ESMO 2019: FORWARD I Study of Mirvetuximab Soravtansine in Ovarian Cancer Did Not Meet Primary Endpoint of Progression-Free Survival

General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.
General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

The full data and exploratory analyses from the Phase III FORWARD I study (NCT02631876) evaluating mirvetuximab soravtansine, also known as IMGN853, compared to chemotherapy in women with folate receptor alpha (FRα)-positive, platinum-resistant ovarian cancer were presented during an oral presentation at the European Society for Medical Oncology (ESMO) 2019 Congress, being held in Barcelona, Spain, September 27 – October 1, 2019.

Mirvetuximab soravtansine, being developed by ImmunoGen, is the first folate receptor alpha (FRα)-targeting antibody-drug conjugate or ADC.

The investigational agent uses a humanized FRα-binding antibody to target the antibody-drug conjugate specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells.

ADC Bio
Lonza
MabPlex
 

Study results
The study results, presented during the ESMO 2019 Congress, show that the FORWARD I trial did not meet the established primary endpoint of progression-free survival (PFS). However, the trial results show promising efficacy results in folate receptor alpha (FRα) high patients and a favorable tolerability and differentiated safety profile compared to chemotherapy.

Kathleen Moore, MD, Director, Oklahoma TSET Phase I Program; Associate Professor, Section of Gynecologic Oncology. Moore is the Jim and Christy Everest Endowed Chair in Cancer Research as well as the director of the gynecologic oncology fellowship program. She also serves as the Associate Director of Clinical Research and Medical Director of the Clinical Trials Office for the Stephenson Cancer Center. Moore has published more than 200 peer-reviewed publications and serves on the editorial board for four academic publications.

“While it is disappointing that FORWARD I did not meet the primary endpoint of progression-free survival, mirvetuximab soravtansine demonstrated consistent and meaningful efficacy signals in patients with high levels of FRα expression and was well tolerated with a differentiated safety profile in both the ITT and FRα high populations,” explained Kathleen Moore, Associate Director of Clinical Research at the Stephenson Cancer Center at the University of Oklahoma.

“Despite recently reported advances in frontline treatment with the addition of PARPi maintenance therapy, the majority of patients will unfortunately develop platinum-resistant disease with limited therapeutic options characterized by low response rates, short progression-free survival, and significant toxicities,” she said.

“The encouraging data from FORWARD I suggest the potential for a significant improvement over single-agent chemotherapy in the FRα high population and I look forward to the continued development of mirvetuximab soravtansine for these patients in the upcoming Phase III study,” Moore added.

FORWARD I Trial
The FORWARD I Phase III trial randomized 366 patients 2:1 to receive either the investigational drug mirvetuximab soravtansine or the physician’s choice of single-agent chemotherapy (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel).

Patients eligible to receive the treatment were diagnosed with platinum-resistant ovarian cancer that expresses medium or high levels of folate receptor alpha (FRα) and were treated with up to three prior regimens.

The primary endpoint of this study was progression-free survival (PFS), which was assessed using the Hochberg procedure in the entire study population and in the subset of patients with high FRα expression. Based on an analysis of available data, aproximately 12,000-14,000 patients per year in the U.S. meet these criteria, with a comparable number in the major markets in Europe.

The Hochberg procedure enables the simultaneous testing of two overlapping populations. Under this statistical analysis plan, if the p-value of the primary endpoint in either population is greater than 0.05, the p-value in the other population needs to be less than or equal to 0.025 to achieve statistical significance. Simply said, the Hochberg procedure decreases the number of false positives.

Key Findings
The study shows that in the entire study population, the confirmed overall response rate (ORR) was higher for mirvetuximab soravtansine than for chemotherapy (22% vs 12%, p-value 0.015), without a significant difference in the primary endpoint of PFS (HR 0.981, p-value 0.897) or overall survival (OS) (HR 0.815, p-value 0.248).

Furthermore, in the pre-specified FRα high subgroup (218/366, 60%):

  • Median PFS (mPFS) was longer in patients who received mirvetuximab soravtansine compared with chemotherapy (4.8 months vs 3.3 months, HR 0.693, p-value 0.049). Given that the p-value in the entire study population exceeded 0.05, the statistical analysis plan for the study required the p-value in the high subset to be less than or equal to 0.025 to achieve statistical significance;
  • Confirmed ORR was higher for mirvetuximab soravtansine than for chemotherapy (24% vs 10%, p-value 0.014);
  • Overall survival (OS) was longer in patients who received mirvetuximab soravtansine compared with chemotherapy (HR 0.618, p-value 0.033);
  • The trend in improved OS in patients who received mirvetuximab soravtansine compared with chemotherapy persisted with an additional 6 months of follow-up (updated through August 2019: HR 0.678, with median OS [mOS] 16.4 months vs 12.0 months, p-value 0.048).

The study also showed that mirvetuximab soravtansine was well-tolerated, with fewer patients experiencing grade 3 or greater treatment emergent adverse events (TEAEs) (46% vs 61%), fewer dose reductions (20% vs 31%), and fewer discontinuations due to drug-related TEAEs (5% vs 8%) compared with chemotherapy.

The safety profile of mirvetuximab soravtansine was confirmed, with the most common drug-related adverse events including nausea (46% all grades; 1% grade 3 or greater), blurred vision (42% all grades; 2% grade 3 or greater), and keratopathy (33% all grades; 1% grade 3 or greater).

Over twice the percentage of patients who received mirvetuximab soravtansine compared with chemotherapy reported improved quality of life, as measured by at least a 15-point improvement in the abdominal/GI symptom subscale of the EORTC-QLQ OV28 (32% vs 14%).

Exploratory Analyses
“While FORWARD I generated promising outcomes in the FRα high subgroup, the anti-tumor activity did not reach the levels we have observed in our previous studies with mirvetuximab soravtansine,”

“Accordingly, we have undertaken a comprehensive assessment of the factors that may have contributed to the outcomes in FORWARD I. These exploratory analyses demonstrate that the use of a simplified scoring method to assess tumor samples for FRα expression inadvertently introduced a population of patients into FORWARD I with lower levels of FRα than intended,” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.

“When we reassessed the FORWARD I tumor samples using the scoring method from our previous studies, we determined that a significant percentage of patients included in FORWARD I had low levels of FRα expression that should have precluded enrollment. For those patients with medium or high levels of FRα expression upon rescoring, we observed efficacy outcomes for mirvetuximab soravtansine much more in line with our previous experience, with improved activity correlating with FRα expression and the strongest treatment effect for all efficacy endpoints in the intended FRα high patient population,” Berkenblit added.

“These findings have informed the design of our planned Phase III registration trial in FRα high patients,” she concluded.

PS2+ scoring method
Previous studies with mirvetuximab soravtansine have used a PS2+ scoring method to assess tumor samples for FRα expression to determine eligibility. The PS2+ scoring method assesses both intensity of staining (0, 1+, 2+, or 3+) and percentage of tumor cells staining at each intensity, with at least 50% of cells with at least 2+ staining considered FRα medium and at least 75% of cells with at least 2+ staining considered FRα high.

In preparation for launch of a companion diagnostic for commercial use, a simplified scoring method to assess FRα expression, known as 10X, was implemented prior to the start of FORWARD I.

In this case, eligibility was determined by scoring the percentage of tumor cells with positive membrane staining by ≤10X magnification without the need to separately assess level of intensity. A bridging study indicated that the 10X scoring method was sufficient for patient selection: staining visible at ≤10X magnification correlated with higher intensity staining (2+ and 3+), with lower intensity staining visible only at higher magnification.

However, aomparison to the much larger dataset from patients enrolled in FORWARD I suggested a significant population shift towards increased prevalence of FRα expression under the 10X scoring method as compared to the PS2+ scoring method.

Rescoring of the FORWARD I tumor samples by an independent pathologist, blinded to treatment assignment, using the PS2+ method demonstrated that 34% of patients enrolled in FORWARD I had FRα expression below the intended level. In addition, the FRα high subset enrolled in the study also contained a mixture of FRα expression when scored using the PS2+ method.

Scoring for FRα Determination
Exploratory efficacy analyses of the FORWARD I patients scored using the PS2+ method demonstrated improved outcomes correlated with FRα expression, with the strongest treatment effects for all efficacy endpoints in the PS2+ FRα high population (n=116). Compared with chemotherapy, mirvetuximab soravtansine was associated with:

  • Longer PFS (mPFS 5.6 months vs 3.2 months, HR 0.549 [95% CI 0.336, 0.897]);
  • Higher confirmed ORR (29% vs 6%); and
  • Longer OS (updated through August 2019: mOS 16.4 months vs 11.4 months, HR 0.678 [95% CI 0.410, 1.119]).

“With the results of these exploratory analyses, we have developed a clear view of which patients benefit most from mirvetuximab soravtansine and how to best identify those patients,” said Mark Enyedy, ImmunoGen’s President and Chief Executive Officer.

Registration trial
“We are working closely with U.S. Food and Drug Administration (FDA) to finalize the design of a Phase III registration trial for mirvetuximab soravtansine , which we call MIRASOL, and believe that the robust data generated from the FORWARD I analyses increase the likelihood of a positive outcome with this next study. We anticipate enrolling the first patient by the end of the year with topline readout in the first half of 2022,” Enyedy concluded.

* ImmunoGen partnered with the GOG Foundation, a leader in clinical research in gynecologic malignancies, on FORWARD I, which was conducted in North America and Europe.

Clinical trials
PH3 Study of Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in Women With FRa+ Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer (FORWARD I) | NCT02631876

References
Moore K, et al. FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC). ESMO Abstract #992O). Presented on Sunday, September 29, 2019 at 8:30 a.m. CEST/2:30 a.m. ET.