 lung cancer test.”
[2023–2024] CD47 implosion & ten-year retrospectives
[2023] Fierce Biotech. “Gilead gives 4.9B antibody solid-tumor plan unravels.”
[2024] Fierce Biotech. “New EHA data reveal how Gilead’s 4.9B bet on CD47 imploded.”
[2024] BioPharma Dive. “Gilead/Magrolimab discontinue ENHANCE study in MDS.”
[2024] BioPharma Dive. “Cancer immunotherapy decade — Keytruda, Opdivo, PD-1 oncology.” Ten-year retrospective on the PD-1 era.
[2024] Johns Hopkins Medicine. “Immunotherapy: A Game Changer.” (July 2024).
[2024] Drug Hunter. “That Jimmy Carter Drug.” Origin of the public nickname.
[2024] DrugWonder. “Keytruda: the journey of a blockbuster drug from discovery to market dominance.”
[2025] PD-1/VEGF bispecifics, TIGIT post-mortem, subQ launch
[2025] Bloomberg. “Experimental, cheaper treatments — cancer capitalism.” Long-form investigation into Keytruda dosing, pricing, and the off-label landscape.
[2025] Fierce Pharma. “Akeso/Summit PD-1 bispecific crushes Merck Keytruda — new standard in lung cancer?”
[2025] BioPharma Dive. “Summit ivonescimab + chemotherapy lung cancer (HARMONi WCLC).”
[2025] BioPharma Dive. “PD-1/VEGF inhibitors — cancer immunotherapy bispecific startups.”
[2025] Oncology Pipeline (ApexOnco). “5,000 patients later, Roche scraps its TIGIT.”
[2025] Oncology Pipeline (ApexOnco). “Roche reins in TIGIT expectations.”
VIII. PD-L1 Biomarker Heterogeneity
Sources supporting Part Three’s discussion of PD-L1 assay messiness, sampling error, and pathologist concordance.
Munari, E. et al. “PD-L1 expression heterogeneity in non-small-cell lung cancer: defining criteria for harmonization with surgical specimens.” Journal of Thoracic Oncology (2021). 52% discordance between biopsies and surgical resection; sample-size dependent.
Spatial heterogeneity of PD-L1 expression in breast cancer (PubMed 28195880).
Park, Y. et al. “Spatial and temporal heterogeneity of PD-L1 expression in gastric cancer.” Clinical Cancer Research (2020).
IX. Analysis & Commentary
Liang Chang. “Can AI Make Better Decisions Than Humans?” Substack. The “send today’s AI back in time to June 2012” experiment on the BMS vs Merck biomarker fork.
Derek Lowe. “The Keytruda Story.” In the Pipeline (Science).
Matt Pech. “Precision oncology, AI, and commercial viability.” LinkedIn (2025). MFP’s analysis of why imperfect biomarkers are commercially load-bearing.
Matt Pech. “Adoption hurdles for Keytruda Qlex, the subcutaneous formulation.” LinkedIn (2025).
X. Audio & Video
FDA Oncologic Drugs Advisory Committee (ODAC) — PD-L1 cutoffs in upper-GI cancers (full meeting, YouTube). Source for the 0.55 inter-pathologist correlation, BMS’s argument against narrowing labels.
