Cel-Sci Corporation's (CVM) Phase III trial using Multikine in advanced head and neck cancer continues while still awaiting its endpoint. The reader is referred to my Seeking Alpha article entitled: Cel-Sci Corporation: This Phoenix Will Rise dated October 29, 2018 for a full explanation of Multikine and Cel-Sci's Phase III trial. Cel-Sci, investors and scientists have all assumed the trial would be completed long before now. So why hasn't the endpoint been reached? The delayed clinical effects of using immunotherapy is likely the reason.
Immunotherapy for cancer has changed dramatically since Cel-Sci began their Phase III study using Multikine in head and neck cancer almost nine years ago. The reason for this 180 degree turn is largely based on the clinical successes of anti-Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors (also called checkpoint inhibitors) which has signaled a new era of cancer immunotherapy research. These findings also led to the selection of "Cancer Immunotherapy" as the 2013 "Breakthrough of the Year" by the journal Science.
During the time it took for the interest in immunotherapy of cancer to revive, researchers faced several obstacles before realizing that immune therapy was different from chemotherapy in terms of survival kinetics.
When Ipilimumab (Yervoy® - Bristol Myers Squibb - 2018 est. sales of $1.5B) was in clinical trials, the study's primary endpoint was Best Overall Response Rate (BORR). In one of the ongoing Phase II studies, an observation was made that led researchers to challenge the status quo of study designs for cancer immunotherapy.
In this dose ranging study, patients previously treated for melanoma were randomized to obtain .3mg/kg, 3mg/kg or 10mg/kg of ipilimumab. Final results showed the BORR only ranged from 0% to 11% between the three dosing arms. However, Overall Survival (OS) indicated an 8-month delayed clinical effect and a dose-response effect on long term survival. This observation resulted in Bristol Myers Squibb changing the primary endpoint from BORR to OS in the company's pivotal Phase III study before the study had been unblinded. The final analysis confirmed the unique survival kinetics of ipilimumab with a four month clinical effect delay and a long term survival of approximately 20%.
The overlapping of the survival curves in the first 4 months indicated a delay in the clinical effects of ipilimumab. The delayed separation of survival curves demonstrated that the probability of survival did not decay at a constant rate between treatment arms so the statistical assumption of proportional hazards was violated.
Other studies have demonstrated the delayed clinical effect related to immunotherapy of cancer. Larkin et. al. reported on a study using nivolumab (Opdivo® - Bristol Myers Squibb - 2018 est. sales of $1.6B) and ipilimumab as a combination or each as monotherapy in untreated melanoma. He found the progression free survival (PFS) curves for all three arms overlapped during the first 3 months. Additionally, Postow et. al. reported on a study that compared ipilimumab as a single agent or combined with nivolumab in treating newly diagnosed melanoma. A delay in clinical effect of 3 months was observed in the combination arm.
The concept of a delayed clinical effect when using immunotherapy is logical. In contrast to chemotherapy's immediate and direct toxic effect on the cell, immunotherapy stimulates the patient's immune system to mount an anti-tumor response. The time needed to mount this response results in a delay in the clinical response relative to chemotherapy.
I believe the phenomenon of a delayed clinical effect is being observed in Cel Sci's Phase III trial and why the anticipated end point has not yet been reached.
Disclosure: I am/we are long CVM.