Trial Tuesday: Wisdom Of The Masses

Crowds gave us democracy. They also gave us the 2008 housing bubble. So can they really be trusted? The Athenians thought so, when they invented the vote. Google thinks so too, as it uses data from thousands of phones to predict traffic better than any traffic department. On the flip side, you have conspiracy theories, the 2008 housing price bubble, WhatsApp forwards (for our US/UK readers, think hoax email chains from the 2000s).

Which brings us to oncology. At ASCO, the masses are usually right. The attendees, who are typically oncologists or industry insiders who know what matters, are good at predicting what qualifies as practice-changing data. In 2022, Enhertu received a rare standing ovation for its overall survival benefit in HER-2 low breast cancer patients, subsequently becoming standard of care for that group.

This year, Revolution Medicines’s daraxonrasib received a standing ovation from the audience at ASCO. It helped nearly double the overall survival duration, compared to the control arm, in patients with previously treated metastatic pancreatic adenocarcinoma (PDAC) in data presented at the conference.

WHAT HAPPENED

In the global Phase 3 RASolute 302 trial, which enrolled 500 patients with metastatic pancreatic cancer at 59 sites across six countries, patients who had been previously treated with one line of chemotherapy were randomized to daraxonrasib or a second line of chemotherapy.

In the overall study population, daraxonrasib delivered a hazard ratio for death of 0.40, with a median overall survival of 13.2 months compared to 6.7 months with chemotherapy. Patients treated with daraxonrasib also reported significantly delayed deterioration in cancer-related pain, overall global health status, and quality of life compared to those treated with chemotherapy.

The mechanism is worth understanding. Rather than targeting a single mutant form of RAS – the approach that had worked in lung cancer but failed to translate to pancreatic cancer – daraxonrasib is a RAS(ON) multi-selective, tri-complex inhibitor that binds and blocks the active, GTP-bound state of both wild-type and mutant RAS, including the G12, G13, and Q61 variants most commonly found in pancreatic cancer. That breadth is why the survival benefit held across the full trial population, not just the RAS G12 subgroup that formed the primary endpoint. For decades, RAS was considered undruggable, which explains the standing ovation.

WHY YOU SHOULD CARE

The KRAS mutation is present in roughly 90% of pancreatic cancers, and RAS mutations more broadly drive a significant proportion of all solid tumors – including colorectal and lung cancer. What Revolution Medicines has demonstrated in RASolute 302 is not just a drug that works in one indication, but that pan-RAS inhibition can work at the mechanism level.

BMS used ASCO to finally put numbers behind its mezigdomide Phase III win in relapsed/refractory multiple myeloma. The topline hit had already been announced in March.

WHAT HAPPENED

The SUCCESSOR-2 trial compared mezigdomide combined with Kyprolis and dexamethasone against Kyprolis and dexamethasone alone in 479 patients, more than 92% of whom were triple-class exposed and nearly 86% refractory to an anti-CD38 monoclonal antibody. Median PFS in the mezigdomide arm reached 18 months against 8.3 months in the control arm, with an overall response rate of 80.2% versus 53.4% and a complete response rate of 26.7% versus 8.9%. These are the first Phase III results for any CELMoD agent. BMS also presented Phase Ib data for golcadomide – its third CELMoD – combined with Roche's Polivy, rituximab and chemotherapy in relapsed/refractory diffuse large B-cell lymphoma, where complete metabolic response rates reached 69% and 82% at the two dose levels tested, with twelve-month PFS rates of 88% and 96% respectively.

WHY YOU SHOULD CARE

The strategic intent behind the data is explicit. BMS has designed mezigdomide and iberdomide to play differentiated roles: mezigdomide, as the more potent of the two, is positioned for combinations with proteasome inhibitors like Kyprolis and bortezomib in the post-lenalidomide, post-anti-CD38 setting, while iberdomide is the more suitable partner for anti-CD38 monoclonal antibodies like Darzalex and Sarclisa. The SUCCESSOR-1 trial is testing mezigdomide against pomalidomide in earlier relapse, and the EXCALIBER-Maintenance trial is comparing iberdomide to lenalidomide as maintenance after transplant. The FDA approval decision for iberdomide is expected by August 17.

BMS is not running a single drug program. It is running a franchise replacement strategy for a class – IMiDs – that built a multi-billion dollar revenue base and is now facing generic erosion from Revlimid (lenalidomide) biosimilars. Mezigdomide and iberdomide are designed to occupy the same backbone role that lenalidomide and Pomalyst (pomalidomide) held, across the full range of combination settings, with the CELMoD mechanism providing deeper responses in patients already exposed to the drugs they are meant to succeed. If the SUCCESSOR-1 and EXCALIBER-Maintenance readouts hold, BMS will have Phase III data supporting CELMoD use from newly diagnosed maintenance through late relapse.

Taking a quick break from ASCO, let’s talk about the general state of clinical trials.

WHAT HAPPENED

Citeline's Annual Completed Clinical Trials Report tracked 4,364 industry-sponsored studies in 2025, down 11% from 4,903 the prior year. The decline was not evenly distributed. Infectious disease trials collapsed 55%, returning to near pre-pandemic volumes after the COVID-driven surge. Vaccines fell 28%, genitourinary 37%, CNS 15%. The only therapeutic area to grow was metabolic and endocrinology – up just 1.1% – driven by GLP-1 investment, with GLP-1 trials accounting for 73% of completed obesity trials and 59% of completed type 2 diabetes trials. Metabolic displaced CNS from third place in the therapeutic area rankings for the first time. Oncology, the largest area by volume, fell only 3%.

WHY YOU SHOULD CARE

Fewer trials meeting a higher bar is a different problem than it appears. The winnowing is happening at the portfolio level – capital discipline and funding pressure are forcing more selective trial initiation – and the aggregate success rate improvement reflects that selection, not necessarily a step-change in underlying science. The autoimmune surge is the exception worth watching: 83% of the pipeline-status drugs connected to positive pivotal outcomes across the top three therapeutic areas are being developed outside the top 20 pharma firms, including a contingent of Chinese companies whose data will likely support local rather than global filings. That concentration of innovation outside large pharma, in a funding environment that is actively compressing the number of trials that reach completion, is the dynamic that will shape deal flow and licensing activity for the next two years more than any single conference readout.

In the midst of the industry’s busiest cancer conference, Agios quietly dropped data from its tebapivat that showed it failed in lower-risk myelodysplastic syndrome.

WHAT HAPPENED

In an open-label, multicenter, 24-week dose-finding trial evaluating once-daily tebapivat at 10 mg, 15 mg, and 20 mg in 65 patients with LR-MDS and anemia – a heavily pretreated, heterogeneous population – the trial did not meet the company's predefined threshold for advancement. Tebapivat showed "evidence of biological activity," but the lack of sufficient clinical benefit means Agios will not be pursuing the drug in this indication. Agios continues to see significant potential for tebapivat in sickle cell disease, with Phase 2 topline data expected in the second half of 2026.

WHY YOU SHOULD CARE

LR-MDS is a crowded and difficult indication, and pyruvate kinase activation was always a mechanistic argument rather than a proven path. The sickle cell readout in the second half of 2026 is now the only remaining clinical test for tebapivat, and it carries more weight than it would have if the MDS program had survived. Sickle cell disease now represents the molecule's sole remaining clinical pathway.

The standing ovations will be quoted for months; the discontinuations and the missing trials are the ones that move next year's deal sheets.

See you tomorrow.