Adding Rituxan (rituximab) to standard chemotherapy for previously untreated chronic lymphocytic leukemia patients gives them an unprecedented overall survival advantage, but the headline data, presented at the American Society of Hematology meeting in New Orleans Dec. 7, likely won't do much to grow Roche's U.S. bottom line.

In New Orleans, Roche investigators added an additional 12 months of follow-on data to the already practice-changing results they reported at last year's meeting in San Francisco (¹ Health News Daily, Dec. 9, 2008). The triple drug regimen of rituximab plus fludarabine and cyclophosphamide chemotherapy (FCR) "is very likely becoming the new first-line treatment for CLL patients," Michael Hallek, University of Cologne, Germany, the senior investigator on the Phase III CLL8 study, predicted at the time. And Hallek apparently was right.

For CLL in the U.S., "our first-line share is very high, close to 80 percent," Roche Hematology Franchise Leader Myriam Mendila told analysts during a Dec. 8 pipeline update from ASH. "Our second-line share is 60 percent, and with more and more patients receiving it first-line, there is probably limited potential in the second line," she said.

"In refractory, we do not expect a big potential because ... CLL8 data [for] overall survival benefit clearly indicate that the drug should be used in the first-line setting to provide the maximum benefit."

The CLL8 trial tested rituximab plus fludarabine and cyclophosphamide against FC alone in 817 patients. After more than three years of follow-up, 87.2 percent of FCR patients were alive compared to 82.5 percent who received FC alone (p=0.012).

CLL8 is the first trial "to show an overall survival benefit for patients with CLL," Nancy Valente, senior group director for hematology clinical development, emphasized during the update.

The patients, who averaged 61 years of age, were treated at 191 centers in 11 countries; the 2009 ASH presentation was based on an analysis at a median observation time of 37.7 months. Since the 2008 report, median progression-free survival improved from 42.8 months to 51.8 months, Valente said. Patients who received FC alone had a median survival time of 31.8 months.

In general, the therapy was well-tolerated with no new safety signals. "Neutropenia was increased with the addition of Rituxan to FC chemotherapy, but the rate of infection was not significantly increased," Valente pointed out, as did Hallek last year. In the FC group, 21 percent of patients experienced at least one grade 3-4 neutropenia event, while 33.7 percent of FCR patients did (p=<>

U.S. Application Got A "Complete Response"

The triple therapy for CLL has gained approval in both the first-line and relapsed settings in the EU, and Mendila said Dec. 8 that Roche was in "final label discussions" with U.S. regulators on those indications, but FDA approval may prove trickier than that.

U.S. marketers Genentech and Biogen Idec received a "complete response" from FDA on the supplementary BLAs for both indications Nov. 18. FDA requested no new data, the companies said, and they will continue label discussions.

Nonetheless, the FDA approval is not likely to have a major impact for the brand, as the market is already penetrated. Unlike Europe, where reimbursement is generally more connected to labeling, in the U.S. it is possible to gain coverage for cancer drugs based on compendia listings of clinical evidence, such as the tasty results of the CLL8 study.

With an eye on building evidence to support rituximab use, Roche conducted studies that paired it with other therapeutic agents against CLL, all with good results, Valente said. Rituxan in combination with bendamustine, chlorambucil and fludarabine showed "acceptable toxicity ... with impressive efficacy," she said. Overall response rates ranged from 84 percent to 91 percent, and, "importantly, in the chlorambucil [with] Rituxan study, the median age was 70.5 years, which is representative of a very typical population of CLL patients," she said.

The anti-CD20 antibody already has U.S. approval in several settings as a treatment for CD20+ B-cell non-Hodgkin's lymphoma. In addition it is approved as a second-line therapy for treatment of adult patients with severe active rheumatoid arthritis.

In their September 2009 Therapeutic Categories Outlook report, Cowen analysts - noting that rituximab is the top-selling cancer drug in the world - attribute the success to high penetration of the NHL and CLL markets, including deep penetration of frontline settings based on off-label use. The Cowen team suggests maintenance use is a potential driver of additional sales.

Subcutaneous Rituximab In The Works

Roche is developing a subcutaneous formulation for rituximab that will employ a proprietary injection device developed by Roche Diagnostics, Mendila told analysts. A Phase I dose-finding trial enrolled the first patient this fall, and Roche hopes to start a Phase III clinical bridging trial in 2010, she said. The goal is to have European approval in 2013.

A subcutaneous formulation would enable patients to get their therapy at home (a quality of life benefit), offers the potential of fewer infusion-related reactions, and would lead to reduced use of hospital resources, Mendila said.

A Broader Range Of Cancers

While Roche has a lock on the solid tumor market with blockbusters Avastin and Herceptin , the Big Pharma sees additional commercial opportunities in the area of hematological cancers, particularly as it looks beyond the anti-CD20 mechanism. That includes a mix of novel drugs as well as expanded indications for already marketed products.

Indeed, it is exploring anti-angiogenic Avastin in Phase III studies against diffuse large B-cell lymphoma and in Phase II against multiple myeloma. "We aim to develop Avastin and all our pipeline molecules in a broader range of other hematological diseases," Mendila said.

Roche is trying new molecules that intervene in pathways common to solid and hematologic cancers. Including extensions for approved drugs, three of 30 oncologics in the Roche/Genentech clinical pipeline are being focused on hematologic indications and seven are aimed at both.

Roche/Genentech also are still refining their oncology pipeline. On Dec. 11, Seattle Genetics announced Genentech had terminated their agreement for dacetuzumab, a Phase Ib anti-CD40 antibody for hematologic cancers, as a result of "ongoing portfolio review."

Chief among the new drug candidates in the hematology pipeline is GA101, the pretender to the throne now occupied by rituximab, which has led the blood cancer market since its U.S. launch in 1997 and shows no sign of flagging.

The next-generation CD20 antigen is designed "to improve on the efficacy of [rituximab] and ultimately to replace [it] in the treatment of all these diseases," said Mendila. The first U.S. filing is anticipated in first-line CLL in 2012.

At ASH, Roche reported new findings from two ongoing Phase I/II studies of '101. The first, GUIGUIN (B020999), is examining the antibody in both indolent and aggressive NHL, as well as in CLL, in 133 patients. The second, GAUSS (B021003), with 200 patients, demonstrated promising efficacy in heavily pretreated patients with B-cell hematological malignancies, and is being expanded by a large Phase II cohort in indolent NHL.

The initial Phase III program for GA101 includes two studies. The first, GAO4753g, looks to test 360 patients with indolent refractory NHL on a regimen of bendamustine with and without GA101, starting in the second quarter of 2010. With the second Phase III trial, B021004, slated to start before the end of 2009, Roche is going after a direct head-to-head comparison of '101 with rituximab, both in combination with chlorambucil, in first-line treatment of 780 CLL patients.

Genentech took over development of the glycol-engineered type II CD20 antibody (also known as RG7159) from Roche subsidiary GlycArt just over a year ago (² Also see "Genentech Takes Over GlycArt Anti-CD20 Antibody Work" - Pink Sheet, 3 October, 2008.).

The carbohydrate engineered into the GA101 molecule - the first of its kind - "markedly increases the strength of the interaction between the antibody and the host receptor cells that mediate killing of CD20+ cells" by as much as ten-fold, Sandra Horning, Senior VP, global head of hematology clinical development, explained. The type II antibody also has lower complement-dependent cytotoxicity, another improvement over first-generation rituximab.

Overcoming Apoptosis Evasion

Resistance to apoptosis, or programmed cell death, is a hallmark of virtually all malignancies, but Roche's BH3 mimetic RG7159/ABT-263 is designed to thwart that resistance, Horning said.

The orally available compound, on which Roche is partnered with Abbott Labs, is being studied for CLL and lymphoid malignancies, though it might also have some efficacy against solid tumors, predominantly non-small cell lung cancer.

At ASH Roche reported data from an ongoing Phase I study in relapsed or refractory CLL showing encouraging single-agent activity and acceptable safety, with thrombocytopenia as an on-target but dose-limiting toxicity, Valente said. The molecule also shows preliminary evidence of activity in fludarabine refractory patients, as well as those with very poor prognostic factors, such as 17p and 11q deletions.

ABT-263 targets the family of pro- and anti-apoptosis proteins that includes Bcl-2, which is anti-apoptosis, and BH3, which drives cell death. Many lymphoid tumors overexpress Bcl-2, hence their ability to avoid death, while ABT-263 imitates BH3, inhibiting Bcl-2 and favoring apoptosis, Horning explained.

- Shirley Haley ( ³ s.haley@elsevier.com )

Roche Reports Rituxan Survival Data For CLL But Has Captured U.S. Market Before Approval

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