Benefit for patients with disease that has spread to the brain put a special shine on top-line data rolled out by Seattle Genetics Inc. (Seagen) from the HER2Climb study, an experiment to test the oral small-molecule tyrosine kinase inhibitor (TKI) tucatinib, designed as highly selective for HER2 without significantly knocking down EGFR.

Clay Siegall, CEO, Seagen

CEO Clay Siegall, with a nod to the other TKIs on the market, Tykerb (lapatinib, Novartis AG) and Nerlynx (neratinib) from Los Angeles-based Puma Biotechnology Inc., said during a conference call with investors that London-based Glaxosmithkline plc, original developer of the former compound, likely hoped for "a profile much like tucatinib's."

In HER2Climb, Bothell, Wash-based Seagen compared tucatinib in combination with Herceptin (trastuzumab, Roche Holding AG) plus capecitabine to Avastin/capecitabine in patients with locally advanced unresectable or metastatic HER2-positive breast cancer.

The trial met the primary endpoint of progression-free survival (PFS), showing that adding tucatinib brought an effect superior to trastuzumab and capecitabine alone, with a 46% reduction in the risk of disease progression or death. Patients had previously tried Avastin, Perjeta (pertuzumab, Roche Holding AG) and Kadcyla (ado-trastuzumab emtansine, or T-DM1), and 47% had brain metastases (mets) when they signed up.

The findings (hazard ratio (HR)=0.54 (95% confidence interval [CI]: 0.42, 0.71); p<0.00001) came with further news that the trial met the two key secondary endpoints at interim analysis. The tucatinib arm showed an improvement in overall survival (OS), with a 34% reduction in the risk of death (HR=0.66 (95% CI: 0.50, 0.88); p=0.0048) compared to Avastin and capecitabine alone. For patients with brain involvement at baseline, the tucatinib arm also demonstrated superior PFS, with a 52% drop in the risk of disease progression or death compared to those who received only Avastin plus capecitabine alone (HR=0.48 (95% CI: 0.34, 0.69); p<0.00001). "This was the first of many planned interim looks in OS," Siegall said. "And when you look at the first of the interims, you don't necessarily always expect it to hit the number." That it did, he said, was "somewhat stunning."

The three-way combo was generally well-tolerated with a manageable safety profile, Seagen said. The most frequent adverse events (AEs) in the tucatinib arm included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue and vomiting. Grade 3 or greater AEs in the tucatinib arm compared to the control arm included diarrhea (12.9% vs. 8.6%), increased aspartate aminotransferase (4.5% vs. 0.5%), increased alanine aminotransferase (5.4% vs. 0.5%) and increased bilirubin (0.7% vs. 2.5%). No patients needed prophylactic antidiarrheals. AEs leading to discontinuations were infrequent in the tucatinib arm as well as the control arm (5.7% and 3%).

More than 271,000 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019, and 15% to 20% of cases worldwide are HER2-positive, a form known as more aggressive and more likely to recur than HER2-negative. In patients whose disease spreads, first metastases most commonly occur in bone, followed by lung, brain and liver, but 30% to 50% of metastatic HER2-positive patients eventually develop brain cancer.

Seagen will provide more data in December at the San Antonio Breast Cancer Symposium (SABCS) in Texas. "This is the type of trial that, literally, as you cut the data in lots of different ways," continues to impress, said Siegall, telling investors he's looking forward to the symposium. Meanwhile, Wall Street is rejoicing over the data public so far.

Safety 'not perfect but acceptable'

Cowen analyst Boris Peaker called the results a "home run" for Seagen. "We believe investors will be focused on how the data at SABCS compare to currently marketed TKIs," he wrote in a report. "Our consultants have noted that the control arm could be expected to produce a PFS of four to six months." Macrogenics Inc., of Rockville, Md., which is developing FDA fast-tracked margetuximab in HER2 breast cancer, saw its control arm of Herceptin plus capecitabine yield a median PFS of five and a half months; Puma's phase III bid called Nala with Nerlynx or Tykerb on a background of capecitabine turned up an 8.8-month median PFS for the Nerlynx arm and 6.6 months for the Tykerb arm. Assuming PFS of around five and a half months in the control arm of HER2climb, "the PFS hazard ratio would suggest that tucatinib may have achieved a median PFS of nine to 10 months, depending on the shape of the survival curves," Peaker wrote. "Should this be the case, tucatinib would be best-in-class TKI from a PFS perspective." SVB Leerink's Andrew Berens said the favorable brain results may mean tucatinib will be used "throughout all lines of therapy in anyone diagnosed with brain mets."

In late September, Macrogenics provided an update on encouraging results from a phase II study of margetuximab, an Fc-optimized monoclonal antibody, plus anti-PD-1 Keytruda (pembrolizumab, Merck & Co. Inc.) in a chemotherapy-free regimen designed to engage innate and adaptive immunity for patients with advanced HER2-positive gastroesophageal adenocarcinoma previously treated with chemo and Herceptin in the metastatic setting.

BTIG analyst Thomas Shrader called the results "exciting" overall. "The drug clearly looks more powerful than Tykerb and easier to take than Nerlynx," pointing out in a report that the "CNS efficacy looks very positive and probably represents the largest data [package] for this setting generated to date" although, "for early lines, safety of the background regimen is non-trivial and tucatinib adds to most of the safety signals," thus it's likely unfit as an all-comers therapy. "The liver signal is significant," he added. J.P. Morgan's Cary Kasimov allowed that "the safety profile is not perfect" but "looks acceptable in this advanced patient population." Seagen's planned NDA filing in the first quarter of next year "comes in ahead of our expectations," he said.

Shares (NASDAQ:SGEN) closed Monday at $100.89, up $13.49, or 15.4%.