You can’t get past the month of October without knowing that it’s dominated by all things breast cancer (officially, it’s National Breast Cancer Awareness Month). Instead of screening this year, the big news seemed to revolve around genetic testing, in particular the BRCA1 and BRCA2 gene mutations. Here’s a sampling of breast cancer news from 2013:
1) The best news this year for women with breast cancer
The FDA approved two new treatment options. There’s a chance that treating women at high risk for the disease earlier may make it less deadly—possibly shrinking tumors or delaying or preventing a recurrence. That’s the idea behind Perjeta® (pertuzumab), the first FDA-approved drug for use in breast cancer pre-surgery (approved Sept. 30th). It’s intended for women with HER2-positive, early-stage breast cancer for whom there’s a good chance of the cancer recurring, spreading or being lethal. Clinicians have called the therapy “game-changing.” U.S. regulators also approved Kadcyla® (ado-trastuzumab emtansine), a follow up to Herceptin® (trastuzumab), indicated for patients with HER2-positive, late-stage breast cancer who have not responded to other therapies. Kadcyla is the only FDA-approved antibody-drug conjugate (ADC) for a solid tumor (approved Feb. 22nd) and it delivers a powerful punch to kill cancerous cells. Both drugs were developed by Roche/Genentech.
2) Genetic testing, radical options
Actress Angelina Jolie’s disclosure in May that she had chosen to have a preventive double mastectomy after genetic testing showed that she carried the BRCA1 gene mutation, which placed her at an 80 to 90% risk for developing breast and ovarian cancer, did a lot to further the dialogue about breast cancer risks and women’s choices in 2013. The media subsequently reported a run on genetic testing by women—and on average American women at risk for breast cancer opting to having one or both breasts removed rather than having to face a future cancer diagnosis or a recurrence. The American Cancer Society urged caution for women considering more radical options like Jolie. In January, months before Jolie’s announcement, double mastectomies were reported to be on the rise, both among women with cancer in only one breast and for women at genetic risk who hadn’t yet been diagnosed. Maybe Jolie’s much-publicized decision wasn’t so much a driving force for women facing the same dilemma as it was just a part of a trend already in progress?
3) Historic SCOTUS decision
Some positive news in June on genetic testing: The Supreme Court issued a landmark ruling and said that human genes such as BRCA1 and BRCA2 could not be patented, putting a crimp in Myriad Genetics’ long-held monopoly on testing for those genes. The SCOTUS ruling finally opened up the marketplace to some real competition and that decision is already showing progress in making BRCA genetic testing not only cheaper, but more widely available to many more women. Quest Diagnostics is already offering their BRCAvantage tests nationwide, at a cost of about $2,500, well below Myriad’s tab of $3,000 to $4,000. Other smaller companies have also jumped on the bandwagon.
4) Redefining premalignant cancers
Strike the word “carcinoma” from the lexicon for premalignant conditions, a group of experts to the National Cancer Institute (NCI) advised in July. The suggestion included renaming the precancerous breast condition known as “ductal carcinoma in situ (D.C.I.S.).” Changing the terminology might reduce the needless overdiagnosis and overtreatment that many women experience and also lessen the fear factor that words like carcinoma invite. But Dr. Larry Norton, deputy physician-in-chief of breast cancer programs at Memorial Sloan-Kettering, pointed out one of the issues inherent in a discussion on changing cancer’s terminology and its more indolent forms: “Which cases of D.C.I.S. will turn into an aggressive cancer and which ones won’t?,” he asked in a New York Times article.
5) Anti-estrogen drugs as prevention
The U.S. Preventive Services Task Force (USPSTF) in September issued final guidelines recommending that doctors offer tamoxifen and raloxifene, two medications which block estrogen in the breast tissue, as an option to healthy women who are at an increased risk of breast cancer. Data presented at ASCO showed that, for women who’d already had breast cancer, taking tamoxifen for ten years instead of the recommended five made the disease less likely to recur. In spite of adverse side effects, including blood clots and strokes, the benefits of taking the anti-estrogen drugs were found to outweigh the risks for women at risk for developing breast cancer. For women who can’t or don’t want to take these two medications, plenty of other non-pharmaceutical ways to reduce breast cancer risk were also on the radar this year, including simply walking.
6) New HER2 guidelines
Recently an updated guideline was jointly issued by ASCO and the College of American Pathologists (CAP) recommending that all women with invasive breast cancer should be tested for the HER2 gene and protein. The guideline is meant to better standardize testing and ensure that women with HER2-positive cancers receive HER2-targeted therapies which can substantially improve these patients’ survival. Likewise, the guideline said that HER2-negative women should only be treated with therapies appropriate to their particular subtype of cancer in order to avoid the side effects and costs associated with the HER2-targeted drugs.
And just for the record, as of 2013 physicians now have four FDA-approved HER2-targeted therapies to choose from for their patients: Kadcyla (2013), Perjeta (2012), Tykerb® (lapatinib) (2007) and Herceptin® (trastuzumab) (1998).
By Nancy Ciancaglini, OBR Daily Managing Editor
In recent years, angiogenesis inhibition, and VEGFR inhibition in particular, has been the most promising therapeutic target in advanced ovarian cancer, and the VEGF-targeted monoclonal antibody Avastin® (bevacizumab, Roche/Genentech) has been the major player in drug development for this tumor type. With Phase III trials conducted in multiple settings in ovarian cancer, Avastin has demonstrated a progression-free survival (PFS) benefit in first-line1,2,3, recurrent platinum-sensitive4, and recurrent platinum-resistant5,6 patients, and in the past two years, it has received regulatory approval in the European Union for use in the first-line/maintenance and recurrent platinum-sensitive settings. Other small molecule VEGFR inhibitors have followed Avastin into late stage development in ovarian cancer; Votrient® (pazopanib, GlaxoSmithKline) and cediranib (AstraZeneca, development discontinued) have demonstrated positive results in Phase III trials in the first-line maintenance and recurrent platinum-sensitive settings, respectively7, and an ongoing Phase III trial is evaluating Vargatef™ (nintedanib, Boehringer Ingelheim) as first-line/maintenance therapy.
Trebananib (Amgen) is a first-in-class agent that inhibits angiogenesis through a different pathway: the angiopoietin axis. Trebananib, a recombinant peptide-Fc fusion protein (peptibody), prevents the interaction of ligands angiopoietin 1 and 2 (Ang1 and Ang2) with the Tie2 receptor, thereby inhibiting a signaling pathway that is normally involved in vascular growth, remodeling, and stabilization. Amgen has initiated a comprehensive Phase III development program for trebananib in ovarian cancer, with the TRINOVA-1 and TRINOVA-2 trials in recurrent patients with platinum-resistant or partially platinum-sensitive disease and the TRINOVA-3 trial in the first-line/maintenance setting.
The results of the TRINOVA-1 trial were presented on Tuesday, October 1 at the 2013 European Cancer Congress (ECC)8. This double-blind Phase III trial (NCT01204749) randomized 919 recurrent patients with advanced ovarian, primary peritoneal, or fallopian tube cancer to receive weekly paclitaxel (80 mg/mg2) plus placebo or trebananib (15 mg/kg). Patients could have received up to 3 prior regimens and must have had a platinum-free interval (PFI) of less than 12 months after their most recent line of therapy; about half of patients in each arm had a PFI of less than 6 months, a threshold which is often used to define platinum resistance. The primary endpoint of the trial was PFS, and secondary endpoints included OS, ORR (using RECIST criteria), CA-125 response rate, and quality of life (FACT-O, OCS, and EQ-5D measurements).
The trial met its primary endpoint, with the addition of trebananib to paclitaxel significantly increasing PFS (see Table 1, mPFS: 7.2 vs. 5.4 months, HR: 0.66, p<0.001), and this benefit was consistent across multiple subgroups, including patients with a PFI less than 6 months as well as those with a PFI between 6 and 12 months. Patients with prior anti-angiogenic therapy (e.g. Avastin) were allowed in the study, but due to the large degree of variability in the PFS results for those patients (HR: 0.69, with 95% CI of 0.41 – 1.17), the efficacy results in that subgroup are inconclusive based on the data presented. In addition to PFS, the overall response rate was also improved in patients who received trebananib plus paclitaxel (38.4% vs. 29.8%, p<0.0071). However, although there was a slight numerical improvement, an interim analysis did not find a statistically survival benefit of adding trebananib to paclitaxel (mOS: 19.0 vs. 17.3 months, HR: 0.86, p=0.19); mature survival data are expected in 2014. Interestingly, the dose of trebananib used in TRINOVA-1 (15 mg/kg) was increased from the highest Phase II dose (10 mg/kg) in the hopes of improving drug efficacy. An analysis of the Phase II data found a trend toward an increased PFS in patients with a higher drug exposure (AUC of at least 9.6 mg*h/mL) that was not routinely reached in patients who received the 10 mg/kg dose9.
The toxicity profile of the trebananib and paclitaxel combination was manageable, and the addition of trebananib barely increased the incidence of Grade 3+ adverse events (56%) compared to paclitaxel alone (54%). Adverse events (of all grades) that were increased in the paclitaxel plus trebananib arm included localized edema (57% vs. 26%), peripheral neuropathy (21% vs. 16%, thought by the presenter to be related to increased paclitaxel exposure), ascites (20% vs. 12%), pleural effusion (13% vs. 4%), upper abdominal pain (12% vs. 7%), and generalized edema (11% vs. 3%). There was little to no increase in the incidence of typical VEGFR inhibition-related adverse events, such as hypertension (6% vs. 4%), proteinuria (3% in both arms), arterial thrombotic events (<1% in both arms), impaired wound healing (<1% in both arms), and GI perforation/fistula (1% vs. <1%), in the paclitaxel plus trebananib arm compared to pacliltaxel alone.
Considering these data, what will be trebananib’s regulatory and commercial fate? This question is best viewed through the prism of Avastin’s experience. To date, all Phase III trials evaluating Avastin in ovarian cancer have shown a significant PFS benefit, but no OS benefit. Based on these data, Avastin has been approved by the European Medicines Agency (EMA) for use in the first-line/maintenance setting as well as the recurrent platinum-sensitive setting; however, Roche has not yet filed for approved in Europe in the recurrent platinum-resistant setting. In contrast, Roche has not filed for approval in the U.S. in any setting in ovarian cancer, strongly suggesting that the FDA has provided guidance that a PFS benefit without an OS benefit would not be approvable. If trebananib’s experience with the European and U.S. regulatory agencies reflects that of Avastin, then it will likely be approved by the EMA with only the current PFS benefit, but if the mature OS data do not show a significant survival benefit, then it is unlikely to be approved by the U.S. Federal Drug Administration (FDA). However, it is possible that the high unmet need in platinum-resistant patients and the reasonable toxicity profile of trebananib might sway U.S. regulators in favor of the drug.
If approved, how will trebananib fare against Avastin, which will be its primary competitor in the recurrent setting? Based on the fact that the TRINOVA-1 trial include recurrent patients who were platinum-resistant as well as those who were partially platinum-sensitive, the patient population in this trial is not directly comparable to either the AURELIA or OCEANS trials of Avastin in recurrent platinum-resistant and platinum-sensitive patients, respectively. In general, however, the 1.8 month PFS benefit seen in the TRINOVA trial is somewhat smaller than the 3.3 month and 4.0 month PFS benefits observed in the AURELIA and OCEANS trials, respectively (see Table 2). Therefore, it is unlikely that physicians would routinely prefer trebananib over Avastin.
Due to their different mechanisms of action, however, Avastin and trebananib do have very distinct safety profiles, and this distinction could easily lead to the two agents being used in slightly different patient populations. Avastin administration generally results in typical VEGFR-related toxicities such as hypertension, proteinuria, and in rare cases, GI perforation and bleeding. In contrast, trebananib does not cause these VEGFR-related side effects, but does increase the incidence of edema, ascites, and pleural effusions. These side effect profiles, combined with recent data presented at the 2013 ECC suggest that first-line Avastin is more effective in higher-risk patients3, and also suggest that Avastin will be more likely to be utilized in high risk or highly symptomatic patients who already have baseline ascites and other similar symptoms. In contrast, trebananib might be more likely to be used in patients with co-morbidities that increase the risk of serious side effects from Avastin, such as a history of cardiovascular disease.
The data from the TRINOVA-1 trial also raise several additional questions about the use of these two agents. For example, how should these agents be sequenced? In patients who receive Avastin in the first-line setting, re-treatment with Avastin is unlikely, and that may be the primary opportunity for trebananib. Considering the non-overlapping safety profiles, another major outstanding question is whether trebananib and Avastin (or other VEGFR-targeted agents) should be used in combination. Although these questions will not be answered conclusively anytime soon, the results of the ongoing TRINOVA-2 and TRINOVA-3 trials of trebananib should become available within the next few years, and these results should provide a better understanding of how trebananib will best fit into the treatment paradigm for ovarian cancer.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, Analyst, Clinical and Scientific Assessment, Kantar Health