Recently, TESARO, Inc.(NASDAQ:TSRO) presented Phase 2 TOPACIO Data of niraparib in combination with an anti-PD-1 monoclonal antibody, KEYTRUDA® during a plenary session at the 2018 Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in New Orleans, Louisiana. The data demonstrate "activity in platinum-resistant and platinum-refractory ovarian cancer patients, regardless of biomarker status". However, RBC analyst Kennen MacKay said in a note "these data look to be inferior vs. competitor immuno-oncology combo data seen yesterday from ImmunoGen's (NASDAQ:IMGN) (drug known as) mirvetuximab soravtansine and Keytruda" in a heavily pre-treated group of ovarian cancer patients. Is that true?
TESARO-Niraparib + Keytruda: 60 evaluable patients (TOPACIO)
Data indicate "an overall response rate (ORR; including CR and PR) of 25% and a disease control rate (DCR; CR+PR+SD) of 68%; Response rates were not dependent on biomarker status". "ORR was 24% in the platinum refractory population. ORR was 26% (9/34) in patients without a tumor BRCA mutation (tBRCAwt), and 29% (7/24) in patients with HRD-negative tumors."
"For patients with platinum-resistant ovarian cancer, response to chemotherapy is 5-18%, Platinum refractory patients typically have even lower response rates. Historical response to PARP inhibitors is 5-10% in patients without BRCA mutations who have platinum resistant disease and 0-14% in those with BRCA mutations and platinum refractory disease. Response rates of 10-15% have been reported with anti-PD-1 antibodies in this ovarian cancer population."
ImmunoGen- mirvetuximab soravtansine + Keytruda: 14 patients (FORWARD II)
Data indicate "an overall response rate (ORR) of 63% in the subset of 8 patients with medium or high folate receptor alpha (FRα) expression levels."
"For all patients, the confirmed ORR was 43 %"
At a first glance, the ORR of 43% from FORWARD II is much higher than the ORR of 25% from TOPACIO. However, when you dig deep into the data, you will find out that TESARO TOPACIO data are compelling. Why? Let’s do the calculation.
FORWARD II is a study of mirvetuximab in combination with Avastin® (bevacizumab), pegylated liposomal doxorubicin, or Keytruda® (pembrolizumab) in patients with FRα-positive platinum-resistant EOC. All 14 patients enrolled is FRα-positive as mirvetuximab soravtansine (IMGN853) is the first FRα-targeting ADC. It uses a FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells.
In FORWARD II, 8 of 14 patients have a medium or high FRα expression level; these 8 patients have an ORR of 63% (8 x 63% = 5), which means 5 patients have responses. The other 6 patients have a low FRα expression level. Overall response rate for all 14 patients was 43% (14 x 43% = 6), which means total 6 patients have responses. Therefore, the ORR for patients with low expression of FRα was only 16.7% (1/6). The ORR of 16.7 % is close to the reported response rate of 10-15% for anti-PD-1 antibodies alone, and is much lower than the ORR of 25% in TOPACIO (which was not dependent on biomarker status).
In FORWARD II, 43% (6 of 14) of patients have low expression of FRα, while 57% (8 of 14) of patients have medium or high expression of FRα. Data show the combination of mirvetuximab soravtansine + Keytruda was only effective in patients with medium or high FRα expression. This is not a surprise based on the mechanism of this drug. Based on these data, ImmunoGen is enrolling an additional 35 patients with medium or high FRα expression levels in an expansion cohort in the FORWARD II study.
A recent study indicated a FRα expression rate of roughly 82% in patients with serous ovarian cancer. If the ratio of medium or high FRα expression vs. low FRα expression in FORWARD II study is true for a big population, then the combination of mirvetuximab soravtansine + Keytruda probably works in 47% platinum-resistant and platinum-refractory ovarian cancer patients (82% x 57% = 47%). For patients with low FRα expression or FRα negative (53%), Niraparib + Keytruda data (ORR of 25%) are compelling. Please note that in TOPACIO trial, 45% patients had been treated with 3 or more prior lines of chemotherapy, 97% with prior taxane, 63% with prior bevacizumab.
Conclusion: Data from TOPACIO (Niraparib + Keytruda) look to be superior vs. competitor immuno-oncology combo data from ImmunoGen's (IMGN) (mirvetuximab soravtansine +Keytruda) for heavily pre-treated platinum-resistant and platinum-refractory ovarian cancer patients with low FRα expression or FRα negative (25% ORR vs. 16.7% ORR).
Disclosure: I am/we are long TSRO.