WMIF MAIN SITE
2027 Event Site
Solid tumor treatment has progressed through successive waves of chemotherapy, targeted therapy, immunotherapy and increasingly precise approaches to previously difficult targets. Aamir Mecklai and Rebecca Heist MD joined Roy Baynes MD, PhD, Ryan Cohlhepp PharmD and Jonathan Lim MD to explore what is changing now.
Baynes described a new phase of precision oncology enabled by better molecules, diagnostics, patient segmentation and trial design. Lim used RAS as an example of a target once considered undruggable that has opened through new chemistry, while emphasizing that the next gains will likely depend heavily on combination therapy.
Cohlhepp described a similar effort to revisit TGF-beta by targeting tumors more precisely and reducing the toxicities that limited earlier approaches. Across the panel, the focus was not simply on discovering more targets, but on improving first-in-class innovation, moving promising therapies into earlier treatment settings and designing trials that make better use of every patient who participates.
Session Focus
Solid tumors have been among the hardest problems in oncology, resistant to durable response and in many cases resistant to treatment at all. The panel’s title asked whether that is changing.
The framing data point was an FDA approval from the previous month: the first broad RAS-targeted molecule approved for pancreatic cancer, which doubled overall survival compared with chemotherapy, against a target considered undruggable for over 40 years.
The Waves of Oncology Development
Roy Baynes MD, PhD, previously chief medical officer and head of development at Merck for about a decade, laid out the sequence: surgery, radiation, chemotherapy, then precision oncology 1.0 with the Gleevecs, then the immuno-oncology revolution, then antibody-drug conjugates, cell therapies, degrader strategies and bispecifics, and now precision oncology 2.0.
His structural observation was that the periodicity of these waves has shortened and they increasingly overlap.
He attributed the acceleration to a concatenation of events rather than any single advance. Chemical matter has improved and large molecules have improved, so the field works with better molecules. Expectations at regulatory, clinical practice and patient levels have risen dramatically, which he framed as good for patients because it forces meaningful advances.
He gave particular credit to the FDA, noting that over the last 20 years, particularly under Rick Pazdur, oncology has acquired the most clearly defined regulatory pathway, clinical pathway, trial pathway and statistical hurdles of any therapeutic area.
On commercial structure he made a counterintuitive point. Fragmentation is not necessarily bad for commercialization, because segmentation often converts an incident population into a prevalent one, which expands the addressable patient population.
What remains hard: identifying, discovering and developing novel first-in-class medicines, and the unavoidable fact that a drug still has to be proven to work in humans through the clinical trial process.
What Actually Broke RAS
Jonathan Lim MD, whose company name reflects its mission to erase RAS-driven cancer, traced the specific scientific steps.
In 2013 Kevan Shokat and colleagues took a novel allosteric approach to a target previously considered undruggable, identifying the switch II pocket and devising chemistry that could covalently bind a cysteine residue there. That combination broke open the field for G12C, particularly for KRAS in the inactive GDP state.
Separately, Greg Verdine and colleagues at Warp Drive Bio worked more than a decade ago on targeting RAS in its active state through cyclophilin A binding and a ternary complex approach, with Revolution Medicines building on that idea.
His own background sits in precision medicine 1.0 at Ignyta, going after rare TRK and ROS1 fusion drivers, which he characterized as relatively low-hanging fruit among strong oncogenic drivers.
Why the field matters: RAS drives about 30 percent of all solid tumors.
His view of what comes next is unambiguous. The name of the game is combination therapy. There is room for better safety and tolerability in RAS-targeting agents generally, room for better efficacy, and particular importance in frontline settings across tumor types. He estimated the combination work could take the rest of his lifetime to prosecute.
Making TGF-beta Safe
Ryan Cohlhepp PharmD described a mechanism worked on for nearly 40 years with limited to no success in oncology, largely because of safety.
His company’s molecule is an EGFR TGF-beta trap. The early view was that the limitation had been getting TGF-beta inhibition to where it needed to be, namely the tumor, so the design uses EGFR, a well-known oncology target, to deliver the drug there.
On the safety side, early programs produced cardiomyopathy and cardiac-related side effects. The molecule was designed to dial that out by targeting the cancer-associated isoforms of TGF-beta specifically.
The historical problem he described is that untargeted molecules required high systemic drug levels to achieve a pharmacodynamic effect at the tumor. Targeting EGFR allows activity at lower exposure, with both durability and depth of response drawing on both components of the molecule.
Asked why durability matters beyond response rate, he identified it as a defining solid tumor challenge. Shrinking a tumor is one thing; doing so durably is another, because the problem is not only tumor cells but the environment. Drug has to penetrate the tumor and sustain its effect, and shifting durability is what the panel believes drives the outcome that matters, overall survival.
Where AI Earns Its Place
Baynes noted AI in drug development is not new. Machine learning was deployed roughly three decades ago in chemistry design and synthesis, which he called a proof point where it absolutely revolutionized medicinal chemistry.
Among design tools he cited AlphaFold and proprietary company tools as genuinely moving novel molecules forward, while noting these custom tools require tremendous attention to detail. At his own company, the single largest group of employees is software engineers.
Applied uses he described as having found their niche, some of them prosaic. First drafts of regulatory documents are often produced by AI, still requiring human supervision but speeding things dramatically. AI is deployed in safety assessment, initial efficacy assessment, and competitive intelligence, which he called hugely dependent on it. Hyperscale AI plays a major role in organizing and distilling medical knowledge.
His verdict: there is a lot of hype about AI, and there are many proof points establishing its value proposition in the industry.
Key Takeaways
1. The first broad RAS-targeted molecule for pancreatic cancer doubled overall survival against a 40-year undruggable target.
2. Development waves are shortening and overlapping, from chemotherapy through IO to precision oncology 2.0.
3. Oncology has the clearest regulatory roadmap of any therapeutic area, built over 20 years.
4. Segmentation expands rather than shrinks addressable populations by converting incident populations into prevalent ones.
5. RAS broke open through allosteric pocket chemistry in the inactive state and ternary complex approaches in the active state.
6. Targeted delivery solved TGF-beta’s safety problem, allowing activity without the cardiac toxicity of systemic exposure.
7. Durability rather than response rate is the metric that translates into overall survival in solid tumors.
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