ADCs are becoming hot assets in oncology and the most recently approved one is Tivdak (tisotumab vedotin), which came on 20th September 2021 in previously treated recurrent or metastatic Cervical Cancer. This ADC is being co-developed by Seagen and Genmab under an agreement in which the companies share costs and profits for the product on a 50:50 basis. The drug is designed to target tissue factor (TF) which is highly expressed on many solid tumors, including ovarian, prostate, bladder, esophageal, endometrial, and lung tumors.
The companies at ESMO 2021 presented the interim results from two dose expansion cohorts (Cohort D and Cohort F) of the phase Ib/II innovaTV 205/ENGOT-cx8/GOG-3024 in recurrent or metastatic cervical cancer.
Cohort D: Tivdak + Carboplatin in 1L setting
The combination in 1L setting showed an encouraging result with the ORR of 55% with the median follow up of 7.9 months. The median time to response was 1.4 months with median duration of response of 8.3 month and median PFS was 9.5 months. Whereas In 1L setting, Keytruda plus chemotherapy has shown impressive results with an ORR of 65.9% (KEYNOTE-826 study) which shows better efficacy than TV. But the results of TV are interim and in a smaller cohort. So more data would be needed before a clear comparison can be drawn between the two.
Cohort F: Tivdak + Pembrolizumab in 2L+ setting
The combination in 2L+ setting achieved an ORR of 38% and PFS was 5.6 months. The median time to response was 1.4 months with median follow-up of 13.0 months and a median duration of response of 13.8 months.
Yesterday, the FDA granted accelerated approval to TV as a potential treatment for patients with recurrent or metastatic cervical cancer with progressive disease on, or following, chemotherapy. The approval was based on results of the phase II single-arm innovaTV 204 trial, which examined TV monotherapy in patients with previously treated, recurrent, or metastatic cervical cancer. The results showed an ORR of 24% and median PFS was 4.2 months while median OS was 12.1 months.
Comparatively, approval of Keytruda in 2L cervical cancer was on the basis of 14.3% ORR in the KEYNOTE-158 trial. In terms of ORR, TV as monotherapy is better than Keytruda, the only difference is that Keytruda was approved for tumor expressing PD-L1 while there are no such criteria in TV. But the results of the TV + Keytruda combination in 2L+ are better compared to both these drugs as monotherapy. We do understand that the results of TV + Keytruda are in a smaller cohort but they seem to be quite encouraging.
The results of KEYNOTE-826, which were also presented at the ESMO 2021, showed the efficacy of Keytruda and its potential in 1L setting. The others drugs in development for 2L setting such as Libtayo and balstilimab are PD-1 therapy similar to Keytruda. The use of Libtayo and balstilimab will be less and even discouraged in 2L after the approval of Keytruda in 1L considering the administration of a PD-1 therapy in 1L i.e., Keytruda. The recent approval in 2L gives a perfect opportunity for TV to establish itself in 2L as a monotherapy initially and later in a combination with Keytruda.
INSIGHTS: Although ADCs and immunotherapies are altogether different targeting platforms in oncology, Delveinsight strongly believes that both the programs have their own identity and significance in terms of their anti-tumor activities. As far as toxicities of the clinical assets are concerned, ADCs might face stumbling blocks as they are highly packed with black box warnings pertaining to higher cases of interstitial lung disease and others as compared to immunotherapies. But we remain quite optimistic with the current approval of Tivdak in the 2L+ setting and expect its easier approval in the earlier settings as well. Pertaining to Keytruda’s results in Keynote-826 presented at this medical meeting, we are highly confident and expect its approval sooner than Tivdak in the first-line setting.