March kicked off with ImmunoGen stock prices dissipating by more than half in a day, from $4.72 to $2.30 per share. This came in response to the public release made by the US-based biotechnology company revealing that their folate alpha receptor (Fα)-targeting antibody-drug conjugate (ADC), mirvetuximab soravtansine, failed to extend progression-free survival (PFS) over chemotherapy for Fα-positive platinum-resistant ovarian cancer patients in the pivotal FORWARD I study.

Although the leadership at ImmunoGen remains optimistic with their lead drug candidate, the trial data underlines the possibility that mirvetuximab soravtansine may have trouble with market entry and may end up being another discouraging example for other Fα targeting strategies, which are in the early-stage ovarian cancer pipeline.

In FORWARD I, 366 women with up to three lines of prior therapy were given mirvetuximab soravtansine or investigator’s choice of single-agent chemotherapy (PEGylated liposomal doxorubicin, topotecan, or paclitaxel) in a 2:1 ratio. For the entire trial population, there was no significant benefit favouring the use of mirvetuximab soravtansine, with a PFS hazard ratio of 0.98 and p-value of 0.987 failing to demonstrate a statistical difference from chemotherapy.

Results from FORWARD I signal concern for Fα-targeting strategies. Previously, Fα-targeting drugs have suffered from shortcomings in terms of efficacy and trial design that impacted their overall utility for prolonging PFS in ovarian cancer.

In 2007, Eisai acquired the rights to farletuzumab through a $325m merger with Morphotek ; farletuzumab is an anti-Fα monoclonal antibody that failed in Phase III trials due to lack of PFS benefit in platinum-sensitive ovarian cancer patients. Endocyte’s small molecule drug conjugate vintafolide, with its failure in Phase II clinical trials, led to the breakup of a partnership with Merck & Co. that was once valued at $1bn.

ImmunoGen will have to revisit trial design for future development of mirvetuximab soravtansine. Although the company primarily views mirvetuximab soravtansine as a monotherapy, the Phase I/II FORWARD II study assesses mirvetuximab soravtansine in combination with the anti-angiogenic drug Avastin (bevacizumab), PD-1 immunotherapy Keytruda (pembrolizumab), and various chemotherapy agents in both platinum-sensitive and platinum-resistant Fα-positive ovarian cancer patients. In this cohort, the overall drug response rate for platinum-resistant patients hit 48% when given with Avastin. In contrast, the overall response for the entire patient population in FORWARD I remained at 22%.

ImmunoGen also reported data from a pre-specified patient subgroup with high Fα expression for which the drug response, PFS, and overall survival rates were collectively higher. If ImmunoGen directed Phase III trials on this patient subgroup, their chances of hitting clinical endpoints may be improved. However, a similar subgroup analysis for farletuzumab couldn’t reverse the outcome of that development program.

ImmunoGen President and Chief Executive Officer reiterated strongly that the company has the financial means, $295m in cash, which suggests that ImmunoGen can initiate a new clinical trial that would incorporate better patient selection criteria, multiple treatment arms, and an improved trial design. However, ImmunoGen needs to tread carefully in order to turn around mirvetuximab soravtansine and set an example for other Fα-targeting strategies.