CHICAGO - Roche's current focus in oncology is on establishing longer treatment durations for its oncologics, including its mega-blockbuster Avastin (bevacizumab).

"This year, the key message for us is treatment duration," Pharmaceuticals Chief Operating Officer Pascal Soriot said in opening a June 6 analyst event held in conjunction with the American Society of Clinical Oncology annual meeting in Chicago.

Roche's highlights of research presented at ASCO emphasize longer periods of utilization of the oncologics, as well as in use for multiple lines of therapy and as maintenance treatment. "We're trying to maximize the clinical benefit of our drugs through this approach," Soriot said.

Soriot's comments particularly referenced targeted oncologics, typically biologic agents with specific activity that have far greater tolerability than chemotherapy; Roche is a leader in this area.

"Now is the time to start looking at the biologic agents, at least some of them, with a different set of eyes," he said. "They work differently from cytotoxics and probably what we need to do is ... give them to patients for much longer periods of time, and possibly extremely long periods of time, until the deaths of those patients, in some cases."

Soriot acknowledged that longer use of biologics will increase the total cost to the health care system. But he quickly defended those costs as justified by increased patient benefit. "By increasing treatment duration, we strongly believe that the value side of the value/cost equation will increase, because clearly patients will benefit from this longer treatment duration, and as a result we will bring more value to the medical community and the payers," the exec said.

He also alluded to Genentech's price cap to limit the cost for Avastin to approximately $56,000, and indicated parent company Roche may be considering ways to expand that program: "We have strategies in place, or we're looking at even more ideas to look at how do we manage these costs, ... like we've put in place in the U.S. and in a number of countries in Europe [as] a cost strategy for us to manage the cost of this expanded treatment regimen."

Ovarian Study Has Dual Benefit

The GOG-0218 study in ovarian cancer, which was selected for the ASCO plenary session, not only established Avastin's efficacy in another tumor setting, but also demonstrated its benefit as maintenance treatment.

"This was a definitive experiment that showed the longer-term Avastin was superior to shorter-term Avastin," said Jakod Dupont, associate group medical director for Genentech.

Stefan Frings, the franchise director for Avastin, underscored this value during the on-site analyst event. The ovarian results are "important data, and not just for Avastin opening a new indication, but ... it gives us insight into how to best administer Avastin."

Roche has made previous attempts to establish longer durations of treatment with Avastin, designing trials with a control and a control plus Avastin treatment to progression, including the E2100 study in breast cancer and the first- and second-line colorectal cancer trials.

"And in multiple instances, the health authorities asked us 'what basis you have to claim that you actually should treat [further on with Avastin] after discontinuation of chemotherapy,'" Frings said. "Now the GOG trial is really the first definitive trial that tells us that it's good to stay on Avastin."

Ovarian Results Mark Significant Success

GOG-218 studied 1,800 patients with previously untreated ovarian cancer, and included two regimens of Avastin. With follow-up to 15 months, the study used a control arm of carboplatin and paclitaxel for six cycles with placebo. The chemo regimen was combined with Avastin (15 mg/kg) for five cycles in another arm. A third arm used the five cycles of Avastin with the chemo and then treated with Avastin alone up to 15 months (for 16 cycles of maintenance).

The primary endpoint was changed from overall survival to progression-free survival - a move questioned by Elizabeth Eisenhauer, head of the National Cancer Institute of Canada, during her discussion of the study at the June 6 plenary (see sidebar: " ¹ Avastin's Outlook In Ovarian Cancer Is Not Entirely Rosy ").

There were two PFS analyses of the trial, which is an acceptable endpoint for front-line ovarian cancer. Because the sponsor used the biomarker CA-125 as an indicator of progressive disease, FDA and the European Medicines Agency worked out an agreement with the company to conduct an alternative analysis censoring the CA-125-only progressions. When only patients with progression indicated by standard RECIST criteria were included, median PFS was 18 months for the maintenance Avastin arm versus 12 months for the control. This compares to 14.1 months vs. 10.3 months when including patients with either RECIST or CA-125 progression.

It is too early to assess overall survival. Only a quarter of the population had died at the time of the data lock and, after the primary endpoint was changed, the potential for cross-over has affected the ability to get a clear reading from this trial.

Given the strong results of GOG-218, Roche is already discussing the ovarian cancer indication with regulators, though another trial is due to report later this year (ICON-7) and Roche confirms that trial will be supportive of a potential submission. There are also previous single-arm Phase II trials of single agent Avastin in ovarian cancer that show activity, but in small populations. "We also have registration intent in recurrent ovarian cancer in platinum-sensitive disease," Dupont said, with the pivotal OCEAN study expected to report in 2011.

Gathering Evidence For Longer Duration In CRC

Roche is working to establish longer lengths of therapy with Avastin in colorectal cancer, the product's first approved indication, as well. It presented the ARIES study, a CRC observational cohort study designed to evaluate the association between early exposure to Avastin beyond first progressive disease and survival beyond first PD. ARIES suggested that Avastin treatment beyond progression may yield superior overall survival.

The ARIES results were "spot on" with the data gathered from the BRiTE registry (published in 2008), the company said. Even after adjusting for possible biases, the hazard ratio for use of first-line Avastin has a "very strong effect" of 0.52 for median overall survival from initiation of first-line therapy of 27.5 months versus 18.7 months for a non-Avastin regimen; in comparison, the hazard ratio for the BRiTE registry (again with multivariate analysis) was 0.51.

Frings relayed that Dan Sargent, the noted Mayo Clinic biostatistician who has also done work with FDA, called the data "unbelievable - either you did the same mistake twice, or you're really on to something."

The Roche exec continued, "I believe we're really onto something, because based on the mode of action, this is practically what we would want to see with Avastin, that you want to suppress the angiogenic capacity of VEGF, keep it at bay and don't allow the tumor with its growth factor again to grow."

ARIES "strengthened the hypothesis we have already based on BRiTE and based on our entire understanding of the mechanism of action of Avastin - that longer treatment duration with Avastin, in this case meaning through multiple lines, should provide meaningful benefit for patients," he concluded.

Roche recently completed enrollment in a formal controlled study to test this idea - a study initiated four years ago. This study will use first-line standard therapy with Avastin and, upon progression, 810 patients will be randomized to conciliation with Avastin or standard second-line chemotherapy. Overall survival is the primary endpoint. Depending on the event rates, results of study ML18147 are expected "as early as later in 2011."

Roche Not Ruling Out Gastric Cancer

Not all the data released on Avastin were positive. But Roche used the presentation of full results at ASCO to point out that bevacizumab still demonstrated efficacy and may have a path forward in at least one indication where an initial Phase III was unsuccessful.

In February, Roche announced that bevacizumab had failed in the Phase III AVAGAST gastric cancer trial. The final data were presented at ASCO.

"Certainly we take risks when we run our trials," Frings noted. Roche's silver-lining view of the AVAGAST trial was that it was "a near miss on overall survival," and that there were differences by region that may have affected the results.

But the "good news is that Avastin is without a doubt active," Frings maintained. It did meet secondary endpoints and showed a superior response rate. The franchise director also indicated that the signs of effect were similar to the early signs in other settings. "As we have seen across multiple indications, typically Avastin is around 10 percent absolute response rate," he pointed out. There was also superior progression-free survival, and though the median may not have been as impressive as in some other areas, the hazard ration was "strong" and significant at 0.80.

The safety results were reassuring as well, with none of the severe toxicity of GI perforations. And while venous thromboembolism was more frequent with Avastin, the 60-day mortality favored the Avastin arm, Frings reported.

Roche plans to use those signals of a potential for Avastin in gastric cancer as a foundation to move forward in the setting.

"We're still looking for explanations for the heterogeneous efficacy results across regions," Frings said. The firm is also leveraging its broad biomarker program.

While Roche is not filing for gastric cancer based on the dataset in hand, "with those intriguing data, we're keenly exploring next steps and evaluating options [for] how we can increase a chance of success in case we would go for a second gastric cancer trial," Frings said. Since overall survival with gastric cancer is 10 to 12 months, it would be a trial that "can be done in a rather reasonable timeframe, and it's an indication where we have a franchise in place," Frings pointed out, noting Xeloda is a global backbone for the franchise and Herceptin awaits approval for HER2+ gastric cancer.

Frings also used a failed trial in prostate cancer to further Roche's overall thesis on Avastin - but didn't hold out the same possibility for further study in the indication. There was meaningful progression-free survival in the Avastin plus docetaxel arm, but the overall survival primary endpoint was missed in this study, CALGB 90401.

Frings pointed to a subgroup analysis included in the presentation by lead investigator William Kevin Kelly, Yale School of Medicine, of the Phase III results, suggesting that patients with a worse prognosis may have done better on Avastin.

Frings also implied that the trial didn't use a sufficient duration for Avastin: "What was concerning for us was the treatment duration on Avastin and placebo, that patients really didn't stay even as long as chemotherapy on Avastin, and this may have been the issue with this placebo-controlled experiment, because investigators really didn't know what the patient was receiving and they may have just decided unfortunately to stop too early. And this is particularly unfortunate because we believe, thanks to the experiment with ovarian cancer, that if you stay longer on drug, you have even a better outcome." The possibility that longer treatment may improve outcomes in prostate cancer was suggested during the ASCO discussion of study.

Rituxan In Maintenance Therapy For Lymphoma

Roche's focus on long durations of treatment with targeted oncologics isn't limited to Avastin. Another encouraging presentation for Roche was the PRIMA trial with Rituxan / MabThera (rituximab), which supported longer-term use of the CD20 antibody.

Previous studies have supported Rituxan's benefit as maintenance therapy in patients with untreated and relapsed follicular lymphoma and standard of care has become Rituxan plus CHOP chemotherapy.

PRIMA's objective was assessing whether two years of maintenance with rituximab after induction with rituximab and chemotherapy improved PFS in previously untreated patients. The trial doesn't allow for a real look at overall survival, but principal investigator Gilles Salles, Centre Hospitalier Lyon-Sud, France, concluded that the effect of rituximab maintenance in first-line is superior than what was previously seen in relapsing patients, and that it "constitutes a new platform to further develop more efficient (and well tolerated) strategies."

Just ahead of ASCO, Roche announced that it was stopping enrollment of the Phase III MAIN trial in aggressive non-Hodgkin's lymphoma, which was using a combined regimen of Avastin and Rituxan, after an interim look at the first 720 patients showed an unfavorable risk/benefit for the addition of Avastin to Rituxan plus CHOP.

Testing out combinations of targeted oncologics is another theme of Roche's oncology program, It is also a recognized need across the field to see if attacking cancer with multiple strategies yields improved outcomes.

Soriot highlighted how Roche is testing combinations of its products with different pathways, including late-stage trials testing Herceptin in combination with Avastin (AVAREL in first-line HER2+ metastatic breast cancer) as well as with pertuzumab (NeoSphere and CLEOPATRA). Roche is also testing pertuzumab with its trastuzumab drug conjugate T-DM1 (MARIANNE and a Phase Ib/II trial) and has early-stage trials of its PI3K agent RG7321 plus T-DM1 and its MEK inhibitor RG7420.

- Mary Jo Laffler ( ² m.laffler@elsevier.com )

Roche's Long View: ASCO Marks Progress In Shifting To Lengthier Treatment Duration For Avastin, Rituxan

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