With the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO), which was held in Chicago, Illinois, May 29 – June 2, now a few weeks behind us and our post-conference review of the latest data from numerous abstracts, trial updates and presentations in full swing, two clinical trial/drug development programs have caught our attention: IMGN853 (mirvetuximab soravtansine; ImmunoGen) and IMMU-132 (sacituzumab govitecan; Immunomedics).
The first trial program is that of mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting Antibody-drug Conjugate. FRα is highly expressed in many cases of epithelial ovarian cancer as well as on other types of solid tumors including endometrial cancer and some non-small cell lung cancers (adenocarcinoma), making it a good target for the potential treatment of these cancers.
The drug, being developed by ImmunoGen, is the first and only FRα-targeting ADC to enter clinical testing. It is currently being assessed for the treatment of FRα-positive, platinum-resistant ovarian cancer and for FRα-positive relapsed/refractory endometrial cancer, with additional assessments anticipated.
Mirvetuximab soravtansine comprises a FRα-binding antibody which is conjugated to a highly potent maytansinoid (DM4) that induces cell-cycle arrest and cell death by targeting microtubules. The antibody serves to target the DM4 specifically to FRα-positive cancer cells which the DM4 can then kill. 
Platinum-resistant Ovarian Cancer
Mirvetuximab soravtansine targets an important unmet need in the treatment of ovarian cancer. Each year, there are approximately 21,300 new cases of ovarian cancer diagnosed in the United States and more than 14,200 women die from the disease.  Researchers at ImmunoGen estimate that approximately 2,000-3,000 of these women have FRα-positive, platinum-resistant ovarian cancer previously treated with at least three prior lines of therapy.
The standard, first-line, therapy for ovarian cancer is a platinum-based regimen, including carboplatin (Paraplatin®; Bristol-Myers Squibb/BMS plus a taxane and potentially additional agents). Once the cancer becomes platinum-resistant, which means that the disease recurs rapidly (within six months), patients may receive non-platinum-based chemotherapies given as single-agent therapy, such as pegylated liposomal doxorubicin (Doxil®/Caelyx®; Janssen Biotech) or paclitaxel (Taxol®; Bristol-Myers Squibb/BMS). However, response rates with these agents in the second-/third-line setting are typically around 15-20%.  Unlike current treatment for platinum-sensitive patients, treatment in the platinum-resistant setting typically yields low tumor response rates. Patients also experience shorter progression-free survival (PFS) and overall survival (OS). In the advanced setting, treatment becomes largely palliative.
Clinical trial eligibility
Before considered eligible for enrollment and participation in the expansion cohort with mirvetuximab soravtansine, patients must have ovarian cancer that responded to primary platinum therapy, but has then progressed within six months or progressed on or within six months of treatment with subsequent platinum therapy. The cancer must also be FRα-positive, assessed by immunohistochemistry. Approximately 80% of patients screened met this criteria based on the CLIA lab assay.
To obtain additional experience in this patient population, the expansion cohort has been expanded from 20 to 40 patients.
Mirvetuximab Soravtansine (IMGN853): Trial Results
This year trial results were presented during the annual meeting of the American Society of Clinical Oncology (ASCO) of the first clinical findings in a disease-specific patient population with ImmunoGen’s unique, FRα-targeting ADC, mirvetuximab soravtansine (ASCO abstract #5518) 
The findings reported at this year’s are from an ongoing Phase I trial. Once the recommended Phase II dose (RP2D) of mirvetuximab soravtansine was established during dose finding (ASCO abstract #5558), an expansion cohort was opened to assess the safety and activity of this ADC specifically in the treatment of patients with FRα-positive platinum-resistant ovarian cancer. Approximately 80% of the patients screened have met the criteria for having FRα-positive disease.
Twenty-two patients were included in the analysis reported during ASCO – two from the dose-escalation phase of the trial and the twenty enrolled in the expansion cohort at the time of data cutoff for presentation (April 30, 2015). All had FRα-positive platinum-resistant ovarian cancer and had received mirvetuximab soravtansine at the RP2D (6.0 mg/kg, given every three weeks). Furthermore, all participating patients had previously received taxane as well as platinum therapy. Thirteen of these patients were still on study at the time of data cutoff.
The majority of adverse events reported were low grade (grade 1 or 2), with diarrhea, blurred vision, nausea, vomiting, fatigue, and abdominal pain the most common treatment-emergent events reported ( > 20% of patients).
Seventeen of the 22 patients were included in the efficacy analysis; the other five patients were still on study and had not yet reached their first assessment.
Other findings included:
- Nine of these 17 patients had an objective response (8 partial responses, 1 complete response) to treatment, for an ORR of 53%.
- The responses in six of these nine patients were ongoing at the time of data cutoff, with five of these six patients on treatment for more than 15 weeks.
“These initial clinical findings with mirvetuximab soravtansine in the treatment of patients with FRα-positive platinum-resistant ovarian cancer are highly encouraging,” noted Kathleen Moore MD, Mai Eager Anderson Chair of Cancer Clinical Trials, Stephenson Cancer Center, University of Oklahoma HSC. “There is a significant need for new therapies for patients with ovarian cancer, including platinum-resistant disease.”
Single agent treatment
“Based on these findings, we are implementing a development plan designed to advance mirvetuximab soravtansine as quickly as possible while also recognizing the potential to benefit the greatest number of patients,” commented Charles Morris, M.B., Ch.B. MRCP, Executive Vice President and Chief Development Officer at ImmunoGen. “We’re preparing to initiate a Phase II trial in late 2015 that will assess this ADC as a single-agent treatment for patients with FRα-positive platinum-resistant ovarian cancer. It is possible that this trial could be used for registration in this patient population.”
“At the same time, we’re preparing to initiate testing of mirvetuximab soravtansine in combination regimens as a potential therapy for patients with less heavily pretreated ovarian cancer. We’re also continuing to explore this promising ADC as a treatment for other types of FRα-positive solid tumors, including target-positive endometrial cancer. To complement our own research, ImmunoGen recently entered into a collaboration with the National Comprehensive Cancer Network® (NCCN) Oncology Research Program to investigate mirvetuximab soravtansine in additional preclinical and clinical studies,” Morris continued.
Sacituzumab govitecan (IMMU-132): Impressive results in SCLC
The second antibody-drug conjugate to be noted by our team was that of the investigational drug sacituzumab govitecan (IMMU-132) for the treatment of patients with relapsed/refractory metastatic non–small cell lung cancer (NSCLC) who have failed two prior lines of therapy, including targeted therapies such as an ALK inhibitor, EGFR inhibitor, and, if applicable, a PD-1 inhibitor.
The investigational drug, which was recently awarded fast track designation by the U.S. Food and rug Administration (FDA) and considered to be a next-generation antibody-drug conjugate, is also assessed in patients with relapsed small cell lung cancer (SCLC). The data presented at this year’s ASCO meeting was welcome news since SCLC, a fatal disease, has not seen new drug approvals for nearly 2 decades.
Sacituzumab govitecan targets the cell surface glycoprotein called TROP-2 on cancer cells. This glycoprotein is highly expressed in most epithelial cancers, including non-small and small cell lung cancers (NSCLC and SCLC). In contrast, there is little or no expression of TROP-2 in normal tissues. Various studies show that TROP-2 expression correlates with tumor aggressiveness. Combined with the fact that TROP-2 is selectively expressed in tumor cells, interest in TROP-2 as a potential -attractive – therapeutic target for the treatment of cancer immunotherapy has over the last decade, increased. 
Sacituzumab govitecan is an antibody-drug conjugate being developed by Immunomedics in which the antibody part of the drug binds to TROP-2. Further, the antibody part of the drug (the anti–TROP-2 humanized monoclonal antibody hRS7) is site-specifically linked to the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), SN-38, using a proprietary linker.
In contrast to most antibody-drug conjugates in clinical development that use hyper-toxic drugs and stable linkers, sacituzumab govitecan includes a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker.  However, in vitro and in vivo preclinical data confirms that sacituzumab govitecan is most efficacious at a high drug-antibody ratio (DAR) of 7.6 (7.6 moles SN-38/IgG). The same data shows that in a human cancer xenograft the investigational drug is capable of delivering up to 136-fold more SN-38 than its parental drug irinotecan.
A phase I study confirmed that sacituzumab govitecan has acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. 
Trial results of a yet another trial of 19 patients with SCLC treated with sacituzumab govitecan, presented at this year’s ASCO meeting were impressive: 26% of patients had partial responses, and another 27% had stabilization of disease. (ASCO abstract #2504) 
Triple Negative Breast Cancer
Sacituzumab govitecan is also associated with encouraging clinical activity and limited toxicity in patients with metastatic triple-negative breast cancer (TNBC) who have received multiple prior lines of therapy, including topoisomerase inhibitors, but were refractory or relapsing to these prior therapies. 
Patients with metastatic TNBC, which is negative for estrogen and progesterone receptors, as well as human epidermal growth factor receptor 2 (HER2), have an aggressive disease with only limited therapeutic options. This type of breast cancer comprises about 15-20% of all invasive breast cancers and is more prevalent in young and African-American women. Despite the fact that initial responses with chemotherapy are high, TNBC characteristically has a high recurrence rate and is perhaps the most difficult type of breast cancer to treat successfully with current cytotoxic agents. Media progression-free survival (PFS) in the range of 2.9 – 3.7 months has been reported in recent clinical studies in patients with metastatic TNBC following chemotherapy. Currently, there are no targeted treatments available for TNBC. Hence, there is a major unmet need for better therapies.
TROP-2 is highly expressed in most TNBC ( > 90%) and clinical trial data presented at this year’s ASCO meeting of 174 patients with relapsed/refractory diverse epithelial tumors (including 49 patients with TNBC; median age = 51 ys (range, 33-81), median of 4 prior chemotherapies) who have been treated with sacituzumab govitecan, confirm that further studies with this novel agent are, indeed, warrants.
The data included 49 patients with metastatic triple-negative breast cancer evaluated for response to treatments with sacituzumab govitecan in a mid-stage clinical study. In total, 31%, or 15 patients, showed a reduction in tumor size of 30% or more. This include 2 patients with complete response (CR). Response assessments were based on the rules set by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Adding the 22 patients with responses between less than 30% tumor shrinkage and less than 20% tumor increase, the disease control rate was 76%.
“Given that a majority of the patients enrolled into this study had failed 4 or more prior cancer therapies, some as many as 11, we are quite encouraged with sacituzumab govitecan in this late-stage setting in an aggressive disease that is difficult to treat,” noted Aditya Bardia, MD, MPH, an Instructor at Department of Medicine, Harvard Medical School, and Assistant Physician, Medical Oncology, Massachusetts General Hospital Cancer Center in Boston, MA who presented the data.
The data presented at this year’s ASCO meeting – for both mirvetuximab soravtansine and sacituzumab govitecan – offers renewed hope for patients with difficult to treat cancers.