Glen Clack, Chief Medical Officer at TheraCryf, shared on LinkedIn:
“The antibody-drug conjugate moves up the batting order.
For most of its career the antibody-drug conjugate has been a late-order batsman, sent in once the chemotherapy had been tried and the immunotherapy had failed. Since the spring it has been promoted, and those of us who develop these agents might usefully take stock.
First, the front line.
- In May the FDA approved datopotamab deruxtecan as initial treatment for metastatic triple-negative breast cancer in patients unsuited to immunotherapy; in TROPION-Breast02 median survival was 23.7 months against 18.7 with chemotherapy.
- In June sacituzumab govitecan followed, alone for the same group and with pembrolizumab for PD-L1-positive disease.
At ASCO, an interim analysis of OptiTROP-Lung05 showed sacituzumab tirumotecan with pembrolizumab cutting the risk of progression or death by 65% against pembrolizumab alone in first-line PD-L1-positive lung cancer. A survival advantage has yet to be shown, and the comparator was pembrolizumab without chemotherapy.
Second, curable disease.
- On 15 May trastuzumab deruxtecan received its first early-stage indications, before and after surgery for HER2-positive breast cancer.
- On 10 July enfortumab vedotin with pembrolizumab was approved either side of cystectomy for muscle-invasive bladder cancer, cisplatin-eligible patients included.
Third, new formats and targets.
- In June China approved izalontamab brengitecan for nasopharyngeal carcinoma: the first bispecific ADC anywhere, aimed at EGFR and HER3 together.
The FDA is due to rule by
- 10 October on ifinatamab deruxtecan in small cell lung cancer, which would be the first against B7-H3. Two of the molecules named above were invented in Chengdu.
The fly in the ointment is what happens afterwards.
All but one of these agents carry a topoisomerase I payload, and the tumor that has learned to shrug off one seems to keep the knack.
In a retrospective series of 179 patients with HER2-low breast cancer given two such conjugates in turn, the second held the disease for a median of 2.7 months, and 54.4% of patients showed primary resistance to it. Prospective sequencing trials are under way; as far as I can find, none has reported.
For the small company with a novel conjugate, the matter assumes a different complexion.
The patients arriving in a first-in-human study two years hence will very probably have had an ADC already, with a topoisomerase payload, and earlier in their disease than today’s patients did. The payload, the comparator and the eligibility criteria all want choosing with that patient in mind.
The protocol template from 2022 will need more than a new date.”
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