Photo: San Deigo Bay from Harbor Drive, San Diego, CA, USA. Photo Courtesy: This photo has been released into the public domain by its author, Jon Sullivan. This applies worldwide.
Photo: San Deigo Bay from Harbor Drive, San Diego, CA, USA. Photo Courtesy: This photo has been released into the public domain by its author, Jon Sullivan. This applies worldwide.

Sacituzumab govitecan, Immunomedics’ lead investigational antibody-drug conjugate or ADC, produced durable responses that exceeded one year in some patients with metastatic triple-negative breast (TNBC), small-cell lung cancer and non-small-cell lung cancer. In other patients with less than 1 year of response duration, their responses are continuing.

These positive trial results were presented by David M. Goldenberg, MD, Immunomedics’ Chairman, Chief Scientific Officer and Chief Patent Officer during the 6th World ADC Conference, being held October 19 – 22, in San Diego, CA.

Tripple Negative Breast Cancer
One presentation discussing the results of sacituzumab govitecan on Tripple Negative Breast Cancer or TNBC in the treatment of patients who relapsed after 2 or more prior lines of therapy that included taxane, a class of chemotherapy agents used to treat solid cancers, such as breast, gastric, head and neck, lung, ovarian, pancreatic, and prostate.

At the time of this analysis, 56 enrolled patients had received sacituzumab govitecan at the optimal dose of 10 mg/kg given on days 1 and 8 of a 3-week cycle, and in some patients the therapy continued for many months. The median number of prior lines of therapy for the patients enrolled with metastatic TNBC was 5 (range, 2 – 12).

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Treatment response, assessed by computed tomography (CT) according to the rules set by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1), was available for 52 patients. The objective response rate was 29% (15/52), with 2 confirmed complete responses. The interim median progression-free survival (PFS), a measure of time patients are living without their cancer progressing, was 7.0 months, which appears to be longer than the best PFS results in this patient setting achieved by currently-used agents. Forty-six percent of these TNBC patients had experienced a PFS event. Overall survival (OS) data were too early to report because 86% of patients are still alive.

These results are very interesting given the serious disease of TNBC. In the United States, the diseases has an annual incidence estimated of about 40,000 people, 20,000 for metastatic TNBC (mTNBC), and with a median survival of 10-13 months and median PFS of 2-3 months for mTNBC.

Metastatic Triple negative Breast Cancer or mTNBC is insensitive to most of the available targeted therapies for breast cancer treatment. This includes HER2-directed therapy (such as trastuzumab), and endocrine therapies (such as tamoxifen or the aromatase inhibitors). There is currently no single standard chemotherapy to treat patients with relapsed/refractory mTNBC. Duration of response is usually short, with rapid relapse, and visceral and brain metastases are very common. In second-line therapy and later, most chemotherapeutics have shown a PFS of up to 3.5 months.

Lung cancer
For metastatic lung cancers, a total of 33 patients with NSCLC, having received a median of 3 (range, 1 – 7) prior therapies, were enrolled to receive sacituzumab govitecan at the 8.0 mg/kg or 10 mg/kg dose level. Among the 29 patients that were assessable, an objective response (partial response) rate of 28% (8/29) was observed, including patients with both squamous cell and adenocarcinoma NSCLC types. For the 25 patients at the 10 mg/kg dose, the interim median PFS was 3.8 months, with 48% of patients in this dose group having experienced a PFS event.

In Small-Cell Lung Cancer or SCLC, of the 27 patients, with a median of 3 prior therapies (range 1 – 5), enrolled at the doses of 8.0 mg/kg and 10 mg/kg, 25 were assessable for response. Six patients achieved a partial response (objective response rate = 24%). Interim median PFS for the 12 patients at the 10 mg/kg dose level was 3.6 months and 83% of patients had experienced a PFS event. Since 96% of NSCLC patients and 100% of SCLC patients were still alive at the time of analysis, OS data at the optimal dose of 10 mg/kg are too early to report.

SCLC is a histologic subtype of lung cancer with a distinct biology, treatment regimens, and patient population. It accounts for approximately 15% of bronchogenic carcinomas. Median survival is measured in months when untreated, and the 5-year survival rate is in the range of 4- 5%. Thus, there is a tremendous need for new therapies that can be given to patients after failing initial therapy, and initial chemotherapy for metastatic disease is unsatisfactory. These patients relapsing after a platinum-containing therapy have a median survival of only 4 to 5 months. Single-agent topotecan is approved by the FDA as a subsequent therapy for patients with SCLC and leads to a survival of only 16 to 21 weeks, and an overall response rate of 2-7% in platinum- refractory patients.

Estimated new cases and deaths from both NSCLC and SCLC in the United States in 2015 are 221,200 and 158,040 respectively. Lung cancer is the leading cause of cancer- related mortality in the United States. All patients with advanced or metastatic NSCLC either relapse or die. More than 60,000 patients die in the U.S. each year from squamous NSCLC, which is more than the annual deaths from breast cancer and colon cancer combined.

Approved drugs
Currently, only erlotinib is registered for this indication. This treatment is only indicated for patients who have not yet received EGFR TKIs regardless of the performance status. Recently, two checkpoint-inhibiting antibodies targeting PD-1 have been approved in patients with advanced NSCLC.

Metastatic urothelial cancers
Goldenberg also presented results, for the first time, on 15 patients with metastatic urothelial cancers, mostly urinary bladder cancers. At the time of analysis, 6 of 11 patients who relapsed to a prior platinum-containing therapy and evaluable by CT achieved a partial response (objective response rate = 55%), with 5 patients still continuing treatment.

Sacituzumab govitecan continues to demonstrate a highly tolerable safety profile. Among the 261 patients enrolled to-date, only 8 patients had reported adverse events that temporarily interrupted the infusion. In the 118 patients receiving the ADC at the dose of 10 mg/kg, the major toxicity reported was Grades 3 or 4 neutropenia in 20% of patients.

Urothelial bladder carcinoma (UC) is the sixth most frequent cancer. Cisplatinum-based combination chemotherapy is the only known therapy that has demonstrated a survival benefit for patients with advanced disease. Unfortunately, only a small subset will attain long-term survival. For those participating in clinical trials, the median overall survival is 15 months and the five-year survival is only 15%. Following progression within 6-12 months of platinum-based chemotherapy (platinum-resistant urothelial carcinoma), whether delivered in the peri-operative or advanced setting, survival is only 4-9 months for those eligible for clinical trials and no therapy is approved in the U.S., with only vinflunine being approved in Europe. Developing effective second-line therapies for advanced urothelial cancer represents an important unmet medical need.

“These efficacy and safety results reaffirm the high therapeutic index of sacituzumab govitecan in TROP-2-expressing solid cancers, which, we believe, distinguishes it from other ADCs approved or in development,” remarked Cynthia L. Sullivan, President and Chief Executive Officer. “The Phase 2 study will be further updated at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November, and the San Antonio Breast Cancer Symposium in December,” Sullivan added.

Sullivan further commented, “We continue to advance our regulatory preparations with the FDA to move sacituzumab govitecan to a Phase III registration trial in patients with late-stage, metastatic TNBC, while we also focus on our business development activities for this agent. We will continue to expand our studies in patients with metastatic NSCLC, SCLC, and urothelial cancer. We believe this novel ADC will also show important activity in other cancer types, based on preclinical and early clinical results.”

First-in-class
Sacituzumab govitecan is a first-in-class ADC developed by the Company by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to antibody, to a humanized antibody that targets the TROP-2 receptor expressed by many solid cancers. The ADC has received Fast Track designation from the FDA for the treatment of patients with TNBC, SCLC and NSCLC, and has also been designated an orphan drug for the treatment of patients with SCLC or pancreatic cancer in the U.S., and for the treatment of patients with pancreatic cancer in the European Union.