Based on a pre-clinical study, treatment of patients sacituzumab govitecan, also known as  IMMU-132 (Immunomedics), in patients with metastatic triple-negative breast cancer (mTNBC) has the potential to be further improved when combined with agents that inhibit DNA repair pathways both in patients with mutated and wild-type BRCA1/2.

Results from this pre-clinical study were published online in Clinical Cancer Research, which is the official publication of the American Association for Cancer Research (AACR).

“This preclinical study is part of our ongoing strategy to broaden the applicability of this important asset for the treatment of patients with solid cancers and the positive results we have achieved thus far are a testament to the strength of our talented team. The progress we have made affirms our commitment to continued product development,” remarked Cynthia L. Sullivan, Immunomedics’ President and Chief Executive Officer.

IMMU-132 is a first-in-class antibody-drug conjugate or ADC developed by Immunomedics, is a clinical-stage biopharmaceutical company by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high drug-to-antibody ratio (DAR) to a humanized antibody that targets the Trop-2 receptor expressed by many solid cancers. In a single-arm Phase 2 study, this ADC has produced rapid and durable responses in metastatic TNBC patients, with only limited and manageable Grade 3 or 4 toxicity, and has received a Breakthrough Therapy Designation from the FDA in this cancer setting.

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Active metabolite of irinotecan
SN-38 is the active metabolite of irinotecan (Camptosar), which is used to treat certain solid cancers as a part of combination therapies. It exerts its cell-killing activity by inhibiting topoisomerase I, an enzyme needed by the cell for normal DNA replication. This inhibition results in breaks in the DNA during replication, leading ultimately to the cell’s death if left unrepaired by the cell. The goal of this preclinical study was to determine whether the DNA-damaging property of IMMU-132 can be augmented by agents that inhibit the repair of DNA.

Poly (adenosine diphosphoribose) polymerase or PARP is a family of enzymes whose primary function is to repair DNA breaks. It is one of several proteins used by cells for this purpose.  PARP inhibitors (PARPi), such as olaparib (AZD-2281; Lynparza®; AstraZeneca) and talazoparib (BMN-673; Medivation) are currently under investigation in cancers whith existing DNA-repair defects (BRCA1 and BRCA2).

BRCA1 and BRCA2 are a pair of genes that encode proteins important in a cell’s ability to repair double-stranded DNA breaks. In cell culture, the cytotoxicity of IMMU-132, when combined with one of three different PARPi’s, olaparib, talazoparib, and rucaparib (AG-014699, PF-01367338; Clovis Oncology), produced synergistic growth inhibition in BRCA1 and BRCA2-defective human TNBC tumor lines.

Furthermore, combining IMMU-132 with these PARPi’s also demonstrated synergy in BRCA1 and BRCA2 wild-type tumor lines in which the DNA-repair pathways are not defective. In mice bearing human TNBC tumors with mutated BRCA1 and BRCA2, a combination of IMMU-132 plus olaparib or talazoparib produced significantly improved antitumor effects and delay in time-to-tumor-progression, compared to monotherapy. Most importantly, in mice bearing tumors that are not defective in DNA repair (BRCA1 and BRCA2 wild-type), the combination of IMMU-132 plus olaparib imparted a significant antitumor effect and survival benefit above that achieved with monotherapy. Noteworthy, this combination was well tolerated, with no substantial changes in hematologic parameters.

“These preclinical results indicate that the combination of PARPi and IMMU-132 could broaden the range of tumors that are usually treated with the former to a TNBC patient population that includes BRCA1/2 wild-type tumors. Given the promising results obtained thus far with IMMU-132 in patients with TNBC, the logical next step is to combine this therapy with PARPi to further improve clinical outcome,” Ms. Sullivan noted.

Treatment GroupsNTime-To-Tumor (TTP) Progression
  TTP (days  )  IMMU-132 vs. Control
  Combination vs. Control
  TTP (days)  IMMU-132 vs. Control
  Combination vs. Control
  IMMU-132 + PARPi 1036.9 ± 8.1N.A.N.A.21.8 ± 9.6N.A.N.A.
IMMU-132 alone9  17.6 ± 3.9N.A.<0.0001  7.9 ± 6.6N.A.0.0021
PARPi alone9  9.1 ± 4.80.0009<0.0001  5.9 ± 5.90.50990.0005
Saline Control10  7.7 ± 5.0<0.0001<0.0001  4.2 ± 1.90.07090.0001

N = Number of mice per group
N.A. = Not Applicable

Table 1.0: Improved efficacy of IMMU-132 when combined with olaparib or talazoparib in mice bearing TNBC tumors that are deficient in DNA repair.

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