On February 2, 2021 Secura Bio, Inc. ("SBI") – (www.securabio.com), an integrated, commercial-stage pharmaceutical company dedicated to the worldwide development and commercialization of impactful oncology therapies, reported the publication of new data confirming the efficacy of the approved dose/schedule of FARYDAK and demonstrating a considerably improved safety profile for FARYDAK in combination with subcutaneous ("SC") bortezomib (as opposed to intravenous administration) and oral dexamethasone (Press release, Secura Bio, FEB 2, 2021, View Source [SID1234574513]).
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Panobinostat ("Pano"), an oral pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma in combination with bortezomib (Velcade) and dexamethasone in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent ("IMiD"). The original registrational trial, PANORAMA-1, used intravenous ("IV") bortezomib, and demonstrated a significant progression-free survival benefit with FARYDAK / bortezomib / dexamethasone (FVd) as compared with placebo / bortezomib / dexamethasone (Vd); adverse events ("AEs") were expectedly reported as being more frequent with FVd (San-Miguel J. et al., Lancet Oncol. 20). A new study, PANORAMA-3, was undertaken to optimize FVd dosing by investigating three different Pano regimens with SC bortezomib (and oral dexamethasone).
In an oral poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) and in a subsequent publication in Lancet Oncology, results were reported for PANORAMA-3: Efficacy and Safety of the FVd combination in Relapsed or Relapsed/Refractory Multiple Myeloma. This study was a randomized, open-label, international, multicenter phase 2 study.
Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients primarily refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen); Pano 20 mg twice weekly (BIW), or Pano 10 mg three times weekly (TIW), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs >75 years). For Cycles 1–4, all patients ≤75 years old received SC bortezomib 1.3 mg/m2 BIW and oral dexamethasone 20 mg on the day of and day after bortezomib injection. Patients aged ≤75 years from Cycle 5 onwards, and patients >75 years for all cycles, received SC bortezomib 1.3 mg/m2 once weekly (QW) and oral dexamethasone 20 mg on the day of and day after bortezomib injection.
Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR), and safety.
Pano 20mg TIW dosing demonstrated efficacy results comparable to and more durable than those seen in PANORAMA-1, with an ORR of 62.2% (N=78), compared to 60.7% (n=387) in PANORAMA 1; and a median duration of response of 22 months, compared to 13.1 months in PANORAMA 1. For the 20mg TIW group, the incidence of diarrhea across all grades was 66.5% (versus 68% in PANORAMA-1), with Grade >3 diarrhea occurring in 11.5% of patients (versus 25% in PANORAMA-1). Further details of the efficacy and safety results can be found HERE for the ASH (Free ASH Whitepaper) abstract and HERE for the Lancet Oncology paper.
The conclusion of the authors was that the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with the most durable and deepest responses observed in the 20 mg TIW arm. As noted in part above, rates of several important AEs, including severe diarrhea, with Pano 20 mg TIW were considerably lower in PANORAMA-3 than those observed with the same dosing regimen in PANORAMA- 1, suggesting SC administration of bortezomib meaningfully improves tolerability of the triplet, as compared with IV administration. All three regimens of FVd proved generally manageable. Pano 20 mg TIW yielded the greatest durable efficacy, most notably a median DOR of 22 months.