Oral Taxane Boosts PFS in HR-Positive MBC

An oral taxane plus reduced-dose capecitabine increased the progression-free interval in metastatic breast cancer (MBC) by about 3 months, initial results from a randomized trial showed.

Patients treated with tesetaxel and capecitabine had a median progression-free survival of 9.8 months as compared with 6.9 months with capecitabine monotherapy. Two-thirds of patients in the tesetaxel arm had disease control at 24 weeks versus half of those in the placebo group, and the all-oral combination regimen led to significantly more objective responses.

The benefits were consistent across prespecified subgroups and occurred within the context of a manageable side-effect profile, Joyce O’Shaughnessy, MD, of Baylor University Medical Center in Dallas, reported during the San Antonio Breast Cancer Symposium virtual meeting.

“Tesetaxel plus a reduced dose of capecitabine is a potential new treatment option for patients with hormone receptor (HR)-positive, HER2-negative breast cancer,” she said in conclusion.

Manufacturer and trial sponsor Odonate Therapeutics said it plans to file a U.S. marketing application in mid-2021.

Chemotherapy, with its frequently debilitating side effects, remains standard of care for most patients with metastatic breast cancer. O’Shaughnessy said alternatives are needed that combine robust efficacy with preserved quality of life. Preclinical studies showed that oral tesetaxel achieved higher intracellular concentrations and greater tumoricidal activity than either paclitaxel or docetaxel.

In a phase 2 trial, tesetaxel produced an objective response rate of 45% in patients with HR-positive, HER2-negative MBC. With regard to safety, analysis of 211 patients who received the recommended phase 2 dose of tesetaxel (alone or with capecitabine) showed a 3% incidence of grade ≥3 neurotoxicity, a 5% incidence of grade 2 alopecia, and no hypersensitivity reactions, providing the basis for the phase 3 CONTESSA trial.

Patients were enrolled who had HR-positive, HER2-negative MBC, either untreated or no more than one prior regimen for MBC, and prior exposure to a taxane in the neoadjuvant or adjuvant setting. Eligibility criteria had no limit on prior endocrine regimens. Patients were randomized to tesetaxel and reduced capecitabine or to single-agent capecitabine at a standard dose. Treatment continued until disease progression or development of unacceptable toxicity.

PFS, as assessed by independent radiologic review, served as the primary endpoint. The trial was powered to detect a 29% reduction in the hazard ratio for progression or death (median PFS difference of 2.5 months). Median follow-up was 13.9 months.

Data analysis included 685 patients whose median age was 56-57. In addition to the required prior taxane exposure, 80%-90% of patients had received anthracyclines, alkylators, and endocrine therapy. About half had prior exposure to a CDK4/6 inhibitor. Fewer than 10% had prior chemotherapy for MBC.

The analysis yielded an absolute difference of 2.9 months in median PFS in favor of tesetaxel, representing a 28.4% reduction in the hazard for progression (HR 0.716, 95% CI 0.573-0.895, P=0.003). Subgroup analyses showed a similar benefit of tesetaxel regardless of age, performance status, disease-free interval after prior taxane, prior CDK4/6 inhibitor therapy, presence/absence of visceral or brain metastases, or geographic region.

The addition of tesetaxel to reduced-dose capecitabine resulted in an objective response rate of 57% versus 41% for capecitabine monotherapy (P=0.0002). Disease control rates at 24 weeks were 67% with tesetaxel and 50% with single-agent capecitabine (P<0.0001). Overall survival data, a secondary endpoint, remain immature; O’Shaughnessy said they’re are expected in 2022.

Treatment-emergent adverse events (TEAEs) occurred more often with tesetaxel and capecitabine, with the exception of hand-foot syndrome (50.7% vs 66.2% with single-agent capecitabine). The most common grade ≥3 TEAEs in the tesetaxel arm were neutropenia (71%, febrile in 13%) and diarrhea (13.1%). Almost twice as many patients in the tesetaxel arm discontinued treatment because of adverse events (23.1% vs 11.9%).

During the discussion that followed the presentation, moderator Kathy Albain, MD, of Loyola Medicine in Chicago, asked about the use of reduced-dose capecitabine with tesetaxel as opposed to a direct comparison of the two drugs as single agents. O’Shaughnessy replied that CONTESSA was designed as a registration trial and followed precedent set in prior trials of docetaxel (with or without capecitabine) and paclitaxel (with or without gemcitabine).

In response to a question from the virtual audience, O’Shaughnessy declined to comment or speculate on differences between tesetaxel and another oral taxane in development, aside from suggesting that tesetaxel might be more convenient.

Some audience members questioned whether a 2.9-month gain in PFS is clinically meaningful in the absence of overall survival data. O’Shaughnessy said the results are similar to what was observed in trials with the IV taxanes in combination with capecitabine or gemcitabine.

“It gives patients now an all-oral option,” she added.