Genentech Aims For Broad Access To Avastin In Cervical Cancer, But Needs To Figure Out How To Get There

FDA approval is fifth indication for Roche/Genentech’s Avastin. Number of cases in the U.S. is low and set to decline with better prevention, but disease is considered a major global health problem.

Genentech Inc. intends to make Avastin (bevacizumab) broadly accessible worldwide in cervical cancer, though the details have yet to be worked out market-by-market.

“Ultimately, what we are striving to do is to make this treatment available to all women who need it,” Philippe Bishop, VP of clinical development and global head of the angiogenesis franchise at Genentech, said in an interview.

That will take some creative thinking on the company’s part, as Avastin is a high-cost oncologic and the disease is a problem in emerging markets – as prevention efforts in the more developed world are highly successful.

The company’s approach will be tailored to the needs of each particular market, Bishop said.

Avastin was cleared Aug. 14 as an add-on treatment to chemotherapy for cervical cancer that is persistent, recurrent or metastatic, a use supported by the drug’s demonstration of a significant improvement in overall survival compared to standard chemotherapy alone. FDA noted that the drug “was approved in less than four months” under FDA’s priority review program and marks the first approval in cervical cancer since the 2006 clearance of topotecan with paclitaxel. Chemotherapy has been the typical treatment option for cervical cancer and Avastin is the first biologic to become FDA-approved for the indication.

For Roche/Genentech, this marks the blockbuster’s fifth cancer indication, in addition to metastatic colon cancer, non-squamous cell lung cancer, glioblastoma and metastatic renal cell carcinoma.

The company also submitted for approval of Avastin in cervical cancer in Europe in June.

Approval in the U.S. and Europe would help pave the way for clearance in other countries where cervical cancer is more common due to less effective prevention programs, but where resources are also scarcer. Genentech plans to pursue filings in other regions of the world, though it would not provide specifics.

In an interview after the approval, Bishop said that “the development of Avastin is for all women, regardless of geography.” Approval in the U.S. and Europe would represent important milestones that could allow expansion to other parts of the world, the exec said.

Evidence Meets Gold Standard

Approval was supported by the four-arm GOG 240 study, which tested Avastin with paclitaxel and cisplatin or paclitaxel and topotecan against the chemotherapy regimens alone. The study was sponsored by the National Cancer Institute, with financial support from Roche/Genentech.

Labeling notes that median overall survival was 16.8 months for chemotherapy and Avastin versus 12.9 months for chemotherapy alone, a 26% reduced risk of death and an absolute difference of 3.9 months. Looking at the results by chemotherapy type, median overall survival was 13.3 months for the topotecan/paclitaxel/Avastin regimen (24% reduced risk of death) versus 15.5 months (28% reduced risk) for cisplatin/paclitaxel with Avastin. The overall response rate was also higher for chemotherapy combined with Avastin at 45% versus 34% for chemotherapy alone.

Side effects were in line with what is known about Avastin. Doctors who treat cervical cancer say they are already very aware of managing the risks, including gastrointestinal perforations, due to prescribing for endometrial and ovarian cancers.

Where’s The Market?

Cervical cancer is becoming less of a problem in the U.S. due to prevention efforts – the current rate of 12,000 new cases in the U.S. each year is expected to decline with further vaccination for human papilloma virus, which causes cervical cancer, noted the University of California, Irvine’s Krishnansu Tewari and colleagues, reporting trial data in the New England Journal of Medicine on Feb. 20.

“However, for vulnerable populations without access to health care in the United States and throughout the world, cervical cancer remains a considerable problem, with 500,000 new cases and 250,000 deaths annually,” the authors noted.

The drug’s ability to improve overall survival as an add-on to chemotherapy in cervical cancer in the pivotal GOG 240 cervical cancer study was highlighted in the plenary session of the 2013 American Society of Clinical Oncology meeting, where the data were described as “practice changing” (Also see "Avastin Takes One Step Forward, One Step Back At ASCO" - Pink Sheet, 3 Jun, 2013.). During an investor briefing at the meeting, Roche Chief Operating Officer Daniel O’Day pointed out that the disease is the second-leading cause of cancer death for women globally and there is “huge medical need out there,” with very few treatment options for recurrent cervical cancer.

“FDA approval gives the data its legitimate credence,” Massachusetts General Hospital gynecologic specialist Don Dizon said on behalf of ASCO. “It says this is important data … women need to know about this and doctors should offer this.”

Dizon expects chemotherapy plus Avastin to become the standard of care in U.S. for women with recurrent cervical carcinoma. Up to now, it’s been an option sanctioned by the National Comprehensive Cancer Network compendia. And even before the release of GOG 240 data, there were Phase II data supporting use of Avastin. Dizon said that many insurers have been willing to cover Avastin up to now and that following FDA approval, he expects that they will be obliged to cover it.

The NCCN upgraded its guidelines for Avastin in cervical cancer in August, determining that Avastin plus cisplatin and paclitaxel should have the highest recommendation for use of Category 1, up from Category 2A. The NCCN also added Avastin plus topotecan and paclitaxel as a Category 2B recommendation.

Weighing Cost Vs. Benefit

However, Dizon also predicts approval will trigger a debate “locally, nationally and globally” about the cost and value of Avastin, taking into account a roughly four-month long overall survival benefit.

“I’d like to think with the FDA approval, bevacizumab would be widely available regardless of insurance across the U.S. and globally. However, I don’t think that’s going to be the case,” Dizon said.

Genentech notes that it offers its well-staffed “Access Solutions” program to help navigate reimbursement policies and provide the drug free of charge to uninsured patients. The company has been at the forefront of payment assistance efforts with the drug, instituting a price cap for patients with incomes under $100,000 a year regardless of insurance – currently set at $66,500 for approved indications, including advanced cervical cancer.

The drug has a monthly cost of $10,000 and the firm estimates that the typical cost for cervical cancer will be $82,000 (8.2 months of use), though the duration of treatment in the trial shows it could extend longer. Investors have previously noted that the longer durations of therapy with some of the cancers Roche is adding to Avastin’s label, like cervical cancer and potentially ovarian, have longer treatment periods and could bust the cap system.

The price cap was introduced in 2006 at $55,000 and has risen incrementally; it was $62,000 in 2013, $61,000 in 2012 and $58,000 in 2011.

Genentech has acknowledged the need for pricing reform, especially as the more expensive therapies start being used in combination and as it moves into emerging markets (Also see "Roche Experimenting With New Pricing Models In Oncology" - Pink Sheet, 10 Jun, 2013.).

The firm notes that it remains committed to assisting patients with the cost of therapy and has more than 300 employees dedicated to Access Solutions, who helped more than 175,000 patients in 2013 with issues including co-pay assistance for eligible patients, free medicine for patients without insurance or who are underinsured as well as help for patients who are denied coverage by their payer (see www.Genentech-Access.com).

Nita Karnak Lee, assistant professor in obstetrics and gynecology at The University of Chicago, also predicts there will be a debate weighing the value of a roughly four-month OS improvement, due to the high cost of Avastin. However, she believes that the value is clearly justified for women with a profile suggesting they will be good candidates for Avastin, so that risks are minimized. Women with cervical cancer may be very functional and young – in their 40s and 50s with children at home.

“I would argue that for some women this is a really big deal … gaining time is really still very valuable for these women,” Lee said in an interview.

While Avastin offers hope to patients in Western countries, Roche execs acknowledged during the company’s 2013 ASCO call that the need is particularly strong in emerging markets.

This suggests opportunities and also challenges about how to approach those markets appropriately, Chief Operating Officer Daniel O’Day said during that call. In the six years preceding 2013, the percentage of Roche’s oncology sales from emerging markets has risen from 15% to 23%. The company has been experimenting with different pricing models to make Avastin available to more patients, such as second-brand strategies in India and also a different type of capitation program for China, which has “really expanded the use of Avastin in China significantly.”

In Brazil – one of Roche’s major world markets – there are more cases of recurrent cervical cancer than in the U.S. and Europe combined. The company is very enthusiastic about looking for ways to “penetrate the public sector even more in countries like Brazil,” O’Day said.

A Look At The Pipeline

The NEJM article stressed the unmet need for treatments of advanced cervical cancer in developing countries, particularly in sub-Saharan Africa, Latin America and Southeast Asia. Cost-effectiveness studies are needed to evaluate the regimen with cisplatin/paclitaxel and Avastin “because of the societal burden involved in making expensive therapies available to those in greatest need,” they suggested.

“However, the key to solving the global burden of cervical cancer continues to be the implementation of screening and vaccination programs,” the authors concluded.

The low and dropping number of cases in the U.S. means less incentive for industry to develop treatments for recurrent cervical cancer. Recruiting patients for trials can be challenging and there has not been as much interest as “there could be or should be” from industry in this disease setting, but collaborative efforts between public and private organizations can really make a difference, said Lee. The development of Avastin in cervical cancer is an example of how successful that can be, as the NCI ran that trial.

The NCI is currently testing a range of therapies in cervical cancer, including Bayer AG/Onyx Pharmaceuticals Inc.’s Nexavar (sorafenib), AstraZeneca PLC’s PARP inhibitor olaparib and Bristol-Myers Squibb Co.’s CTLA-4 immunotherapy Yervoy (ipilimumab).

The ASCO 2014 press program featured promising results from a small NCI trial of personalized HPV-adoptive T-cell therapy. In that study, two out of nine patients with advanced cervical cancer, including widespread metastases, had complete remissions after a single treatment and were free of cancer for over a year, investigators reported at the meeting.

Dizon views immunotherapy as the most promising approach to treating cervical carcinoma. It makes sense, because cervical carcinoma is “virally mediated and has a viral pathogenesis – and this can be exploited,” the clinician explained. “If we can home in on what are the factors that predict a good response, this is a therapy that is likely to really change the way we treat cervical carcinoma,” he said.

The industry-sponsored pipeline includes immunotherapeutics (see table below).

Inovio Pharmaceuticals Inc. presented positive results for its Phase I trial of VGX-3100 in precancerous lesions at the 2014 ASCO meeting, a candidate that works by stimulating the immune system to eliminate HPV infection.

Advaxis Inc.’ ADXS-HPV is an immunotherapy that targets cells that have been transformed into dysplastic and malignant tissues by HPV.

AstraZeneca PLC’s PD-L1 immune checkpoint inhibitor MEDI-4736 is in early stage development for cervical cancer, along with many other oncology indications (Also see "AstraZeneca Playing Leapfrog In Immunotherapy: How It Plans To Lead From Behind" - Pink Sheet, 9 Jun, 2014.).

In July, Advaxis and AstraZeneca subsidiary MedImmune said they were teaming up to study ADXS-HPV in combination with MEDI-4736 in HPV-associated cervical cancer and squamous cell carcinoma of the head and neck ([See Deal]). Under the terms of the agreement, Advaxis will fund and run a Phase I/II clinical study of the combination in advanced, recurrent or refractory cervical cancer and HPV-associated head and neck cancer. MedImmune gets the right to first negotiation for development of the combination.

Some targeted pathways are also being explored. For example, Novartis AG’s buparlisib (BKM120) is a PI3 kinase inhibitor in Phase II for women with metastatic or unresectable cervical cancer after the failure of cisplatin-based chemotherapy. Novartis has included BKM120 as a potential blockbuster by 2018 (Also see "Novartis Puts Combination, Cellular Therapies In Spotlight As It Revamps R&D Portfolio" - Pink Sheet, 2 Dec, 2013.). The drug is in Phase III for breast cancer and Phase I/II for many other cancers, including endometrial, gastrointestinal, head and neck, glioblastoma and non-small cell lung cancers.

Drugs In Development For Cervical Cancer, Industry-Sponsored Trials*
Sponsor/Drug	Mechanism Of Action
Phase III
Zeria Pharmaceutical’s Z100 (developed ex-U.S. for Asian market)	Immunomodulator
Phase II
Advaxis’ ADXS-HPV	Listeria vaccine against human papillomavirus
Novartis’ buparlisib	Pan-class I phosphoinosotide 3-kinase (PI3K) inhibitor
Karyopharm Therapeutics’ selinexor	Selective inhibitor of nuclear export (SINE) compound
Nanotherapeutics’ triapine	Potent ribonucleotide reductase inhibitor, inhibits DNA synthesis to cause tumor cell death
ISA Pharmaceuticals’ ISA101	HPV therapeutic vaccine
Phase I/II
Inovio’s INO-3112	DNA vaccine introduces plasmids that target the E6 and E7 oncogenes of HPV types 16 and 18
AstraZeneca’s MEDI-4736	PD-L1 inhibitor
Preclinical
Transgene’s TG4001	HPV vaccine
Source: BioMedTracker