Rocapuldencel-T is an autologous dendritic cell immunotherapy for patients with metastatic renal cell carcinoma about which we have written previously. It is produced by isolating patient tumor mRNA, which is then electroporated into patient dendritic cells in the presence of CD40 ligand. The rationale of this approach is to bypass mechanisms by which cancer cells dampen the anti-tumor immune response, including down-regulation of MHC Class I molecules. If the cancer antigens are presented on licensed dendritic cells, logically, the immune system would be appropriately stimulated to attack the cancer.
After encouraging phase 2 data and a green light from the data monitoring committee following a second interim analysis of the randomized phase 3 trial in patients with metastatic renal cell carcinoma who were undergoing cytoreductive or partial nephrectomy, the company recently announced that the data monitoring committee recommended discontinuation of the trial.
What happened and what are the next steps?
In a press release, the company stated –
In conjunction with its clinical and scientific advisors, the company is analyzing the preliminary ADAPT trial data set and plans to discuss the data with the U.S. Food and Drug Administration (FDA). The company plans to leave the ADAPT trial open while the company conducts its ongoing data review and discussions with FDA. Based on these analyses and discussions, the company will make a determination as to the next steps for the rocapuldencel-T clinical program.
“We are extremely disappointed with these results, which included seventy-five percent of the targeted events needed to permit the primary analysis and assessment of overall survival in the study,” said Jeff Abbey, president and chief executive officer of Argos Therapeutics. “We sincerely appreciate the patients and investigators who have participated in the ADAPT Phase 3 trial, and remain convinced in the ability of precision immunotherapy to improve the lives of patients.”
The full results of the trial are not available; but, let’s assume that the primary endpoint of increased overall survival in patients treated with sunitinib (Sutent) and rocapuldencel-T versus patients treated with sunitinib, alone, is not met. The analysis of secondary endpoints included progression-free survival and tumor response, could provide important insights. If the product showed some indication of improvement, perhaps, it may ultimately obtain approval.
A number of factors may modulate response and have affected the study results:
- Patients enrolled in the study were not refractory to prior therapy with sunitinib (or other treatment), rather, they were newly diagnosed. It could very well be that most of the tumors had not yet developed immune-evasive mutations that are overcome by rocapuldencel-T. If this were the case, it would follow that the addition of rocapuldencel-T would not improve clinical response. Perhaps, patients who were refractory to prior treatment would be more likely to have developed immune-evasive mutations and would benefit more from treatment with rocapuldencel-T.
- PD-1/PD-L1 inhibitors were not co-administered to patients. Perhaps, patients receiving rocapuldencel-T would have performed better if PD-1/PD-L1 were blocked so that the immune response triggered by rocapuldencel-T would not be abrogated.
We look forward to the availability of analyses of all endpoints from the phase 3 trial. It is unfortunate that the study does not appear to demonstrate an advantage for rocapuldencel-T. The company’s stock price dropped 74% in a matter of minutes on the news, and the company is currently valued at just ~$50 MM. This the high stakes world of biotechnology – the company raised sufficient funds to undertake a ~500 patient trial. Sadly, the wrong trial may have been performed (early disease, low MHC Class I expression, no co-administration of a PD-1/PD-L1 inhibitor), however, enough money was likely available to perform just one large trial. It would be a shame for a therapeutic approach as promising as this to come to an end.