A potential 2018 launch for DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine (Rova-T) is off the table, as Abbvie Inc. said it will not seek accelerated approval in third-line small-cell lung cancer (SCLC), based on the "magnitude of effect across multiple parameters" in the phase II TRINITY study, news that sent shares of the large-cap stock (NASDAQ:ABBV) sinking 12.8 percent Thursday, losing $14.35 to close at $98.10.

Oddly, though, investor concerns seemed to be less about the data themselves – results, if not stellar, were generally in line with expectations – and more on whether Chicago-based Abbvie might have misread FDA cues regarding the suitability of data from its open-label, single-arm study to warrant an early nod.

"[P]erhaps the company misjudged the bar for what the FDA would deem acceptable for filing," Evercore ISI analyst Joshua Schimmer, wrote in a research note. "For a company which generally touts its precision, this will create a dent in credibility," though he added that it's one that "we believe can be mended with time."

TRINITY, which enrolled patients with DLL3-expressing relapsed/refractory disease, showed an objective response rate (ORR) of 16 percent of a median survival of 5.6 months. Those figures are slightly lower than the ORR of 18 percent and median survival of 5.8 months reported at the American Society of Clinical Oncology meeting in 2016, only months after Abbvie inked a nearly $10 billion deal to acquire Rova-T and earlier-stage antibody-drug conjugate (ADC) programs in a buyout of Stemcentrx Inc. (See BioWorld Today, April 29, 2016.)

Management had previously indicated that a midteens RECIST response rate "was sufficient for filing," noted Piper Jaffray analyst Christopher Raymond in a research report, who admitted being "surprised" by Abbvie's decision to scrap accelerated filing plans. Data are both "relatively in line with standard of care" and "also consistent with management's previously articulated definition of success," he wrote.

After speaking with management following Thursday's news, Raymond said the durability of response data – 4.1 months in TRINITY – was the issue, with the agency "looking for less variability on this metric for accelerated approval."

Leerink's Geoffrey Porges' assessment of Thursday's news, however, was considerably grimmer. With efficacy results comparable to prior readouts, the "major difference in this trial is the safety profile, which we frankly regard as unacceptable for virtually any cancer drug, but particularly for one with a 4.2-month median duration of response," he said.

The most common treatment-emergent adverse events (AEs) in TRINITY were fatigue (38 percent), photosensitivity reaction (36 percent), pleural effusion (32 percent), edema peripheral (31 percent), decreased appetite (30 percent), nausea (26 percent), dyspnea (25 percent), thrombocytopenia (25 percent), constipation (22 percent), vomiting (17 percent), anemia (17 percent), hypoalbuminemia (16 percent), and cough (16 percent). Grade three and higher severe toxicities ≥ 5 percent were thrombocytopenia (11 percent), photosensitivity reaction (7 percent) and pleural effusion (5 percent).

Porges went even further, stating that those "safety liabilities undermine a key component of the Stemcentrx platform, which is their ADC linker chemistry. The adverse events appear to be associated with the toxin included in the ADC, and must be assumed to be a liability for all ADCs coming from Stemcentrx," he wrote in a research note.

Rova-T is by far the most advanced Stemcentrx-derived ADC in Abbvie's pipeline, but the firm has moved five other compounds into early human testing, all in solid tumors.

More trials ongoing

While the safety concerns could fuel further grumbling over the investment in Stemcentrx – the deal involved an up-front payment of $5.8 billion in cash and stock – Abbvie is hardly alone in plunking down big bucks for an underperformer, as Evercore's Schimmer reminded clients. "[W]e would note that most of the large biopharma companies have some overpriced transaction in their rear view mirror," he wrote.

Few analysts had given much weight to Rova-T in their models ahead of readout of the TRINITY study, which launched in early 2016 and enrolled a total of 339 patients, who had received at least two prior regimens, including at least one platinum-based regimen. But even if that study fell short of expectations, the overall Rova-T program is hardly dead in the water for Abbvie, which has two ongoing phase III studies in SCLC.

One (TAHOE) is testing Rova-T against topotecan in about 411 patients with advanced/metastatic SCLC whose tumors harbor DLL3 and who have progressed after front-line treatment, with primary outcome measures looking at ORR and overall survival (OS). The second (MERU) is evaluating Rova-T as a maintenance therapy after first-line platinum-based chemotherapy in about 740 patients, with primary outcomes measuring progression-free survival and OS.

Readouts from both studies are expected in the later part of 2019.

Also ongoing is a phase I study testing Rova-T in combination with PD-1 inhibitor Opdivo (nivolumab, Bristol-Myers Squibb Co.), with or without CTLA-4 inhibitor Yervoy (ipilimumab, Bristol-Myers Squibb Co. in patients with extensive-stage SCLC. That trial is enrolling about 90 patients, with primary estimated completion in the second quarter of this year.

An Opdivo/Yervoy combination already wowed in early testing in SCLC. Data presented at last year's ASCO meeting showed a 23 percent ORR and median OS of 7.8 months with the combination in phase I.

SCLC, which comprises roughly 10 percent to 15 percent of all lung cancers, is more aggressive than the more common NSCLC, with diagnosis for many patients often not occurring until the disease is well-advanced and bearing a five-year survival rate of just 2 percent. Topotecan has remained the standard of care, as investigational treatments have fallen by the wayside over the past decade.

Just last year, Oncomed Pharmaceuticals Inc., of Redwood City, Calif., reported disappointing top-line results from its 145-patient phase II PINNACLE study testing cancer stem cell (CSC)-targeting antibody tarextumab (anti-Notch2/3, OP-59R5) in combination with etoposide plus either cisplatin or carboplatin in previously untreated SCLC patients with extensive-stage disease. (See BioWorld Today, April 18, 2017.)

Rova-T frequently had been compared to Oncomed's drug because they both targeted CSCs. But in the case of Rova-T, it is designed to hit CSC-associated delta-like protein 3, or DLL3, which is expressed in more than 80 percent of SCLC tumors. DLL3 is prevalent on tumor cells, including CSCs, but is not present in healthy cells. Rova-T is designed with a targeted antibody to deliver a cytotoxic agent directly to the DLL3-expressing cells.

Other companies attempting to tackle SCLC via DLL3 include Amgen Inc., which is in phase I development with AMG-757, an extended half-life anti-DLL3 formulated with an anti-CD3 BiTE (bispecific T-cell engager) antibody construct.

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