Immunomedics’ Sacituzumab Has Insufficient Dataset to Pursue Accelerated Approval

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 singlearm 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-tomarket 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).

An improved toxicity profile could give sacituzumab leverage for an approval if further validated in more patients

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 singlearm 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.

A trial needs to show that sacituzumab is superior to anthracycline chemotherapy or other endocrine therapies used in later lines, added Dr. Lajos Pusztai, director, Breast Cancer Translational Research, Yale Cancer Center, New Haven, Connecticut. Non-inferiority to chemotherapy alone would be insufficient, said Soliman.

Furthermore, the impact of CDK4/6 inhibitor treatment still remains to be seen, said Vahdat. As per the abstract, 69% of patients had received prior CDK4/6 inhibitors. All experts said combinations of CDK4/6 inhibitors with hormone therapies have been the SOC in HR+ Her2-negative, since the first approval of a CDK4/6 inhibitor; i.e., for Pfizer’s (NYSE:PFE) Ibrance (palbociclib) in 2015. Previous use of CDK4/6 inhibitor will influence the responses to an ADC like sacituzumab in later lines of treatment, said Ahmad. Efficacy data after CDK4/6 inhibitor use in more patients would also better contextualize sacituzumab’s positioning against current treatments, said Dr. Krystal Cascetta, assistant professor, Medicine, Hematology and Medical Oncology, Mount Sinai, New York.

In addition to being effective, sacituzumab is also well tolerated, most likely because the ADC design makes the chemotherapy more targeted to the tumor, said Tkaczuk. An improved toxicity profile could give sacituzumab leverage for an approval if further validated in more patients, but differentiated patient characteristics -- in terms of number and type of therapies or HR status -- make it difficult to analyze any comparable information on quality of life, said Soliman.

Unfitting comparisons to TNBC subset

Compared to TNBC, where sacituzumab has also been studied, the HR+ breast cancer space is more competitive, despite there being no drug specifically approved for use after exhausting hormone therapies or CDK4/6 inhibitor and hormone therapy combinations, said Pusztai. An accelerated approval for the drug in mTNBC based on a small dataset has greater validity, since there is no accepted SOC after a few lines of chemotherapy, said Soliman.

Immunomedics submitted a BLA to the FDA for sacituzumab in TNBC, as per a 4 June press release. This news service reported in November 2017 that while the company’s registrational TNBC dataset may also be inadequate for an FDA approval, the unmet need may boost its approval chances.

While there is a greater unmet need in TNBC due to the absence of targeted therapies unlike in HR+Her2-negative breast cancer, once endocrine resistance to hormone therapies develops, chemotherapy remains the only available option, said Cascetta. Tkaczuk agreed, adding that these patients do not tend to do well with chemotherapy either.

Both Tkaczuk and Cascetta singled out the fact that responses in the Phase I/II patient cohort were seen despite patients being heavily pretreated with chemotherapy, hormone therapies and some with CDK4/6 inhibitors. A lower response is expected in these patients versus one who received only one line of therapy, and this is encouraging for further exploration, they added.

July 2, 2018

Manasi Vaidya

Reporter

New York

Manasi Vaidya has a Master’s degree in biotechnology. After a stint in a research lab, she spent two years as correspondent in India for BioSpectrum, a publication focused on the Asian biotechnology industry. She then moved to the United States to pursue a Master’s degree in Science, Health and Environmental Reporting at New York University. Manasi has reported primarily on topics that combine health and policy, and her work has appeared in Nature Medicine, Nautilus and Scienceline. Her coverage at BioPharm Insight focuses on cancer.