Rovalpituzumab tesirine (Rova-T or SC16LD6.5; AbbVie), a novel biomarker-specific ‘smart-bomb’ antibody-drug conjugate or ADC targeting the delta-like protein 3 or DLL3 protein, expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors, appears to be safe and shows efficacy in treating patients with advanced SCLC.

Antibody-drug conjugates like rovalpituzumab tesirineare are large molecules in which anticancer drugs are attached to an antibody. The antibody targets a protein that is abundant on the surface of cancer cells, but is preferably rarely found on healthy cells. Following the attachment of the antibody to the target protein on a cancer cell, the cancer cell internalizes the antibody-drug conjugate. Inside the cancer cell, the cancer drug is released from the antibody where it exerts its cancer-killing effect.  In this way, the new trial drug works like a “Trojan horse.”

Because the DLL3 protein is not or rarely expressed in healthy cells the targeted delivery of the novel cancer drugs to cancer cells helps minimizes ‘collateral’ damage to normal – healthy – tissues. In fact, the payload used in the cytotoxic anti-cancer drug in rovalpituzumab tesirine is so potent that it cannot be given systemically as a standalone treatment. However, the studies show that the drug, when attached to an antibody – as an ADC – is relatively safe.

Rovalpituzumab tesirine – Rova-T – comprises of an anti-DLL3 antibody conjugated to a pyrrolobenzodiazepine dimer, a cancer-killing DNA-damaging agent. Pyrrolobenzodiazepines (PBDs) are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. The mechanism of action of the PBDs is associated with their ability to form, an adduct in the minor groove, thus interfering with DNA processing.

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ASCOEarly results
The early results of a first-in-human clinical trial, presented on Sunday, June 5, by a Memorial Sloan Kettering Cancer Center‘s Charles M. Rudin, MD, PhD, Chief of the Thoracic Oncology Service, at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, held June 3 – 7, 2016 in the McCormick Place in Chicago, Ill, show that patients responded better to the drug when their tumors expressed high levels of delta-like protein 3 (DLL3), the protein Rova-T targets (ASCO abstract LBA8505) [1]

The study shows that Rova-T halted tumor growth in 89% of patients with high level of DLL3 in the tumor and shrank tumors in 39%.

Small-cell Lung Cancer
Each year, an estimated 225,000 Americans will be diagnosed with lung cancer. [2] Small-cell Lung Cancer accounts for approximately 15% of all lung cancers, is particularly aggressive — about two-thirds of patients have extensive-stage disease when they are first diagnosed, and the median survival for these patients is less than a year.[3]

The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[4]

Unmet need
To date, combination chemotherapy improves the survival of patients with limited-stage disease or extensive-stage disease.  While combination chemotherpy of platinum and etoposide, the most widely used standard chemotherapeutic regimen, is curative in only a minority of patients and surgical resection or radiation therapy rarely produces long-term survival because patients with SCLC tend to develop distant metastases, there is a large unmet need.[5]

In the United States, the only Food and Drug Administration (FDA) approved drug for the treatment of SCLC is topotecan (Hycaptin ®; Novartis)

However, despite major advances made during the 1970s and in the 1980s, today, treatment success seems to have reached a plateau and substantial therapeutic advances have lagged far behind this of other cancers.

Rovalpituzumab tesirine –  Rova-T  – is the first molecularly targeted drug to show antitumor efficacy in SCLC.

“The goal is always to give the right patient the right drug at the right time, but patients with advanced small cell lung cancer have not benefited from any of the new targeted therapies available to patients with other types of cancer,” Rudin explained.

“They desperately need new treatment options, so the ability to predict whether a patient might respond to Rova-T by testing their tumor for overexpression of the DLL3 protein is crucial because it may ultimately help us give this drug to the patients most likely to benefit from it, and avoid giving it to patients who won’t,” he said.

The phase I clinical trial included 74 patients with SCLC that had progressed after at least one course of systemic therapy. Of the 60 evaluable patients treated with doses in the active range of 0.2-0.4 mg/kg, 68% experienced at least stabilization of disease, meaning their cancer did not get worse, and 18% had significant confirmed tumor reductions.

The study included 26 evaluable patients with tumors that overexpressed DLL3. Stable disease was achieved in 89% of these patients; 39% had significant confirmed tumor reductions.

Twelve of the patients whose tumors overexpressed DLL3 received Rova-T as third-line treatment, for which no approved therapy currently exists. Half of these patients had significant tumor reductions, and 92 percent experienced at least stabilization of disease. Four of these patients lived longer than six months, including two who lived for at least 18 months.

Manageable side effects
The side effects from Rova-T were manageable.  The most common grade 3+ toxicities considered the results of the study-drug included serial effusion (fluid accumulation around the heart or lungs) in 14% of patients, thrombocytopenia (low platelet count) in 12% of patients and skin rash/reactions (8%). Overall, these adverse events could be easily treated with medications, or, in many cases, resolved without specific interventions.

“We’ve seen too few success in recent years for SCLC, which makes these early signs of efficacy all the more encouraging,” Rudin noted.  “Although  these results are preliminary, Rova-T seems to be the first targeted therapy to show efficacy in SCLC and we may have identified DLL3 as the first predictive biomarker in this disease.”

Clinical trials
The findings of this early-stage first-in-human clinical trial need to be confirmed in larger clinical trials.  A single-aim phase II pivotal trial in patients with DLL3-positive SCLC that has worsened despite two prior therapies was launched earlier this year. The researchers are planning other trials designed to evaluate rovalpituzumab tesirine in first line SCLC and other DLL3-espressing neuroendocrine cancers.

“I encourage all oncology physicians and patients to seek out information about clinical trials, as they often give patients the opportunity to receive new drugs and other therapies years before they are more widely available,” Rudin said. “It’s increasingly important to remember that nearly every advance in cancer treatment available today was first evaluated in a clinical trial.”

He added that future clinical trials investigating Rova-T’s efficacy in treating SCLC will generally focus on the subset of patients whose tumors express the DLL3 target.

Open trials
Memorial Sloan Kettering Cancer Center and other participating trial centers currently have an open Rova-T clinical trial for patients with advanced SCLC who have received at least two prior therapies (NCT02674568).  Patients to be enrolled in this pivotal trial will receive Rova-T, as there is no standard third-line treatment to test Rova-T against.

Rudin also noted there are other important lines of research to explore around Rova-T, including how the drug affects the tumor microenvironment, whether it prompts an immune response and if there is a population of patients for whom this drug might not be safe.

A new wave of targeted agents
Commenting on the results of this study, Gregory Masters, MD, FACP, FASCO, an expert in the treatment of lung cancers, noted: “This is another example of a new wave of highly targeted treatments, which deliver anticancer drugs even more precisely to where they needed.”

“These results mark a good, early sign of success against a cancer for which we urgently need better therapy options,” Masters concluded.

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