Two prominent cancer journals have published phase II clinical trial results with sacituzumab govitecan (IMMU-132; Immunomedics) in a total of 104 patients with lung cancer, including advanced small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) patients who relapsed after, or were refractory to, prior treatment with standard chemotherapy or immune checkpoint inhibitors.

Lung cancer is the most prevalent cancer worldwide; 1.8 million patients were diagnosed in 2012. It is also the leading cause of cancer deaths, taking 1.6 million lives annually. The vast majority of lung cancer cases (85%) comprise the NSCLC type, which has had a median life expectancy of 10 months when standard chemotherapy is used. With the introduction of immune checkpoint inhibitors, median survival has increased to almost 15 months when at least 50% of cells were positive for PD-L1.

Pembrolizumab (Keytruda®; Merck & Co) was reported to be more effective than chemotherapy in the frontline setting of patients with metastatic NSCLC at high levels of PD-L1 positivity (progression-free survival 10.3 months vs. 6.0 months for those given platinum-based chemotherapy), but this population only constituted about one-quarter of metastatic NSCLC patients.

MabPlex
 

In pretreated patients with metastatic NSCLC, the objective response rates for the immune checkpoint inhibitors generally range from 14% to 20%.

Aggressive nature
SCLC comprises approximately 15% of all lung cancers, and has the worst prognosis. This is because of its highly aggressive nature, with about two-thirds of patients already having metastatic disease at diagnosis. While palliative first-line therapy of stage IV SCLC (mSCLC) has a high initial response rate of 60% to 75%, the outcome is poor, with a median progression-free survival of only 5.5 months and a median overall survival of <10 months with platinum-based chemotherapy. Responses to second-line therapy have been poorer, such as <10%, with a median survival of only 4 to 5 months following second- or third-line chemotherapy.

Unfortunately, those patients with platinum-resistant mSCLC (i.e., response duration <3 months) fare even worse.

In the United States, the only approved drug in this second-line setting of chemosensitive patients (duration of response exceeding 3 months), since 1998, is topotecan.  This agent, which is reasonably well tolerated, is indicated for recurrent patients who were sensitive to frontline chemotherapy with platinum-containing regimens.[1]

Topotecan, a water-soluble analog, originates from a family of chemotherapeutic agents, including the parent drug Camptothecin, a plant alkaloid extract derived from the oriental tree Camptothecan acuminate, that inhibit the DNA topoisomerase I enzyme, which is responsible for relaxing a supercoiled DNA helix during DNA synthesis. The agent inhibits the religation step of the enzymatic reaction by stabilizing the DNA enzyme complex.  Following this step, it causes accumulation of persistent single strand DNA breaks.

Although is Topotecan the only approved drug,  irinotecan, taxanes, vinorelbine, gemcitabine, and pemetrexed are given frequently to patients with chemosensitive recurrent disease. Even when patients respond to second-line therapies, there is usually no improved survival. Immune checkpoint inhibitors have not gained a role in the management of mSCLC.

Sacituzumab govitecan and Small-cell Lung Cancer
A study advanced small-cell lung cancer published online in Clinical Cancer Research. In this article the authors [2] evaluated sacituzumab govitecan, a second-generation antibody-drug conjugate or ADC, composed of the humanized anti-Trop-2 antibody linked to SN-38, a payload of the active metabolite of irinotecan with a drug-to-antibody ratio (DAR) of 7.6.

Irinotecan and SN-38 inhibit the nuclear enzyme, topoisomerase- 1, resulting in double-strand DNA breaks and death of the affected cells. However, SN-38 is about 1,000- fold more potent than its parental prodrug, irinotecan.

Because SN-38 is delivered selectively by the anti-Trop-2 antibody, it is believed this toxicity is selective for cancer cells having higher levels of Trop-2 than normal cells. This results in a selective targeting and killing of cancer cells having Trop-2, which includes a large number of cancer types.

Because of the way SN-38 is attached to the cancer-targeting antibody, sacituzumab therapy avoids the debilitating diarrhea caused by irinotecan therapy. However, like irinotecan, the major adverse effect is neutropenia, which is manageable either by reducing or delaying therapy, or treating the patient with a drug that stimulates production of neutrophils.

The study published in Clinical Cancer Research  included 50 patients with small-cell lung cancer with metastatic (stage IV) disease who had a median of 2 prior therapies.

The authors noted:

  • Ninety-two percent of the patients evaluated for expression of the target for sacituzumab govitecan, Trop-2, had elevated levels in their archived tumor specimens.
  • Patients given repeated treatment cycles had manageable toxicity, mostly Grade >3 neutropenia (34%), and 60% of those patients experienced tumor shrinkage from baseline CT measurements.
  • The objective response rate was 17% at the optimal dose schedule; the median duration of response and overall survival were 5.7 and 7.5 months, respectively.
  • Activity was observed in patients who were chemosensitive or chemoresistant to frontline chemotherapy, in patients who failed second-line topotecan, and in a subset who relapsed after immune checkpoint inhibitor therapy.

“In contrast, to topotecan, sacituzumab govitecan showed activity in patients who were either responsive or refractive to frontline therapy, and also to those who relapsed to topotecan. A randomized, controlled trial comparing these two agents in second-line therapy, as well as sacituzumab in the frontline setting, should be undertaken,” noted Jhanelle Gray, MD, of the Moffitt Cancer Center, Tampa, FL, the article’s first author.

Promising new therapeutic candidate
“Sacituzumab govitecan represents a promising new therapeutic candidate for advanced mSCLC, a very lethal cancer with a five-year survival rate of only 6 percent,” commented David M. Goldenberg, Immunomedics’ founder.

“Importantly, this candidate potentially could be the first new therapeutic approved for the treatment of metastatic (stage IV) small-cell lung cancer (mSCLC) in twenty years,” he added.

Sacituzumab govitecan and Non-small Cell Lung Cancer
In the second article published online on May 26, 2017, in the Journal of Clinical Oncology, the authors [3] reported the results of the phase II, multicenter trial of 54 heavily-pretreated patients with metastatic NSCLC who received either 8 or 10 mg/kg sacituzumab govitecan on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR). Progression- free survival (PFS) and overall survival (OS) were secondary endpoints.

  • Some of the key findings reported in this article included:
    In the response-assessable study population (N = 47), which had a median of 3 prior therapies (range, 2-7), 67% of patients showed a shrinkage from baseline CT measurements.
  • The confirmed objective response rate was 19.1%, the median response duration 6.0 months (95% CI, 4.8, 8.3), and the clinical benefit rate (CR+PR+SD>4 months) was 43%. Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy.
  • Median intention-to-treat (ITT) PFS was 5.2 months (95% CI, 3.2, 7.1), and median ITT OS was 9.5 months (95% CI, 5.9, 16.7).
  • Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%).
  • Over 90% of 26 assessable archival tumor specimens were highly positive for Trop-2 by immunohistochemistry.

“In a heavily pretreated population like this, the results with sacituzumab govitecan are quite encouraging, suggesting further trials both alone and in combination with other drugs, potentially including immunotherapy, should be strongly considered,” D. Ross Camidge, Director of Thoracic Oncology at the University of Colorado Cancer Center and senior author of this study, explained

“Non-small-cell lung cancer patients will always benefit from additional therapeutic choices, and while immunotherapy and oncogene targeted therapy have certainly revolutionized the treatment for subsets of the disease, the use of ‘smarter’ chemotherapy in the form of an effective antibody-drug conjugate such as sacituzumab govitecan may well be the next major advance we see,” Camidge added.

More promising results
“These promising results in two lung cancer indications, comprising the major cancer killers, attest to the breadth of the therapeutic potential for IMMU-132 in the treatment of metastatic solid cancers. Our principal focus is to seek accelerated approval for this ADC in patients with advanced, heavily-pretreated triple-negative breast cancer (TNBC), for which there is no approved therapy and significant patient unmet need,” noted Behzad Aghazadeh, MD, Chairman of the Board of Immunomedics.

“We have also reported that sacituzumab govitecan, in addition to TNBC, SCLC, and NSCLC, is active in patients with metastatic urothelial cancers, where we hope to update results at a future medical meeting, so we now know it is active in at least four different major solid cancers, Aghazadeh concluded.