Our Perspective on Regulatory News
Lung Cancer Not on the Agenda?
How the May 2025 Oncologic Drugs Advisory Committee (ODAC) Meeting Could Still Impact Future Lung Cancer Clinical Trials
The US Food and Drug Administration (FDA) Oncologic Drug Advisory Committee (ODAC) convened on May 20 and 21 to weigh in on four different regimens across a variety of cancer treatment modalities and indications. These discussions generated important considerations for developers of drugs and biologics for treatment indications across the oncology landscape, including in lung cancer. Read on for main themes, what it means for the lung cancer community, and how LUNGevity is addressing these considerations.
Overall Themes and Key Takeaways Impacting Lung Cancer Drug Development
- Enrolling a well-defined patient population: Trials should enroll appropriate and clearly defined patient populations to minimize the risk of overtreatment, particularly for targeted treatment regimens
- US representativeness of clinical trial populations: Trials must enroll adequately representative populations to ensure the applicability of trial results to US patients
- Variable global uptake of subsequent therapies: Inconsistent regional uptake of therapies after the investigational treatment can significantly impact efficacy analyses
- Single-arm clinical trials: Randomized controlled trials (RCTs) may be expected particularly when it may be difficult to adequately interpret certain clinical endpoints
Enrolling a Well-Defined Patient Population
Key Takeaway
Trials should enroll appropriate and clearly defined patient populations to minimize the risk of overtreatment, particularly for targeted treatment regimens.
ODAC Overview
The committee considered Janssen’s AQUILA trial assessing the efficacy of the anti-CD38 antibody daratumumab/hyaluronidase in treating adult patients with high-risk smoldering multiple myeloma (HR-SMM), a premalignant and typically asymptomatic disease. While the treatment showed a five-year progression-free survival (PFS) advantage and a reduced risk of death, there was concern on how the trial protocol defined HR-SMM as after trial initiation, diagnostic criteria were updated. When the updated criteria were retroactively applied to the AQUILA patient population, less than half of the participants were categorized HR-SMM, raising concerns around applicability to the newly defined HR-SMM population. Ultimately, a majority of six voted affirmatively that the AQUILA trial results provided sufficient evidence of a favorable benefit-risk profile, with two members against, citing concerns of potential overtreatment and high-grade toxicities.
Pfizer’s TALAPRO-2 trial intended to generate evidence to support expanding the indication for its PARP inhibitor talazoparib, which was recently approved in combination with enzalutamide to treat patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), to include such patients lacking the HRR mutation. While the TALAPRO-2 trial demonstrated a radiographic PFS (rPFS) and overall survival (OS) advantage, the FDA argued that patients’ HRR mutation status was not adequately characterized before randomization and expressed concerns with how participants were categorized. Nonclinical data were used to support a biological rationale for use of the treatment in HRR-negative patients and post hoc analyses showed an attenuated improvement in rPFS and OS in the non-HRR mutated subgroup. Ultimately, the committee agreed on the need to formally evaluate efficacy in the biomarker-negative population. The committee also raised concerns about overtreatment, particularly as a majority of patients with mCRPC do not harbor the HRR mutation.
What It Means for Lung Cancer Drug Development
This is a particularly important consideration for drug development in lung cancer, as new targeted therapies continue to be developed for more and more distinct molecular subtypes. Identifying the appropriate patient population is important, not only to optimize the assessment of a treatment’s efficacy, but also to minimize risk of overtreatment and toxicities experienced by trial participants and ultimately by the intended patient population once the regimen is approved. Concerns about overtreatment are also particularly relevant in lung cancer as drug development continues to shift into earlier disease stages. Last July, the ODAC voted unanimously in favor of a proposed requirement that trial design proposals for perioperative regimens for resectable NSCLC include adequate assessment of the contribution of each treatment phase, given concerns of unnecessary toxicity should only one phase be necessary to provide clinical benefit.
What LUNGevity’s Doing
The ODAC session chair stated his belief that no trials should be conducted with unknown biomarker status, especially given the growing pace, sensitivity, and affordability of biomarker testing. In alignment with this, LUNGevity’s Precision Medicine Initiatives aim to advance the adoption and awareness of comprehensive biomarker testing and to support biomarker testing guidelines to ensure patients eligible for targeted therapies or for clinical trials investigating novel targeted treatments are appropriately identified. As for addressing concerns about overtreatment in the early lung cancer space, LUNGevity is actively working with stakeholders to develop innovative trial designs that adequately assess contribution of phase while minimizing trial complexity.
US Representativeness of Clinical Trial Populations
Key Takeaway
Clinical trials must enroll adequately representative populations to ensure the applicability of trial results to US patients.
ODAC Overview
The committee assessed Genentech’s multiregional clinical trial (MRCT) STARGLO supporting a label expansion for the company’s CD20/CD3 bispecific antibody glofitamab as a second-line treatment in diffuse large B-cell lymphoma (DLBCL). Though STARGLO met its primary endpoint, demonstrating a significant OS improvement across the full trial population, FDA expressed concern about the small percentage of US patients enrolled (9% of the intent-to-treat population). Furthermore, the trial data revealed variable treatment effects across subgroups, with hazard ratios (HRs) greater than one for patients identifying as White race, enrolled in Europe, and enrolled in North America. The committee noted that the overall positive trial results appeared to be driven by the Asian population. Citing these inconsistencies and the dearth of US patient data, the committee ultimately voted 8-1 against the proposed expanded indication.
What It Means for Lung Cancer Drug Development
The FDA has become increasingly concerned about marketing applications supported by trials conducted primarily outside the US, given uncertainty as to the applicability of the data to US patients. In 2022, the Agency issued a Complete Response Letter requiring an additional MRCT to assess clinical benefit of an anti-PD-1 antibody as a first-line treatment for NSCLC that had demonstrated efficacy in a trial conducted solely in China. However, the conduct of clinical trials, particularly early phase trials, outside of the country remains a growing trend as other countries’ competitive regulatory timelines, tax incentives, and the cost-effectiveness of using foreign sites have drawn companies to initiate trials in other countries alongside the US. Contributing to this trend, site saturation in the US and difficulties activating new, less experienced sites not only push trials elsewhere but can also limit enrollment of historically underrepresented populations in clinical trials.
What LUNGevity’s Doing
LUNGevity is actively monitoring how FDA expectations around US enrollment rates in oncology trials may shift moving forward, and how the Agency will assess differential clinical outcomes between regions as part of its benefit-risk determination. To address challenges related to site saturation and activating new sites to promote US enrollment, we have assembled roundtables with clinical research organizations (CROs), site personnel, clinical trial investigators, sponsors, and patient advocates focused on alleviating burdens associated with site activation, conduct, and de-risking new sites. LUNGevity is also convening a working group to streamline the schedule of assessments in lung cancer trials to reduce patient burdens and facilitate participation of more sites in clinical trials.
Variable Uptake of Subsequent Therapies in Global Trials
Key Takeaway
Inconsistent regional uptake of therapies after the investigational treatment can have significant impacts on efficacy endpoint analyses.
ODAC Overview
The glofitamab session noted that not only did subsequent new anti-lymphoma therapy (NALT) see higher utilization in STARGLO’s control arm patients overall, but patients in the non-Asian region received “more efficacious” NALT after the investigational agent. The sponsor argued that these differences in subsequent therapy uptake may have contributed to the treatment effect variability across regional subgroups.
What It Means for Lung Cancer Drug Development
Variable availability and adoption of subsequent therapies across regions can hamper the interpretation of endpoints like OS in global trials across indications, including in lung cancer. The FDA acknowledged the impact that these kinds of inconsistencies may have on the interpretability of MRCT study results in the draft guidance Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs issued last September. Variability in uptake of subsequent therapies, along with the analysis of other endpoints not expected to be confounded by such variability (e.g., PFS), should be taken into account when determining a treatment regimen’s benefit-risk profile.
What LUNGevity’s Doing
Factors impacting interpretation of OS, including crossover of patients from the control arm to the experimental arm and variable access to post-progression therapies in global trials, were a key topic of multistakeholder discussion at LUNGevity’s September 2024 Fall Regulatory Meeting. Informed by these discussions, in a comment letter responding to the MRCT draft guidance, LUNGevity requested additional information on how the Agency evaluates OS data in the context of regional disparities in uptake of subsequent therapies. Specifically, we asked for clarity on when OS data are required for marketing applications and how the Agency would assess potential confounding factors in global trials. We also continue to address other concerns surrounding MRCTs, as we plan to discuss considerations for employing the appropriate standard of care in control arms for these types of trials in our upcoming September 2025 Fall Regulatory Meeting.
Single-Arm Clinical Trials
Key Takeaway
Randomized controlled trials (RCTs) may be expected particularly when it may be difficult to adequately interpret certain clinical endpoints.
ODAC Overview
UroGen Pharma put forward an application for mitomycin to treat low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG-IR-NMIBC), based on the single-arm ENVISION trial. FDA had previously communicated that a single-arm design could potentially support regulatory approval provided certain criteria were met, including enrollment of a large number of patients and a sufficiently long follow-up period. The mitocycin-treated patients showed a high complete response rate (CRR) at 3 months, which was largely maintained for an additional 12 months. While acknowledging the substantial response, the FDA cautioned that the response duration could be due to the heterogeneity of the disease course and not the therapy alone. In addition to the duration of response, the meeting highlighted uncertainty around the treatment’s toxicity, including the lack of a formal safety comparison to standard of care, lack of toxicity data past 18 months, and assessment of patient reported outcomes (PROs) only in participants who achieved a complete response. Despite these uncertainties, four members voted “yes” to the investigational therapy’s overall benefit-risk being favorable to patients with LG-IR-NMIBC, while five voted “no.”
What It Means for Lung Cancer Drug Development
This ODAC session highlights key limitations of single-arm trials and the importance the FDA places on RCTs to adequately assess safety and efficacy in support of regulatory approvals, particularly in early disease settings. Additionally, adequate and robust safety and toxicity data are critical to understanding a treatment’s benefit-risk profile. However, conducting RCTs may be challenging in cases where small eligible patient populations hinder adequate trial enrollment, as in the case of targeted therapies for rare molecular subtypes of lung cancer.
What LUNGevity’s Doing
In cases where the conduct of RCTs may be challenging, LUNGevity continues to support the implementation of alternative approaches, including the use of external control arms and the development of relevant and reliable external data sources to generate them. We have voiced our support for these approaches to the FDA and provided recommendations for the Agency to consider in finalizing guidance documents on designing externally controlled trials and on the use of real-world data sources like electronic health records, medical claims data and registries to support regulatory decision-making.
