Immunomedics’ (NASDAQ:IMMU) Phase I/ II sacituzumab govitecan hormone receptor positive (HR+) Her2-negative breast cancer data may not be enough for an accelerated approval despite showing clinically significant responses in a heavily pretreated population and a similar path adopted in triple-negative breast cancer (TNBC), experts said.
On the sidelines of the ASCO meeting last week, the company’s chief business officer, Usama Malik, said that due to the compelling activity seen in Phase I/II (NCT01631552) data, the company will consider their registrational approach in HR+ Her2-negative after discussions with key opinion leaders and regulatory authorities. Immunomedics is considering a number of options like using the Phase I/II data to support a filing or converting the single-arm study to a randomized one, said Malik, but did not comment on specific timelines.
Analysts thought the Phase I/II data established proof-of-concept, and they compared sacituzumab to other CDK4/6 inhibitors like Eli Lilly’s (NYSE:LLY) Verzenio (abemaciclib) -- whose initial approval was based on a single-arm study -- and suggested a similar path for approval. One analyst said the overall response rate (ORR) and median duration of response is in line with data used to file for an accelerated approval in metastatic TNBC (mTNBC), while others expect the Phase II data to support a breakthrough designation and potential fast-to-market path for that indication.
However, experts told this news service that while impressive in a heavily pretreated population, the data would unlikely be adequate for an accelerated approval. They said a direct randomized comparison with a chemotherapy like Roche’s (VTX:ROG) Xeloda (capecitabine) was required to provide further evidence of efficacy, since the HR+ Her2-negative breast cancer space has more options and a higher expectation of efficacy than TNBC.
Not all patients in the dataset were previously treated with CDK4/6 inhibitors in combination hormone therapies -- a key issue since the drug class is now a part of the standard-of-care (SOC) -- which reduced the data’s relevance, as CDK4/6 inhibitor use could impact responses to subsequent sacituzumab treatment, experts added.
Sacituzumab is an antibody drug conjugate (ADC) consisting of an anti-TROP2 antibody linked to SN-38, the active metabolite of irinotecan. While HR+ Her2-negative sales estimates are not available, those in TNBC are expected to be USD 1bn by 2025. The relapsed/refractory (r/r) HR+ Her2-negative subset is expected to be two-three times the number of patients with r/r mTNBC.
Accelerated approval needs more data
The early Phase I/II data has given a good signal, since chemotherapies like taxol or docetaxel are associated with response rates of approximately 20% and 25% respectively, and a therapy with an ORR of 31% is significant, said Dr Awada Ahmad, head, Medical Oncology Clinic, Jules Bordet Cancer Institute, Brussels, Belgium. Among the 54 patients with HR+ Her2-negative metastatic breast cancer in the Phase I/II basket study, the ORR was 31% and 24% among the 37 patients who received prior CDK4/6 inhibitors, as per the ASCO 2018 abstract (no. 1004).
However, while the Phase I/II data could support a breakthrough status for the drug, it would likely be insufficient for an approval as a single-arm study, said Dr Hatem Soliman, associate member, Moffitt Cancer Center, Tampa, Florida. Dr Katherine Tkaczuk, director, Breast Evaluation and Treatment Program, University of Maryland School of Medicine, Baltimore, agreed adding that there is a need for a direct comparison with SOC chemotherapy. But if efficacy was confirmed in a larger trial with a chemotherapy comparison, sacituzumab could get an approval, said Ahmad.
It is not clear if the dataset is adequate for an approval, but it would be surprising if development does not include a randomized study comparing sacituzumab to Xeloda or physician’s choice of chemotherapy, said Dr Linda Vahdat, chief, Cancer Services at Memorial Sloan Kettering Cancer Center Norwalk Hospital Partnership, New York. A comparison is necessary since chemotherapy is still active in HR+ patients in later lines, said Ahmad. Soliman expressed caution on relying too much on early datasets due to registrational trial failures in breast cancer after early signs of efficacy.