419: Assessing Merck and Moderna's mRNA cancer vaccine

Allison DeAngelis, Anna Forrestine, and Elaine Chen introduce an episode recorded around the European Society for Medical Oncology meeting in Spain. Allison and Elaine are in the studio, while Adam and STAT colleague Andrew “Drew” Joseph are reporting from the conference, which drew about 40,000 attendees. The hosts joke that the reporters are enjoying Mediterranean beaches, cocktails, and “my ties” while covering the meeting. The episode’s focus is the major oncology news presented at ESMO, especially detailed results for Merck and Moderna’s personalized mRNA cancer vaccine and new data that could change treatment standards in lung cancer and other tumors. Before the conference discussion, the show runs a sponsor message for Biotech Scorecard, a STAT+ newsletter covering biotech data, deals, companies, and industry figures.

Drew says the most anticipated ESMO data came from the phase 3 study of Moderna’s personalized mRNA cancer vaccine Intismeran, given with Merck’s immunotherapy Keytruda. The trial enrolled patients with melanoma that had already been surgically removed and compared the combination with Keytruda alone, which has been a standard treatment for roughly a decade. The headline result was a 42% reduction in the risk of disease progression. Drew says many doctors who normally treat these postoperative melanoma patients with Keytruda will consider adding the vaccine, but important questions remain. Some physicians are studying whether immunotherapy should be given before surgery, and early results from that approach are also promising; there is not yet a clean comparison showing whether preoperative treatment or adding the vaccine after surgery is better. The result was nevertheless significant because it was the first phase 3 demonstration of strong efficacy for a personalized cancer vaccine, after roughly a century of attempts to develop such treatments. The speakers caution that the result does not prove personalized vaccines will work across all cancers. They may be most effective in tumors already responsive to immunotherapy, and negative studies show they will not work everywhere without the right combinations. Moderna has additional trials underway, including kidney cancer and the much larger test in lung cancer, where Keytruda is dominant and generates much of Merck’s oncology revenue. Moderna CEO Stéphane Bancel told Drew the kidney-cancer data could arrive late this year or early next year.

The hosts broaden the discussion from the melanoma result to what it could mean for cancer treatment. The current study adds Intismeran after surgery to Keytruda, but other studies are moving Keytruda earlier, before surgery. Both strategies may improve outcomes compared with postoperative Keytruda alone, yet doctors still lack direct comparison data to determine which approach is superior. Cost could become a major factor. The hosts expect copycat versions of Keytruda-like drugs to become available at lower prices in a few years, while the personalized vaccine is expected to carry a “hefty price tag.” If earlier immunotherapy produces a similar benefit at lower cost, some physicians and health systems may favor that route over adding an expensive vaccine. The discussion therefore treats the melanoma data as clinically important but not as the final answer on how patients should be treated. Drew also explains the unusual market reaction. An oncology website broke the embargo on the conference data on Thursday, forcing STAT to publish a story that had been scheduled for Saturday; Drew had already largely written it on the flight to Spain. Moderna’s stock fell after the results became public, even though the data were positive. Adam says Moderna had gained about $60 billion in market value since the companies announced in August that the trial succeeded. Investors had therefore priced in a great deal of future success, including possible use in many cancers, despite Moderna having to split revenue with Merck. He describes the decline as a predictable “sell on the news” reaction, not an indictment of the study.

Adam says the vaccine was not necessarily the conference’s most impactful dataset. He points to a study of Amgen’s Imdelltra combined with AstraZeneca’s Imfinzi in extensive-stage small-cell lung cancer, a difficult disease with poor outcomes. The two immunotherapies outperformed Imfinzi alone, reducing the risk of death by 58%. Median survival was 21 months with the combination versus 13 months with Imfinzi alone. The result earned a rare standing ovation, and Adam expects it could become the new standard of care if it receives approval. For him, the study shows that older drugs can find new value in carefully selected patient groups and combinations. The reporters also discuss Roche’s Divarasib in non-small-cell lung cancer with a KRAS G12C mutation. Roche compared it with two older KRAS inhibitors, from Amgen and Bristol Myers Squibb, whose modest efficacy had limited their commercial uptake. Divarasib reduced the risk of death by 44% and the risk of progression by 42%, while also being better tolerated. Doctors at the meeting said it should become the standard treatment in the second-line setting, although competing KRAS inhibitors are coming. The KRAS field is expanding rapidly after Revolution Medicines’ approval of Rasonc—or “ResonQ,” as the hosts correct it—for pancreatic cancer. That drug extended survival in a disease historically treated mainly with chemotherapy. Companies are now pursuing other KRAS mutations, especially G12D, including combinations of G12D inhibitors with chemotherapy intended to improve response rates and durability while reducing toxicity.

Asked whether KRAS inhibitors are a temporary trend or a durable new direction in oncology, Adam says the progress is a major change in treatment for certain cancers, especially pancreatic and lung cancer. Physicians are now debating how to choose among drugs based on both efficacy and side effects, and whether a drug aimed at one specific KRAS mutation is preferable to a broader KRAS approach. The very existence of that debate would have seemed unimaginable a few years earlier, when KRAS was widely considered undruggable. Drew says the approval of Rasonc has “set the race ablaze,” with companies developing inhibitors against multiple members of the KRAS family and testing many combinations. He describes Roche’s Divarasib as a major step for G12C-driven cancers, but notes that its eventual market position will depend on the competitors entering lung cancer. The ESMO data therefore suggest not just one successful drug, but a continuing cycle of improved chemistry, more precise mutation targeting, and combination studies. Adam adds a patient-centered perspective from conversations with pancreatic-cancer specialists. Before Rasonc, chemotherapy was essentially the only available systemic option for many of their patients. Now they have one approved targeted therapy and several more drugs in trials. The physicians, he says, seemed newly energized—after years of feeling left out of the excitement at cancer meetings, pancreatic-cancer doctors and their patients are beginning to benefit directly from the KRAS advances.

At the end of the episode, the hosts announce that Allison DeAngelis is leaving STAT to cover biotech for Bloomberg News, making this her final Read Out Loud episode. The announcement prompts joking references to Allison’s long-running arguments with Adam about “The Great British Baking Show,” including Adam’s claim that she is leaving because she can no longer argue with him about it. The hosts also joke about Bloomberg eventually implanting a “ship” in her brain. Allison says she has loved podcasting with Elaine and Adam over the years. Adam calls working with her a thrill and a joy and suggests she might return as a guest—possibly after scooping STAT on a story. Elaine says she is “slightly terrified” of Allison becoming a competitor but invites her back to sing, prompting another joke about whether Elaine will actually sing. Colleagues then record tributes. Heisen says the show will miss Allison’s conversations with Adam about the baking show. Daphne Zohar, founder and CEO of Seaport Therapeutics, recalls meeting Allison at a networking event and praises her curiosity, humor, willingness to ask hard questions, and balanced reporting. Jason Mast thanks her for welcoming him to STAT and introducing him to the restaurant Din Tai Fung, as well as for her tenacious reporting and sourcing. Former producer Teresa Gaffney calls Allison kind and generous, noting that she helped with stories, friendship, and even moving apartments by finding boxes around Somerville and Cambridge. Allison becomes emotional as the hosts and colleagues say goodbye.