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The US Food and Drug Administration (FDA) Oncologic Drug Advisory Committee (ODAC) convened on April 30, 2026, to evaluate two applications.
In the morning, the committee weighed the evidence for a new drug application (NDA) for camizestrant in combination with a CDK4/6 inhibitor for adult patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer who develop an ESR1 mutation during first-line endocrine-based therapy. In the afternoon, the committee considered the supplemental NDA for capivasertib in combination with abiraterone for adult patients with metastatic hormone-sensitive prostate cancer (mHSPC) that is PTEN-deficient.
Both applications raised cross-cutting questions for oncology drug development:
- Defining meaningful clinical benefit
- How emerging biomarker technologies can and should guide treatment decisions
- Challenges with the interpretation of patient-reported outcomes (PROs)
Hesitancy for Novel Endpoints and Trial Designs: ctDNA-Guided Treatment Switching
Key Takeaway: Using detection of a circulating tumor DNA (ctDNA) biomarker as a trigger for treatment switching introduces novel trial design challenges, including appropriate biomarker validation. The clinical utility of a biomarker to guide treatment decisions requires evidence that it is predictive of treatment benefit, and not simply prognostic of disease course. Furthermore, questions around the appropriate timing of subsequent intervention and the relevance of endpoints measured from the time of ctDNA biomarker detection rather than radiologic progression will need to be resolved for this paradigm to gain broader regulatory traction.
ODAC Overview: The committee reviewed the camizestrant NDA based on results from the SERENA-6 trial, which employed an innovative design: patients receiving standard-of-care (SOC) first-line endocrine-based therapy were continuously monitored via ctDNA testing, and upon detection of an ESR1 mutation in the ctDNA, were randomized to either continue SOC or switch to camizestrant with a CDK4/6 inhibitor. The trial demonstrated a progression-free survival (PFS) benefit in the camizestrant arm, with PFS2 (time to second progression) also reaching statistical significance. Despite these results, the committee raised substantial concerns on biomarker validation and the acceptability of ctDNA biomarker detection to trigger treatment switching, leading to a 6–3 vote against a favorable benefit-risk profile.
ESR1 mutation emergence in ctDNA has been established as a prognostic biomarker, but the SERENA-6 trial was not designed to demonstrate that it serves as a predictive biomarker. The ideal trial would have also included an arm switching treatment at radiologic progression rather than at ctDNA detection, to isolate the contribution of earlier intervention. Further, PFS was measured from the point of ESR1 mutation detection, not from the original start of treatment or from radiologic progression. This design choice made it difficult to contextualize the observed benefit against the backdrop of typical clinical practice and the absence of crossover at radiologic progression further complicated interpretation.
What It Means for Lung Cancer Drug Development: As non-small cell lung cancer (NSCLC) drug development increasingly targets rare molecular subpopulations, sponsors will likely face similar challenges of establishing that a biomarker is predictive rather than merely identifying a prognostically distinct population. Further, liquid biopsy and ctDNA testing are increasingly used in lung cancer to detect resistance mutations, to monitor molecular residual disease (MRD) after curative-intent therapy, and potentially trigger treatment adaptations. As developers explore ctDNA-guided designs in lung cancer clinical trials, the SERENA-6 experience underscores that simply demonstrating that a ctDNA marker is prognostic is insufficient for regulatory purposes—sponsors will need to demonstrate that acting on that biomarker meaningfully benefits patients.
What LUNGevity’s Doing: LUNGevity continues to support discussions on the appropriate validation and use of early markers of disease, not only as prognostic biomarkers but also as predictive biomarkers capable of serving as surrogate endpoints for long-term clinical benefit. Especially in the early-stage disease setting, where clinical endpoints such as OS require a long study duration, more timely endpoints that reliably predict clinical benefit are needed to improve trial efficiency.
Defining Meaningful Clinical Benefit: Weighing Modest Efficacy Gains Against Safety Concerns with Patient-Reported Outcomes
Key Takeaway: When a treatment demonstrates a modest but statistically significant improvement in a surrogate endpoint without a corresponding definitive OS benefit, the magnitude of PFS improvement and severity of associated toxicities become central to the benefit-risk determination. While ideally PRO data can be leveraged to support claims of a benefit-risk determination, the Agency’s concerns with the unreliability of the data continue to overshadow its use in oncology drug development.
ODAC Overview: The supplemental NDA for capivasertib was based on a trial that demonstrated a modest improvement in radiographic PFS in the PTEN-deficient population. Interim OS results did not show detriment, and a favorable OS trend was noted, though no powered OS analysis was performed.
The committee voted 7–1 in favor of a favorable benefit-risk profile, with one abstention, though the deliberations reflected genuine tension about the strength of the evidence. Several committee members debated whether 7+ months of PFS was meaningful for patients with mHSPC, who progress rapidly and for whom delaying the need for more toxic therapies is a tangible clinical goal. Proponents argued that these patients care about PFS outcomes and that earlier disease control can delay pain and the need for chemotherapy. Critics countered that prior approvals in prostate cancer had demonstrated clearer improvements in both PFS and OS. Further, fatal adverse events were more common in the capivasertib arm than the control arm.
While the sponsor characterized the safety profile as manageable, committee members highlighted the PRO data that showed a subset of patients experienced nearly constant diarrhea, which significantly impacts quality of life. The committee acknowledged the tension between access for patients with limited alternatives and the real burden imposed by this safety profile.
In SERENA-6, PROs showed delayed deterioration in global health status, pain, and emotional functioning in the camizestrant arm. However, the committee questioned the clinical meaningfulness of these findings, noting that the PRO baseline was set at ESR1 mutation detection (an asymptomatic timepoint) rather than at progression, and that the changes from baseline were marginal and not controlled for multiplicity, further calling into question the use of these data to support the benefit-risk profile.
What It Means for Lung Cancer Drug Development: As more treatments are developed for lung cancer, demonstrating that the magnitude of benefit in a small, biomarker-selected, and often heavily pre-treated population justifies the associated toxicities will be critical. The meeting reinforced a recurring regulatory theme that poor prognosis alone does not justify approval of a therapy with modest efficacy and meaningful toxicity. This means that demonstrating clinical meaningfulness through robust PRO data, durable OS trends, and well-defined patient subpopulations remains a high bar regardless of the unmet need in a given indication.
What LUNGevity’s Doing: LUNGevity will convene stakeholders at our upcoming Transforming Clinical Trials Initiative (TCTI) Fall 2026 Regulatory Series to discuss challenges leveraging patient experience data (PED) for decision-making, both in the pre- and post-market settings. The discussion will highlight the largest barriers to collection of PED that meets evidentiary standards for inclusion in labeling, identifying specific use cases in which PROs may be determined to be consistent with labeling to provide additional data for clinicians and patients, and potential avenues for additional transparency on the use of PED. These conversations will further the breadth of work LUNGevity has previously conducted focused on the use of PROs in lung cancer trials.
Companion Diagnostic Test Performance and Operational Challenges
Key Takeaway: The real-world performance and turnaround time of diagnostic tests approved alongside therapies has implications for equitable access and the generalizability of trial results.
ODAC Overview: A substantive portion of the afternoon discussion focused on practical concerns about the companion diagnostic, a PTEN immunohistochemistry (IHC) assay. Questions were raised about turnaround time (approximately 6 hours, with overnight results at reference laboratories), the impacts of specimen age and pre-analytic conditions on test performance, and whether inter-reader reproducibility was sufficient across settings beyond highly specialized centers such as Johns Hopkins. The committee also discussed whether PTEN loss was present consistently throughout the tumor sample, and whether the degree of PTEN loss correlated with treatment benefit.
What It Means for Lung Cancer Drug Development: The committee's discussion of the logistical and operational barriers of biomarker testing, as well as the reliability of results, is particularly timely for lung cancer—where access to timely and accurate biomarker testing is a long-standing concern. Practical questions about assay turnaround time, inter-reader variability, and the impact of sample quality are directly relevant to ensuring that biomarker tests including companion diagnostics approved alongside lung cancer therapies are both accessible to patients and provide reliable results for treatment decision-making.
What LUNGevity’s Doing: LUNGevity is working to elucidate key challenges to biomarker testing, particularly in the context of eligibility determination for clinical trial enrollment. A recent LUNGevity patient/caregiver survey revealed that delays related to test turnaround time can influence a patient’s decision to enroll in a clinical trial. We plan to host a multistakeholder discussion on opportunities to advance regulatory solutions to support flexible biomarker testing for trial enrollment at our upcoming TCTI Fall 2026 Regulatory Series. Through its Precision Medicine Initiatives, LUNGevity also convenes a working group to identify and encourage the uptake of best practices for tissue acquisition and pre-analytics for lung cancer biomarker testing.