Staff Writer

An eye-opening overall response rate of 32.7 percent in Phase II trials with antibody-drug conjugate T-DM1 in last-resort breast cancer patients left investors in ImmunoGen Inc. with well-founded hope that partner Roche Holdings AG will file for approval in the first half of next year and get an accelerated nod from the FDA.

"I think we're a long way to validation" fully of the Targeted Antibody Payload technology, but the Phase II results - and Roche's firepower behind them - make up a big step, said Daniel Junius, president and CEO of Cambridge, Mass.-based ImmunoGen.

Scanty ORR results were first disclosed in SEC paperwork last Wednesday, and detailed data from the 110-patient study enlivened the San Antonio Breast Cancer Symposium in Texas over the weekend.

The results are important also because they open farther the door for Roche to move the compound into earlier-stage metastatic breast cancer.

T-DM1 links Herceptin (trastuzumab) from South San Francisco-based Genentech Inc. to a chemotherapy developed by ImmunoGen, which joined forces with Genentech in 2000 to use the TAP approach. (See BioWorld Today, May 9, 2000.)

Genentech since has been acquired by Roche, of Basel, Switzerland, which holds big plans for T-DM1 through the subsidiary. If those plans come to pass, ImmunoGen stands to get substantial royalty payments.

ADCs work by keeping the antibody inactive in plasma, releasing only when it reaches the designated site. "It's toxic where you want it to be toxic: in the cancer cell," Junius said, and the method is becoming increasingly popular among drug developers.

"There have been others that have been in and out of [ADC] work" over the years, so determining which was first isn't easy, he said. ImmunoGen's scientists studied the prospects of the technology even before the company was formed in 1981, emerging from the Dana-Farber Cancer Institute and going public in 1989.

"We've gone through a couple of iterations, looking at different cytotoxins," Junius said. "It was a learning process. Some were potent, but they generated an immune response."

Targeted therapy such as TAP's paves the way to "a range of combination therapies, which you're already seeing Roche examine very broadly," he said, and by conjugating the antibody, "you may be able to use something with a little more systemic toxicity," that causes little harm.

T-DM1 has proven a winner so far. Not only did the drug gain strong ORR rates, but it also yielded stable disease for more than six months in 11.8 percent of patients, with a pretty good rate of progression-free survival, too - a median of 7.3 months.

Only 50 of 110 patients are included the immature data calculated, and full outcomes are expected at a scientific meeting, but the result already beats the 4.9 months of PFS previously reported from an earlier Phase II trial.

"Durability [of response] is going to prove to be important, but you have to start with efficacy and tolerability," Junius said.

Patients in the latest-to-report trial had been given, on average, seven different drugs for their breast tumors, including Herceptin, the compound for HER 2-positive disease that T-DM1 is intended to eventually replace, and London-based GlaxoSmithKline plc's Tykerb (lapatinib).

Among patients who had centrally confirmed HER2-positive cancer, the ORR totaled 39.5 percent, and the clinical benefit rate was 52.6 percent, as measured by an independent review facility. A Phase III trial with T-DM1 in first-line breast cancer is expected to begin next year.

The main adverse events - somewhat more acceptable in a patient population with no treatment options left - amounted to thrombocytopenia in 5.4 percent of patients and back pain in 3.6 percent. No severe (i.e., Grade 3 or worse) heart effects turned up. It all means Roche could win accelerated approval at the end of ongoing talks with the FDA, and approval could come in the second half of next year.

Cambridge, Mass.-based ImmunoGen's stock (NASDAQ:IMGN) closed Monday at $8.57, down 20 cents.

In other news from the breast cancer meeting:

• Ariad Pharmaceuticals Inc., of Cambridge, Mass., updated data from its Phase II study evaluating oral ridaforolimus in combination with Herceptin (trastuzumab) in patients with resistant, metastatic breast cancer. The study met its primary endpoint of objective response rate. The trial in patients with HER2-positive breast cancer was designed to evaluate whether the addition of ridaforolimus to Herceptin in the treatment of patients with metastatic breast cancer who have become resistant to Herceptin would result in objective evidence of tumor shrinkage. Thirty-four patients were enrolled, and the objective response rate was 15 percent.

• Array BioPharma Inc., of Boulder, Colo., disclosed positive interim results with its small-molecule HER2 (ErbB2) inhibitor, ARRY-380, in a Phase I trial in advanced cancer patients, showing that the drug at doses greater than or equal to 200 mg twice daily brought evidence of tumor regression in eight out of 10 heavily pretreated patients with HER2-expressing cancers. Of those eight patients, four had prolonged stable disease for 16 weeks or longer. ARRY-380 has been well tolerated.

• BioTheranostics, of San Diego, which develops oncology diagnostics, reported findings from three studies showing the firm's Theros Breast Cancer Index performed well as a continuous predictor for individual risk assessment.

• Celldex Therapeutics Inc., of Needham, Mass., said a Phase II study with CDX-011 (formerly CR011-vcMMAE) in patients with heavily pretreated, locally advanced or metastatic breast cancers turned up significant antitumor activity in patients whose tumors express the target GPNMB. Encouraging results also were seen in patients with "triple-negative disease" where treatment options are relatively limited due to lack of hormone receptor or HER2-neu expression.

• Cytori Therapeutics Inc., of San Diego, reported results from a preclinical cell-enriched fat grafting study supporting the safety and efficacy of Cytori's method for enriching fat grafts with adipose-derived regenerative cells. Used to enrich the fat grafts, ADRCs were active for several days after implantation and secreted several growth factors within the fat grafts. Interim results from a European clinical trial showed that breast reconstruction using the approach achieved a high rate of patient and physician satisfaction and improvements in overall breast deformity in lumpectomy patients.

• Incyte Corp., of Wilmington, Del., offered positive results from an ongoing Phase I/II trial with its selective oral sheddase inhibitor, INCB7839, involving 46 patients with HER2-positive metastatic breast cancer. The results suggested that, when compared to a historical control study of Herceptin (trastuzumab) as monotherapy, INCB7839 in combination with Herceptin provided improvements in time to progression and response rate. Those improved outcomes were achieved despite the presence of more advanced disease in the study population when compared to the historical control, the company said, and the combination regimen was generally well tolerated.

• Ipsen SA, of Paris, said preliminary results of a Phase I trial in metastatic breast cancer with BN83495, its lead oral, irreversible, steroid sulfatase inhibitor, determined 40 mg once daily as the optimal dose for Phase II trials in that indication.

• Onyx Pharmaceuticals Inc., of Emeryville, Calif., and Bayer AG, of Leverkusen, Germany, said Nexavar (sorafenib) shrank breast tumors in two-thirds of women treated with the drug in combination with paclitaxel in Phase II trials by at least 25 percent, and the patients achieved stable disease for an average of 8.1 months. About half of patients on paclitaxel monotherapy had shrinkage and remained stable for only 5.6 months. Phase II results with Nexavar combined with capecitabine in patients with no more than one prior chemo round yielded a 74 percent improvement in progression-free survival as compared to those who received chemo by itself. The increase in median progression-free survival of capecitabine plus Nexavar vs. capecitabine plus placebo was statistically significant (median 6.4 months vs. 4.1 months).

• Pfizer Inc., of New York, said the oral pan-ErbB inhibitor neratinib (HKI-272) given to patients with human epidermal growth factor receptor-2 (HER2, also known as ErbB2)-positive breast cancer showed activity in a Phase I/II study. The ongoing, two-part trial is testing the safety and efficacy of neratinib in combination with weekly paclitaxel in patients with solid tumors as well as those with HER2 breast cancer. Part one of the study showed that a standard oral dose of 240 mg of neratinib daily can be given with 80 mg/m2 of paclitaxel weekly to patients with solid tumors. In part two, as of Oct. 19, an overall response rate (including both complete and partial responses) of 69 percent was observed from a total of 99 patients with HER2 breast cancer. Also, a Phase II trial with neratinib at 240 mg daily for HER2 breast cancer showed diarrhea developed but decreased over time.

• Roche Holding AG, of Basel, Switzerland, said findings from two studies showed that patients with HER2-positive early breast cancer have a greater chance of cure when they are treated with one year of Roche's Herceptin (trastuzumab), and long-term survival benefits as well as the favorable safety profile of Herceptin were confirmed by two pivotal studies. Both studies, one conducted by the North Central Cancer Treatment Group and another performed by the Breast Cancer International Research Group, showed that Herceptin reduced the risk of the cancer returning by about one-third in women with HER2-positive early breast cancer compared to patients receiving chemotherapy alone. In both studies, at least 80 percent of women receiving one year of Herceptin were alive and free of the disease at a five-year follow-up.

Published  December 15, 2009