Seagen/Genmab's Tivdak Set To Take On Merck’s Keytruda
Executive Summary
Accelerated approval of Tivdak in recurrent or metastatic cervical cancer brings Seagen’s fourth cancer therapy and third antibody-drug conjugate to market. Merck is advancing Keytruda in r/mCC as well.
Seagen Inc. and Genmab A/S have the first approved antibody-drug conjugate for cervical cancer and are looking to compete with a true heavyweight, Merck & Co., Inc.’s Keytruda (pembrolizumab), in the disease.
Tivdak (tisotumab vedotin) obtained US Food and Drug Administration approval for second-line or later recurrent or metastatic cervical cancer on 20 September, just one day after the companies reported data showing efficacy for the ADC in combination with carboplatin or Keytruda in cervical cancer.
Paradoxically, while Tivdak now is set to compete directly with Merck’s anti-PD-L1 therapy, data reported at the European Society of Medical Oncology’s virtual meeting could position Tivdak for combination use with Keytruda in second- and third-line r/mCC. The Phase Ib/II innovaTV 205 trial data presented at ESMO also showed an objective response benefit for Tivdak combined with carboplatin in first-line therapy, a setting Merck is also eyeing for Keytruda.
Tivdak’s accelerated approval is based on data from the Phase II innovaTV 204 study, which produced a 24% objective response rate in 101 cervical cancer patients whose disease progressed on or after chemotherapy. The ADC also yielded a median duration of response (DOR) of 8.3 months. Keytruda was approved to treat second-line cervical cancer in 2020 with a 14.3% ORR in PD-L1-positive patients in the KEYNOTE-158 study. (Also see "Merck's Keytruda Is First Checkpoint Inhibitor To Win US Approval Based On TMB Biomarker" - Scrip, 17 Jun, 2020.)
During a 21 September investor call on the approval, Seagen chief medical officer Roger Dansey also noted that 79% of patients from the Phase II study who had at least one post-baseline scan of their tumors showed a reduction in size of target lesions. Seagen and Genmab, which have a 50/50 development and commercialization partnership for Tivdak, are enrolling an approximately 480-patient Phase III confirmatory study in second-line or later r/mCC to back both full approval in the US and ex-US marketing applications, the exec said.
Executive vice president-US commercial Charles Romp said Tivdak will be priced at approximately $90,000-$120,000 for a course of therapy (estimated based on the Phase II DOR), with discounting of the wholesale acquisition cost expected to bring the price closer to a range of $70,000-$90,000. Seagen and Genmab set the US price based on the “significant benefit provided in this patient setting,” Romp added.
Boxed Warning’s Impact On Uptake Disputed
While Tivdak appears to offer better efficacy in a wider range of cervical cancer patients, analysts wondered whether a black box warning about ocular toxicity included in the product labeling might limit uptake.
Tivdak pairs Genmab’s fully human monoclonal antibody specific for tissue factor with Seagen’s ADC technology, which uses a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody and releases it upon internalization, inducing target cell death. (Also see "Genmab And Seattle Genetics Progress Cervical Cancer ADC" - Scrip, 30 Jun, 2020.)
Ocular events have been seen previously with Seagen’s linker technology, and GlaxoSmithKline plc’s multiple myeloma drug Blenrep (belantamab mafodotin), which uses Seagen’s technology, also carries a black box warning for ocular toxicity. (Also see "GSK’s Blenrep Wins BCMA Race, Carries Ocular Toxicity Warning" - Scrip, 6 Aug, 2020.) Labeling for Seagen’s ADC Padcev (enfortumab vedotin) reports a 40% incidence of ocular adverse events. (Also see "Astellas, Seattle Genetics Break Ground With US ADC Approval" - Scrip, 19 Dec, 2019.)
Tivdak’s label notes that ocular adverse reactions occurred in 60% of patients treated in innovaTV 204. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%) and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. The boxed warning recommends an ophthalmic examination at baseline, before each dose and as needed afterward. Tivdak is administered every three weeks.
H.C. Wainwright analyst Andrew Fein dismissed the ocular toxicity warning as an impediment to uptake of Tivdak in a 21 September note, pointing to the high unmet medical need in r/mCC. Seagen’s Romp told the investor call that roughly 4,000 patients undergo first-line cervical cancer treatment annually in the US, and up to half of them may need subsequent lines of therapy. CMO Dansey noted that the clinical program was “conducted with a very careful eye-management approach.”
“We do not view ocular toxicity as a hurdle for uptake and note 75% of patients from innovaTV 204 who experienced decreased visual acuity to 20/50, resolved within an acceptable timeframe,” Wainwright’s Fein said. “The label also provides detailed protocols for physicians once ocular AEs are detected.”
SVB Leerink analyst Andrew Berens, however, took a dimmer view. “Onerous label may impact opportunity,” his 21 September note asserted, calling the black box warning of ocular toxicity unexpected. “With the Q3W dosing, we think the required ophthalmic exams could prove cumbersome for some patients, especially since ophthalmology centers tend to be non-hospital based,” he said.
Competition Or Combination (Or Both) With Keytruda?
While the innovaTV 205 data at ESMO may position Tivdak to move into combination therapy and possibly the first-line setting, Merck presented data during the meeting that also may expand Keytruda’s use in cervical cancer. The Phase III KEYNOTE-826 study showed that Keytruda combined with chemotherapy, with or without Genentech, Inc.’s Avastin (bevacizumab), improved ORR, overall survival (OS) and progression-free survival (PFS) compared to chemotherapy with or without Avastin. (Also see "Keytruda Expands Cervical Cancer Position With ESMO Data" - Scrip, 21 Sep, 2021.)
The Keytruda combo reduced risk of death by 33% in KEYNOTE-826 (p<0.001). Median OS was 24.4 months for the Merck regimen versus 16.5 months for the comparator regimen, ORR was 65.9% compared to 50.8%, and PFS was 10.4 months compared to 8.2 months. Median DOR was 18.0 months in the Keytruda arm and 10.4 months in the chemotherapy arm, Merck reported.
A readout from the innovaTV 205 study showed that TV plus Keytruda may offer better efficacy than TV alone in second- and third-line r/mCC. The TV/Keytruda combination produced a 38% ORR (13/34), with two patients achieving total response and 11 reaching partial response. Median time to response was 1.4 months, median follow-up was 13 months, median duration of response was 13.8 months, and PFS was 5.6 months.
Tivdak is Seagen’s fourth commercial product, and its third ADC alongside Padcev and Adcetris (brentuximab vedotin). Complementary sales teams are in place for the Tivdak launch, Romp said, and work to detail the product’s benefits with payers has been ongoing for months. “I think there’s an agreement that this is a significant potential advancement for patients with recurrent or metastatic cervical cancer,” he added. (Also see "As Seagen Matures, CEO Siegall Talks About Moving The Growth Goalposts" - Scrip, 21 Jan, 2021.)
Astellas Pharma, Inc. is Seagen’s commercial partner for Padcev; Seagen chief financial officer Todd Simpson said the financial structure of the Genmab and Astellas partnerships are similar, with Seagen booking US sales in both collaborations, with 50% of the profits then flowing through to the partner company.
Wainwright analyst Fein projects that 60% of cervical cancer patients will progress to second-line therapy, with an initial 3% market share for Tivdak growing to 40% by 2029. He anticipates sales of $5m for the drug this year, rising to $300m in 2029.
[Editor's note: This article has been revised to correct data from the KEYNOTE-826 trial and the spelling of Roger Dansey's last name.]