Inside precision oncology’s next chapter with Bill Hinshaw

Novartis veteran and Fore CEO on diagnostics, fragmentation, and the operational realities behind today’s precision paradigm: The BioCentury Show

When Bill Hinshaw looks back across the arc of his career — from his early days helping to commercialize Gleevec to his present role leading Fore Biotherapeutics — he sees a precision oncology field transformed by technological ambition, yet still grappling with many of the structural challenges that defined its beginnings, now compounded by the difficulty of positioning therapies within an ever more complex treatment landscape.

Gleevec proved the power of targeting a genomic driver, but the healthcare system around it was far from ready. “We weren’t able to fulfill the promise as fast as we wanted to until that scaling happened,” Hinshaw told The BioCentury Show — a reminder that even today, precision medicines succeed or fail based not only on their biology but on the infrastructure that enables patients to access them.

Hinshaw joined  Novartis AG (SIX:NOVN; NYSE:NVS) a couple of years after Gleevec’s 2001 approval and spent roughly 14 years at the pharma, ultimately serving as EVP and head of U.S. Oncology. From those years helping scale early targeted therapies to his current role as CEO of Fore Biotherapeutics Inc., he has watched the precision oncology story unfold from the inside — and helped shape parts of it.

Hinshaw sat down with The BioCentury Show to discuss what’s changed, what’s stayed the same, and how he’s applying those lessons to steer Fore’s BRAF-focused program.

Precision progress, persistent challenges

Much has improved since the early days, when precision oncology hinged on obtaining scarce tissue to run a single-gene test, waiting for results, and returning for more tissue if the result was inconclusive. Today, sequential single-gene testing has largely been replaced by broad NGS panels that interrogate dozens of alterations in tissue or blood. However, diagnostic patchiness and turnaround times still influence whether patients receive targeted therapies early enough to make an impact.

Broader testing has also introduced new complexity. As panels identify additional genetic alterations, cancers are increasingly subdivided into ever-smaller molecular niches. That creates a bifurcation: for companies developing next-generation therapies against well-understood tumor drivers, the diagnostic, clinical and regulatory pathway is relatively clear, though still full of operational pitfalls. But small biotechs pursuing newer biology must navigate a very different landscape, often working in areas that are not yet consistently captured in standard panels and where the clinical significance of a variant may not be well-established.

“Now we’re trying to segment and segment,” Hinshaw noted, but “it has to matter; that driver has to be a key driver of the disease or the resistance.” Determining which alterations have genuine causal relevance, and building the diagnostic and therapeutic frameworks to address them, remain formidable challenges.

And while a growing ecosystem of third-party diagnostic partners can help companies develop the necessary companion tests, Hinshaw cautioned that this doesn’t make the path easy for small biotechs, which still must coordinate assay development, generate supporting datasets, and shoulder the technical and regulatory risk.

Through that bifurcation lens, Fore sits squarely in the first camp, developing a next-generation therapy in a well-characterized pathway — one that Hinshaw knows well. His years overseeing BRAF and MEK programs at Novartis uniquely positioned him to recognize what meaningful differentiation looks like in this space.

Hinshaw believes Fore’s candidate, plixorafenib, can target a wider range of BRAF alterations than earlier-generation agents, thereby broadening the market, and with a safety and tolerability profile that can enable patients to stay on an effective dose of the therapy for much longer, improving outcomes and reducing burdensome side-effect monitoring.

This package of features stems from the molecule’s structure, which makes it highly selective for BRAF over other RAF family members and prevents BRAF dimer formation. The selectivity piece reduces the ocular and cardiovascular risks associated with today’s therapies, while the dimer blocking avoids the paradoxical excess dimerization and downstream MAP kinase pathway signaling that necessitated earlier combinations with MEK inhibitors.

Fore’s development approach illustrates several of the choices precision-medicine companies face, such as how to prioritize indications and efficiently test a therapy in as many priority settings as possible to maximize the drug’s impact. Fore is doing so through a master protocol study. While such frameworks are more complex upfront — requiring coordination to adapt the overarching protocol to the cohort-specific and site-specific documents and workflows — they can ultimately streamline development by allowing multiple tumor-specific cohorts to operate under a single overarching design. 

“The benefit of a master protocol is it’s very efficient,” said Hinsahw. “I can go with our team into a major institution and work across the head and neck group, the CNS group, the lung group, et cetera, to support the overall program.”

Another strategic choice many precision-medicine companies face is how to position a therapy within the real-world treatment sequence. Hinshaw emphasized that efficacy alone is not enough; developers must anticipate how clinicians make decisions across lines of therapy. “Okay, great, you’re treating somebody in second line. What is the clinician needing to do next?” It’s important to get clarity on that question, Hinshaw said, to inform “clinical trial design, inclusion, exclusion criteria, and how you fit in that treatment paradigm.”

If a trial isn’t designed with that broader context in mind, he cautioned, a therapy can end up used in the wrong population or relegated to a narrow corner of practice simply because earlier studies didn’t account for how physicians actually treat patients.

Identifying patients “in real time” and at “the right time” to be brought into the trial for treatment are “important operational or tactical components that need to be built into your protocols,” he said. “Because even though the systems are often supportive, it’s an incredibly complex dynamic for the clinicians and their staff.”

Hinshaw closed the conversation with advice for pharma leaders contemplating a move into biotech. Although an increasingly common career pivot, he warned it requires a clear-eyed view of the differences between the two environments and how they relate to an individual’s personality. You’ve got to “understand your drivers, your motivation and your skillset, and where you show up and work best,” he said, noting that strengths in one setting don’t necessarily translate to the other.

The nature of decision-making is a key difference. “In biotech, it is binary. You have to factor in your financial runway in a different fashion.” And while the talent in biotech is exceptional, he emphasized that “you don’t have all the resources that you have at some of the other companies.” For those prepared for a sharper focus and tighter constraints, he believes the move can offer a level of immediacy and impact that larger organizations rarely afford.

He emphasized that leading a biotech requires making tough strategic decisions early based on the company’s stage, its resources, both human and financial, and the expectations of its investors and board. You have to be “really clean and clear” in communicating that strategy, “while keeping your options open in a structured way,” so the company isn’t boxed into a single path too soon.

Fore is looking ahead to several clinical milestones next year, headlined by top-line data from its lead CNS tumor cohort in the second half, which could form the basis of a submission for accelerated approval. Also coming next year are interim readouts from its BRAF fusion and rare V600 cohorts, which could expand plixorafenib’s reach.