Adverse events (AEs) took the shine off Odonate Therapeutics Inc.’s long-awaited top-line data from the phase III trial called Contessa testing the oral taxane chemotherapy tesetaxel in metastatic breast cancer (MBC), and shares of the San Diego-based firm (NASDAQ:ODT) closed at $18.33, down $15.21, or 45%.

Contessa is comparing tesetaxel plus a reduced dose of the anti-metabolite chemo capecitabine to the approved dose of capecitabine by itself. The primary endpoint – improved progression-free survival (PFS) as measured by an independent radiologic review committee (IRC) – was met, with median PFS turning up at 9.8 months for tesetaxel plus the reduced dose of capecitabine vs. 6.9 months for capecitabine alone, an improvement of 2.9 months.

AEs, however, included neutropenia, which turned up at a rate of 71.2% for tesetaxel plus capecitabine vs. 8.3% for capecitabine monotherapy. The rate may have proven worrisome for Odonate backers, although chemo patients are commonly treated for the condition with the colony-stimulating factor Neulasta (pegfilgrastim) from Amgen Inc., of Thousand Oaks, Calif. Odonate could not be reached.

The 685-patient Contessa effort is taking place at 180 sites in 18 countries in North America, Europe, and Asia. Jefferies analyst Michael Yee said in a report that the data rollout was “a big ‘binary’ event” for the firm, adding that the outcome “generally looks good and [tesetaxel is] de-risked,” in his view. He predicted the stock would trade higher on the latest news, though he allowed that there might be “investor debate on perception of AEs and the comments on overall survival [OS].”

Contessa pits tesetaxel at 27 mg/m2 on the first day of each 21‑day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21‑day cycle) against capecitabine alone at 2,500 mg/m2/day dosed orally for 14 days of each 21‑day cycle. Capecitabine is an oral chemo agent considered standard‑of‑care treatment in MBC. Randomized 1:1, patients in Contessa bear EGFR2-negative, HR-positive MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Where indicated, patients in Contessa must have received endocrine therapy with or without a cyclin‑dependent kinase (CDK) 4/6 inhibitor. Secondary efficacy endpoints include OS, objective response rate as gauged by the IRC and disease control rate. Odonate said that although OS data are not mature, a recent interim analysis indicated the absence of an AE effect on this factor. A final OS analysis is expected in 2022.

Meanwhile, in the top-line findings, the risk of disease progression or death was reduced by 28.4% (HR=0.716 [95% CI: 0.573-0.895]; p=0.003) for tesetaxel plus the reduced dose of capecitabine as compared with capecitabine alone. Odonate called the side-effect profile of the paired drugs manageable and consistent with earlier studies’ results. Grade ≥3 treatment-emergent AEs that surfaced in ≥5% of patients were, along with neutropenia: diarrhea (13.4% for tesetaxel plus capecitabine vs. 8.9% for capecitabine alone); hand‑foot syndrome (6.8% vs. 12.2%); febrile neutropenia (12.8% vs. 1.2%); fatigue (8.6% vs. 4.5%); hypokalemia (8.6% vs. 2.7%); leukopenia (10.1% vs. 0.9%); and anemia (8.0% vs. 2.1%).

AEs that led to dropouts in ≥1% of patients included: neutropenia or febrile neutropenia (4.2% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); neuropathy (3.6% vs. 0.3%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). Treatment quits due to any AE occurred in 23.1% of patients treated with tesetaxel plus capecitabine vs. 11.9% of patients treated with capecitabine alone. Grade 2 alopecia turned up in 8% of patients treated with tesetaxel plus capecitabine vs. 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% vs. 0.9%.

Analyst Yee called AEs with the tesetaxel combo “in line with expectations for chemo.” He set the numbers alongside those for Oraxol, an oral version of paclitaxel from Buffalo, N.Y.-based Athenex Inc. that has yielded phase III data. In results offered at the San Antonio Breast Cancer Symposium, grade 3/4 neuropathy was 2% with Oraxol vs. 15% with intravenous paclitaxel. Grade 2-plus alopecia reached 29% with Oraxol vs. 48% with the control. Neutropenia hit 38% with Oraxol vs. 33% with the control, including grade 3/4 events of 30% vs. 28%. More gastrointestinal side effects materialized with Oraxol: grade 3/4 diarrhea at 5% vs. 2%.

Odonate plans to submit an NDA for tesetaxel in the middle of next year. Weighing the candidate’s odds is anything but simple, but other MBC therapies have won FDA clearance based on PFS, an accepted regulatory endpoint given that OS results can take two years or more. New York-based Pfizer Inc.’s CDK 4/6 inhibitor Ibrance (palbociclib) gained its first approval in breast cancer in February 2015. The following year, the drug was given the nod for HR-positive, EGFR2-negative MBC in combination with Faslodex (fulvestrant) – the estrogen receptor antagonist from London-based Astrazeneca plc that went generic last year – in women with disease progression following endocrine therapy. Ibrance missed its OS endpoint but showed encouraging signals in the phase III study called Paloma-3. With tesetaxel, Yee said he would “like to see a numerical [OS] trend in further analysis, and assume[s] the FDA can look at data” on that score when the NDA is filed. “We would not want to see a delay in approval just for FDA to ask for final OS data, though.”

Did Wall Street expect too much from Contessa? The 9.8-month PFS goes beyond what other chemo studies have achieved, conquering the 6.9-month capecitabine bar, which was already pretty high. But the AE specter persists, especially given that some might envision dual therapy for elderly MBC patients who are less able to withstand the drawbacks. If the combo proves intolerable for them, tesetaxel monotherapy might work. Odonate has the phase II Contessa Trio effort underway to find out.

During its long history, tesetaxel has passed through various hands. Genta Inc., of La Jolla, Calif., took control of the compound at the phase II stage from Tokyo-based Daiichi Sankyo Co. Ltd., forking over an undisclosed up-front fee in a deal that included potential milestone payments and royalties on product sales. Eight years ago, Genta went bankrupt, and that’s how the candidate ended up with Odonate.

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