Rovalpituzumab tesirine

After reviewing missing adverse events data midway during its evaluation of Amgen's Imdelltra, the FDA concluded that the updated analysis “did not impact FDA’s interpretation of the trial results in a meaningful way,” When the FDA approved Amgen’s Imdelltra in May, the T-cell engager was hailed as a breakthrough for the treatment of small cell lung cancer (SCLC) and as the first DLL3-targeting therapy of potentially many more to come. But, in granting the accelerated approval, the FDA had to work through a “large number” of underreported adverse events and several protocol deviations from a pivotal trial.The previously missing AE reports, including a big chunk from a trial site in South Korea, were recorded in detail in the FDA’s review documents for Imdelltra.All told, in the phase 2 DeLLphi-301 trial that supported Imdelltra’s go-ahead in previously treated extensive-stage SCLC (ES-SCLC), nearly 400 AEs from half of the study’s entire population were not reported in the drug’s original application, an FDA document (PDF) shows. The data were collected during a sweeping review Amgen conducted in response to concerning findings from an FDA clinical site inspection. They were added midway in the FDA’s review process and were included in Imdelltra’s labeling.The original safety evaluation of DeLLphi-301 trial included 220 patients enrolled in the study who received at least one dose of Imdelltra, also known as tarlatamab, across three arms. One patient may experience more than one AE. The FDA’s safety review considered updated 90-day safety data sets from DeLLphi-301 and the phase 1 DeLLphi-300 trial in 187 patients.Most of the missing events were cytokine release syndrome and neurotoxicity that were mild at grade 1 or 2, and some were expected for the underlying cancer. Among 393 newly identified adverse events, there were 28 grade 3 episodes and three serious cases. At least two deaths were chalked up to tumor progression.After reviewing the 90-day data and the unreported AEs, the FDA considered Amgen’s all-inclusive source data verification for all DeLLphi-301 sites “appear acceptable to support” its application.The updated data “did not impact FDA’s interpretation of the trial results in a meaningful way,” the agency wrote in its review document. In a statement to Fierce Pharma, an Amgen spokesperson noted that the FDA had concluded that the DeLLphi-301 study was consistent with internationally accepted good clinical practice protocols.“Before the approval of Imdelltra, there had been few significant breakthroughs in the treatment of SCLC over the last three decades,” the spokesperson added.The FDA accepted Amgen’s application for Imdelltra in December 2023. Then, major safety data reporting deficiencies were flagged (PDF) during an FDA inspection of a clinical trial site led by Myung-Ju Ahn, M.D., Ph.D., at Samsung Medical Center, Sungkyunkwan University School of Medicine, in Seoul, South Korea, in January. What’s more, the FDA also spotted subjects that were mistakenly enrolled even though they did not meet the study’s eligibility criteria. An FDA Form 483 was issued to the site.The FDA’s inspection identified 61 AEs in the source records that were not reported in Amgen’s application, including two deaths of SCLC itself. Ahn attributed the underreporting to a lack of employees to enter the data into the electronic system on time.Amgen did not respond to Fierce Pharma’s question about whether it expects similar underreporting problem for Imdelltra’s ongoing clinical trials. The Samsung Medical Center is currently listed as a site for the phase 3 DeLLphi-304 trial, which is comparing Imdelltra with chemotherapy in second-line SCLC. The study could serve as the confirmatory trial for Imdelltra’s accelerated approval.Upon the FDA’s request, Amgen checked all five sites in Korea and identified 109 previously unreported AEs among 29 patients.“The large number of underreported AEs by the Korean sites, not captured during the Sponsor’s monitoring activities, is a major concern and put into question the integrity of the safety data submitted to support the approval of tarlatamab for the proposed indication,” the FDA reviewers noted.Amgen then expanded the reevaluation to all sites and came back with 393 previously unreported cases. Before Imdelltra’s approval in May, the DLL3 field was walking on thin ice following the epic failure of AbbVie’s antibody-drug conjugate Rova-T. Significant toxicities were a major reason for Rova-T’s downfall, although the problem was mostly attributed to its payload and weak linker rather than the DLL3 target.DLL3 drug development experienced a renaissance recently. Novartis in November partnered with Legend Biotech on a group of DLL3 CAR-Ts so the Swiss pharma can apply its T-Charge rapid manufacturing platform to the candidates. Merck & Co. recently bought Harpoon Therapeutics for its trispecific T-cell engager platform and then last week partnered with Daiichi Sankyo on a DLL3 candidate coded MK-6070. Last year, Abdera Therapeutics emerged with $142 million in combined series A and B funding to advance a pipeline of radiopharmaceuticals, including its lead asset, which is aimed at DLL3.Amgen’s missteps in Imdelltra’s trial operations also brought to mind the company’s recent setback with the KRAS inhibitor Lumakras. The FDA in December rejected Amgen’s bid to convert Lumakras’ accelerated approval after ruling that results from a phase 3 trial could not be reliably interpreted thanks to various misconducts.