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Rova-T in Advanced SCLC
The Premise and Promise of Rovalpituzumab Tesirine, a New Antibody–Drug Conjugate, in Small-Cell Lung Cancer

Released: November 03, 2017

Expiration: November 02, 2018

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Attempts to identify effective therapies for the treatment of small-cell lung cancer (SCLC), an aggressive tumor characterized by a rapid doubling time and a high propensity for early metastases, have been largely unsuccessful. Despite decades of research, including testing of numerous targeted therapies, the first-line standard of care for patients with extensive-stage (ES) SCLC remains platinum plus etoposide and the only FDA-approved second-line therapy is topotecan for sensitive or relapsed disease, with the survival rate for ES-SCLC being no higher than with that achieved with cyclophosphamide/doxorubicin/vincristine, a regimen developed in the 1970s.

More recently, a prolonged benefit in recurrent ES-SCLC was achieved with immune checkpoint inhibition (nivolumab with or without ipilimumab). However, only small subsets of patients benefit. Clearly, there is a need for novel therapies to treat ES-SCLC, with the antibody–drug conjugate (ADC) rovalpituzumab tesirine (Rova-T) showing particular promise.

Rova-T: Mechanism of Action and Preclinical Studies
ADCs consist of a monoclonal antibody specific to a cell surface protein (ideally abundant in tumors and absent in normal tissues) conjugated to a potent cytotoxic agent through a linker. Once bound to its antigen on a tumor cell, the ADC is internalized and the linker is enzymatically cleaved, releasing the toxin to the cytosol and leading to eventual cell death. Rova-T comprises an antibody that targets the inhibitory Notch ligand DLL3, a linker that is cleavable by the lysosomal protease cathepsin B, and a pyrrolobenzodiazepine dimer toxin that, when released into the cytosol, enters the nucleus and binds to the DNA minor groove leading to tumor cell cycle arrest and subsequent apoptosis of the targeted cell. In preclinical studies, DLL3 was shown to be expressed on the cell surface of 72% and 85% of treatment-naive and recurrent/refractory SCLC tumor biopsy specimens, respectively, but not normal lung biopsy specimens, suggesting it is an ideal protein to selectively target with an ADC. Furthermore, in multiple patient-derived xenograft SCLC tumor models expressing surface DLL3, Rova-T showed rapid tumor reduction followed by durable responses.

Phase I SCRX16-001: First-in-Human Trial of Rova-T in Recurrent SCLC
The phase I SCRX16-001 trial was the first-in-human evaluation of Rova-T. In this study, 74 patients with SCLC who previously received at least 1 systemic therapy were treated with increasing doses of Rova-T. Among enrolled patients, 47% had received 2 previous lines of therapy and 40% were resistant or refractory to first-line chemotherapy. DLL3 expression by IHC was seen in 42 of 48 patients with evaluable tissue (88%), of which 10 (21%) were classified as DLL3-low (expression on 1% to 49% of cells) and 32 (67%) were classified as DLL3-high (expression on at least 50% of cells). The primary endpoints were ORR (intent-to-treat analysis) and safety (maximum tolerated dose, dose-limiting toxicity).

Among the 65 evaluable patients who received active doses of Rova-T, 46 (71%) patients achieved disease control, 11 (17%) a confirmed objective response, and 35 (54%) stable disease. In an exploratory analysis of the 29 DLL3-high patients who received active doses of Rova-T, 10 (35%) achieved a confirmed objective response and 26 (90%) had disease control. Median PFS with Rova-T by central review was 3.1 months for all patients, 2.3 months for DLL3-low patients, and 4.5 months for DLL3-high patients. The most common treatment-related adverse events (any grade) were fatigue (35%), pleural effusion (31%), and peripheral edema (27%).

Data from the SCRX16-001 trial suggest the following: 1) DLL3 is commonly expressed in SCLC and may represent a target for therapy; 2) Rova-T may be particularly useful in patients with high DLL3 expression; and 3) although the median PFS with Rova-T is similar to that seen with topotecan, it is important to remember that findings from these trials are not directly comparable—the 2 studies that led to the approval of intravenous and oral topotecan only allowed patients who progressed after 1 first-line regimen, whereas nearly one half of the patients in SCRX16-001 received 2 previous lines of therapy.

Additional Investigational ADCs in SCLC 
Additional ADCs being investigated in SCLC include lorvotuzumab mertansine, an anti-CD56 antibody linked to maytansinoid DM1, and sacituzumab govitecan, an anti–TROP-2 antibody linked to the irinotecan metabolite SN-38. In early studies, the addition of lorvotuzumab mertansine to carboplatin plus etoposide in patients with previously untreated ES-SCLC did not improve outcomes compared with chemotherapy alone and further development was not pursued. In a small study of patients with heavily pretreated metastatic SCLC, sacituzumab govitecan showed an ORR of 14% with tumor shrinkage in 60% of patients, albeit with grade 3/4 neutropenia in more than one third of patients.

Rova-T in SCLC: Future Directions
Based on promising results from phase I, several studies with Rova-T in SCLC have been initiated (Table). The phase II TRINITY study, which is no longer recruiting patients, is evaluating the role of Rova-T in the third-line setting or beyond, for which there are no approved drugs. Ongoing trials currently recruiting patients include a phase I trial evaluating Rova-T in the frontline setting, the phase III MERU trial evaluating maintenance Rova-T following first-line chemotherapy, the phase III TAHOE trial comparing second-line Rova-T to topotecan in patients with DLL3-high SCLC, and perhaps the most intriguing, a phase I investigation of the combination of Rova-T with nivolumab, 2 of the most promising drugs in SCLC. These agents have no established overlapping toxicities and may be synergistic. I am optimistic that Rova-T will prove to be a clinically meaningful development for patients with SCLC and encourage clinicians to consider enrolling appropriate patients in available clinical trials of this agent.

Table. Ongoing Studies With Rova-T in SCLC

Would you consider ADCs for your patients with ES-SCLC? Please leave a comment below.

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