FDA Pipeline: Two Breakthrough Therapy Designations for Fam-Trastuzumab Deruxtecan-nxki, and More

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Over the past few weeks, the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designations for an antibody-drug conjugate in the treatment of gastric and lung cancers. The Agency has also issued Orphan Drug designations for agents being investigated in chronic myeloid leukemia and hepatocellular carcinoma and has given regenerative medicine advanced therapy (RMAT) designation to an off-the-shelf treatment for renal cell carcinoma.

Fam-Trastuzumab Deruxtecan-nxki Granted Breakthrough Therapy Designation for HER2-Positive Metastatic Gastric Cancer, HER2-Mutant Metastatic NSCLC

Fam-trastuzumab deruxtecan-nxki (Enhertu) has been granted two separate Breakthrough Therapy designations over the past few weeks: for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens, including trastuzumab; and for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy. Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate.

The FDA granted the gastric cancer Breakthrough Therapy designation based on data from the registrational phase II DESTINY-Gastric01 trial and data from the phase I trial published by Shitara et al in The Lancet Oncology. In DESTINY-Gastric01, patients treated with fam-trastuzumab deruxtecan-nxki demonstrated a statistically significant and clinically meaningful improvement in objective response rate, the primary endpoint, and overall survival, a key secondary endpoint, vs patients treated with investigator’s choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The overall safety and tolerability profile of fam-trastuzumab deruxtecan-nxki (dosed at 6.4 mg/kg) in DESTINY-Gastric01 was consistent with that seen in the phase I trial. The most common adverse events were hematologic and gastrointestinal, including neutrophil count decrease, anemia, nausea, and decreased appetite. There were cases of drug-related interstitial lung disease (ILD) and pneumonitis, the majority of which were grade 1 and 2, with two grade 3 and one grade 4. No ILD-related deaths occurred in patients with gastric cancer in the phase I trial or in the phase II DESTINY-Gastric01 trial.

The full results of DESTINY-Gastric-01 will be presented during ASCO20 Virtual Scientific Program.

The FDA granted the lung cancer Breakthrough Therapy designation based on data from ongoing phase II DESTINY-Lung01 trial in patients with HER2-mutant metastatic NSCLC and data from the phase I trial published by Tsurutani et al in Cancer Discovery.

An interim analysis from DESTINY-Lung01 will be presented during the ASCO20 Virtual Scientific Program.

The overall safety and tolerability profile of fam-trastuzumab deruxtecan-nxki in the ongoing DESTINY-Lung01 trial is consistent with that seen in the phase I trial. The most common adverse events to date (n = 42) are gastrointestinal and hematological, including nausea, alopecia, anemia, decreased appetite and decreased neutrophil count. There have been five cases of drug-related ILD and pneumonitis in patients with HER2-mutant NSCLC, all of which were grade 2. There have been no ILD-related deaths.

HQP1351 Granted Orphan Drug Designation for Chronic Myeloid Leukemia

The FDA granted HQP1351 Orphan Drug designation for the treatment of chronic myeloid leukemia (CML).

BCR-ABL tyrosine kinase inhibitors have significantly improved clinical management of CML. However, despite clinical benefits offered by the first-generation BCR-ABL TKI imatinib and several second-generation tyrosine kinase inhibitors, many patients develop drug resistance. Such acquired resistance to tyrosine kinase inhibitors is a major challenge in the treatment of CML. BCR-ABL kinase mutations represent a key mechanism of acquired drug resistance; T315I, which is the most common drug-resistant mutation, occurs in about 25% of patients with drug-resistant CML. Patients with the T315I mutation are resistant to both first- and second-generation BCR-ABL inhibitors, hence presenting an urgent unmet medical need for next-generation BCR-ABL inhibitors to more effectively target the T315I mutation.

HQP1351 is a novel, orally active, potent third-generation BCR-ABL inhibitor designed to effectively target BCR-ABL mutants, including T315I, and it is being developed for the treatment of patients with CML resistant to first- and second-generation tyrosine kinase inhibitors. In July 2019, HQP1351 was cleared by FDA to enter a phase Ib study. The candidate is currently being evaluated in a phase II study in China.

MIV-818 Receives Orphan Drug Designation for the Treatment of Hepatocellular Carcinoma

The FDA granted Orphan Drug designation to MIV-818 for the treatment of patients with hepatocellular carcinoma. 

MIV-818 is a prodrug designed to selectively treat liver cancer cells and to minimize side effects. It has the potential to become the first liver-targeted, orally administered drug for patients with hepatocellular carcinoma.

Regenerative Medicine Advanced Therapy Designation for Ilixadencel in Kidney Cancer

The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to ilixadencel, a cell-based, off-the-shelf immune primer, for the treatment of metastatic renal cell carcinoma. 

Established in 2017 under the 21st Century Cures Act in the United States, RMAT designation is an expedited program designed to facilitate the development and review of regenerative medicine therapies intended to address an unmet medical need in patients with serious conditions. An investigational regenerative medicine therapy (eg, cell or gene therapy) is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious condition and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such a disease or condition. As a cell therapy medicinal product, ilixadencel falls within the definition of a regenerative medicine therapy.

Advantages of the RMAT designation include all the benefits of the Fast Track and Breakthrough Therapy designation programs, including guidance and early interactions with the FDA to discuss potential surrogate or intermediate endpoints to support accelerated approval, as well as potential ways to satisfy postapproval requirements

The FDA’s decision was made based on the previously communicated results from the phase II MERECA clinical trial that evaluated the safety and efficacy of ilixadencel in combination with sunitinib in patients with newly diagnosed metastatic renal cell carcinoma. 

The latest results of the phase II MERECA trial were presented by Lindskog et al at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium (Abstract 11). As of December 2019, the patient follow-up data indicates a separation in Kaplan-Meier survival curves in favor of the ilixadencel treatment group in line with the projected separation based on the data from July 2019. The median overall survival value could not be calculated yet in either group, as the data are not mature. The confirmed objective response rate for the ilixadencel treatment group was 42.2% vs 24.0% for the sunitinib control group.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.