Our Perspective on Regulatory News
Dose-Finding and US Representativeness Under the Spotlight at ODAC’s July 2025 Meeting
The US Food and Drug Administration (FDA) Oncologic Drug Advisory Committee (ODAC) met on July 17, 2025, to review the results of clinical trials DREAMM-7 and DREAMM-8 assessing GlaxoSmithKline’s antibody-drug conjugate (ADC) belantamab mafodotin in two different combinations to treat patients with multiple myeloma (MM) in the second line.
While both regimens demonstrated clinical benefit, the committee raised concerns about applicability of the trial results to the US patient population and the toxicity observed at the chosen dose. These issues hold relevance across the oncology drug development landscape and encompass key topics LUNGevity is addressing through the Foundation’s Transforming Clinical Trials Initiative (TCTI).
Applicability of Trial Results to US Patients
Key Takeaway
Sufficient enrollment of US patients in the pivotal trial and employment of control arm regimens reflective of US standard of care are key factors in FDA’s consideration of the applicability of trial results to the US population.
ODAC Overview
Although both combination regimens met their primary endpoint of progression-free survival (PFS), with one further demonstrating a significant improvement in overall survival (OS), the FDA raised concerns around the low percentage of US patients (less than 5%) enrolled in both DREAMM-7 and DREAMM-8. Furthermore, the Agency highlighted that older adults and Black/African American patients were underrepresented in the trial populations compared to the real-world MM population in the US.
The questionable applicability of the control arm treatments to US practice was also cited as a factor in the uncertain US relevance of the trial results. The Agency noted that the comparator arm employed in DREAMM-7 was not used in the second-line setting in the US, while the comparator arm regimen in DREAMM-8 was not FDA-approved.
What It Means for Lung Cancer Drug Development
The topic of applicability of trial results to US patient populations is not unique to this ODAC, with the May 2025 meeting raising similar concerns about the percentage of US patients enrolled in another pivotal trial for a different drug sponsor’s indication.
These concerns have also been raised for recent trials assessing the safety and efficacy of lung cancer regimens. In 2022 the Agency required an additional clinical trial for an anti-PD-1 antibody as a first-line treatment of non-small cell lung cancer (NSCLC) as the trial supporting its marketing application was conducted solely in China.
While predominantly US enrollment may be desired, challenges hindering the enrollment of representative US patient populations include US trial site saturation and difficulties activating new, less experienced sites for participation in clinical research. Challenges like these not only can limit enrollment of historically underrepresented populations in clinical trials but also, along with competitive regulatory timelines, tax incentives, and other factors, can push trials outside of the country.
Employing the appropriate comparator in the context of multiregional clinical trials (MRCTs) can also be challenging in lung cancer drug development. Ensuring that the control arm adequately reflects current treatment paradigms in the intended use population becomes complicated by the rapid pace of drug development and changes in standards of care. This becomes particularly challenging in global clinical trials when managing differing standards of care across regions.
What LUNGevity’s Doing
LUNGevity is leading efforts to facilitate utilization of a broader range of US trial sites, including convening ongoing roundtables with clinical research organizations (CROs), site personnel, clinical trial investigators, and other stakeholders to address challenges related to site saturation and activation of new sites.
We are also hosting a working group to streamline the schedule of assessments in lung cancer clinical trials to not only reduce patient burden but facilitate the participation of less experienced trial sites. These efforts aim to facilitate participation of more trial sites across the US and, thus, trial populations more representative of US patients.
The Foundation is also engaged in efforts to advance the use of appropriate comparator regimens in randomized clinical trials. At Part 1 of our annual Regulatory Series in September, we will engage multiple stakeholders in a discussion on challenges to ensuring the appropriate standard of care is employed in control arms, particularly in complicated cases including when new regimens are approved while trials are underway, and how to incorporate differing standards of care across regions in global clinical trials.
Finding the Right Dose
Key Takeaway
Identifying the optimal dose that balances efficacy with tolerability of oncology drug regimens continues to be a key priority for the FDA.
ODAC Overview
The FDA expressed concerns about the safety profile of the investigational treatment regimens. More than 75% of patients on the experimental arms of both trials experienced high-grade ocular toxicity, often leading to treatment interruptions and dose modifications. The dose chosen for the studies (2.5 mg/kg) was based on results from dose exploration studies, which the sponsor argued revealed “deeper” responses including very good partial response (VGPR) rates in the chosen dose compared with a lower dose of 1.9 mg/kg. In contrast, the Agency argued that the dose exploration studies demonstrated similar response rates with fewer dose modifications in patients receiving the lower dose at longer treatment intervals. Ultimately the ODAC voted no on the question of whether appropriate dosages had been identified for the proposed patient population, citing a “missed opportunity” to explore alternative doses and identify a dose with similar efficacy and less toxicity.
What It Means for Lung Cancer Drug Development
FDA’s apprehension around the selected dosage in DREAMM-7 and DREAM-8 is the latest evidence of the obligation the Agency places on sponsors to optimize the dose of investigational therapies in clinical trials across cancer indications. The Oncology Center of Excellence (OCE) launched Project Optimus in 2021 to promote the adequate characterization of optimal doses and schedules of administration for oncology drugs before registrational trial initiation. Dose optimization entails various challenges, however, including choosing dose levels far enough apart to differentiate effects while also avoiding administering subtherapeutic doses to patients. Dose optimization may also entail specific considerations for different emerging treatment modalities in lung cancer, including ADCs and radioligand therapies.
What LUNGevity’s Doing
LUNGevity is convening a multistakeholder discussion on lessons learned since the launch of Project Optimus and pressing challenges to dose optimization at Part 2 of our annual Regulatory Series this December. The meeting will feature presentations from FDA on regulators’ evolving thinking on the topic, as well as on sponsors’ experiences with implementing dose optimization strategies and where industry continues to face challenges. The discussion will aim to identify common challenges and potential pathways toward solutions, to facilitate the use of efficient dose optimization strategies in lung cancer clinical trials moving forward.
