HER2-targeted therapy was the star of the show at today’s plenary session at the 2012 ASCO meeting. T-DM1 (trastuzumab emtansine) is Genentech / Roche’s antibody-drug conjugate, consisting of a potent microtubule polymerization inhibitor conjugated to the trastuzumab monoclonal antibody via a highly stable linker. T-DM1 is designed to take advantage of the targeted nature of the antibody to selective deliver the cytotoxic agent to HER2+ breast cancer cells. Roche is hoping that T-DM1 will further expand their franchise in HER2+ breast cancer. Roche’s other product, Herceptin (trastuzumab), currently dominates the HER2+ market, with about 70% utilization in front-line HER2+ metastatic breast cancer patients.† Although Tykerb® (lapatinib, GlaxoSmithKline) is approved in the second-line in combination with Xeloda® (capecitabine, Roche), about half of U.S. physicians choose to rechallenge with Herceptin plus chemotherapy, leaving Tykerb for later-lines of therapy.†
In today’s presentation (LBA1), Roche / Genentech wowed the audience with the impressive results from the EMILIA study, which evaluated TDM-1 monotherapy versus Xeloda plus Tykerb (XT) in relapsed HER2+ metastatic breast cancer patients. TDM-1 showed a progression-free survival (PFS) benefit of 9.6 months versus 6.4 months with XT (HR=0.650, p<0.0001) and improved overall survival – although the median was not yet reached in the TDM-1 arm, the OS was 23.3 months in the XT-arm (HR=0.621, p=0.0005). Adding to the excitement was the improved toxicity profile of TDM-1, showing lower rates of Grade 3 Adverse Events (41% versus 57%), very little gastrointestinal toxicity, and only liver toxicity was increased compared to XT. It would appear that the XT-arm underperformed in EMILIA compared to the Phase III registration-enabling trial for Tykerb, in which XT showed a 8.4 month PFS. Hopefully more detailed future analyses will shed some light on reasons for the apparent discrepancy in XT performance. A cursory analysis of the presented patient demographics does not afford an explanation as the demographics were comparable and discontinuation rates were similar between the two studies.
Based on this impressive data, it will be interesting to see exactly where TDM-1 fits into the treatment paradigm once it is approved. With the success of the CLEOPATRA trial and Perjeta’s (pertuzumab, Roche / Genentech) impending approval in combination with first-line Herceptin, this raises the question of whether TDM-1 will occupy the second-line after Herceptin/pertuzumab, or will Herceptin “rechallenge” remain the second-line treatment of choice, followed by third-line TDM-1? Where will Tykerb fit in? The treatment paradigm in first-line may change again soon, as Roche is studying TDM-1 with or without Perjeta and compared to Herceptin plus Perjeta and taxane in the MARIANNE study. Whichever scenario comes to fruition, it is evident that Roche / Genentech have been successful in muscling out most competitors in this tumor subtype, and TDM-1 gives the company some protection from potential future biosimilar competition that they face for Herceptin.
† Utilization data from the 2011 Kantar Health CancerMPact® U.S. Treatment Architecture.
By Gordon Gochenauer, Director, Commercial Development, Kantar Health
Avastin® (bevacizumab, Genentech/Roche) is currently a first-line standard of care in combination with chemotherapy in both the United States and Europe; however, it is used less often in the first-line by European physicians. Avastin is also labeled for use in the second-line, based on three Phase III trials comparing second-line chemotherapy with or without Avastin in patients who did not receive first-line Avastin. The BRiTE Registry (Grothy, JCO, 2008), which was an observational study that among other treatment patterns evaluated the use of Avastin after progression in metastatic colorectal cancer patients treated in the first-line with Avastin, suggested a benefit for continued Avastin. These results are manifested in Kantar Health’s CancerMPact Treatment Architecture physician survey data, which suggest a large percentage of patients are treated with both first- and second-line Avastin (46% in the US, 38% in Europe). This environment highlighted the need for clinical data asking whether continued VEGF inhibition would provide survival benefit to patients, and are addressed by two trials at ASCO 2012: TML (Treatment across Multiple Lines; ML18147) which examined the efficacy of Avastin and chemotherapy following first-line Avastin and chemotherapy. This trial was initiated by the German AIO study group, but was soon taken over by Roche given the demand of physicians to enroll patients in this trial. The second trial is a subset analysis of the VELOUR trial, which compared the use of Zaltrap™ (aflibercept, Sanofi) in patients pre-treated with Avastin. It should be noted that the primary analysis of VELOUR had already shown a survival benefit in all patients, either previously-treated or not previously-treated with Avastin, in a presentation at the European Multidisciplinary Cancer Conference (Tabernero, Abstract 6 LBA, EMCC 2011). These trials, presented in the same oral session, set up a competition between the two. If Avastin wins out for second-line, where will Zaltrap be used?
Both trials met their primary endpoints of overall survival, but both were underwhelming. The addition of Avastin to chemotherapy improved median overall survival in the intent-to-treat population by 1.4 months (11.2 months versus 9.8 months, HR=0.81, p=0.0211), and improved median progression-free survival by 1.6 months (5.7 months versus 4.1 months, HR=0.67, p<0.0001). In patients stratified by prior Avastin treatment, Zaltrap improved overall survival by 0.8 months (12.5 months versus 11.7 months, HR=0.862) and improved progression-free survival by 2.8 months (6.7 months versus 3.9 months, HR=0.661). Both Avastin and Zaltrap presented comparable toxicities, with hypertension predominating. Avastin use was associated with slightly higher rates of venous thromboembolic events, but given the nature of this type of cross-trial comparison should not influence utilization. VELOUR had one deficiency – the majority of patients from the U.S. were pretreated with Avastin in first-line. This may have influenced the trial’s inability to truly detect an interaction effect for Avastin pre-treatment, forcing statisticians to use a lesser threshold (10%) to detect significance rather than the traditional 5%.
In essence, these data might be construed as a tie, but as such represents a possible victory for Avastin and may relegate Zaltrap to the third-line setting. Physicians already are comfortable with administering Avastin, so these data may not influence their choice of therapy. The discussant (Dr. Alan Venook) indicated that Zaltrap would gain approval based on VELOUR (filed in Europe in December 2011 and with U.S. FDA action expected in August 2012), and Avastin will earn a label addition for these Avastin-pretreated CRC patients. However, he posed an interesting question. If TML (and by extension, VELOUR) predicts that continuing VEGF inhibition beyond progression following first-line Avastin, should VEGF inhibition be continued for all lines of therapy including a third or fourth line? That would have to wait for another trial.
By Gordon Gochenauer, Director, Commercial Development, Kantar Health
There are currently 7 agents (excluding cytokines) approved for use in renal cell carcinoma (RCC), 5 of which are approved for use in the first-line setting, of which 4 are VEGF pathway inhibitors. With so many options, and few definitively differentiating factors, how is a physician (or patient) to choose the best course of therapy? If efficacy is equal (which for many of these agents it has yet to be compared), toxicity is the next logical choice, as it can have a significant impact on treatment intensity and patient quality of life. So how does one (that is, a manufacturer with a new agent in RCC – or any other crowded market) go about demonstrating such differentiation?
Votrient (pazopanib, GlaxoSmithKline) was approved based on demonstrated superior progression-free survival (PFS) benefit compared to placebo in treatment-naïve or cytokine-pretreated RCC. This superiority was sufficient for regulatory approval, but the lack of comparison to other approved agents relegated Votrient to minimal market share, primarily in later lines of therapy. This was despite levels of efficacy that appeared comparable to the market leader, Sutent (sunitinib, Pfizer), and with an apparently improved safety profile. The key words here are “appeared” and “apparently.” In the absence of head-to-head data comparing Votrient with Sutent, physicians have been reticent to adopt Votrient upfront.
Perhaps in anticipation of this, GlaxoSmithKline took the bold move of initiating a patient preference study shortly after gaining regulatory approval for Votrient in advanced or metastatic RCC. The PISCES trial randomized patients to sequential treatment with Votrient (10 weeks) followed by Sutent (10 weeks) or the reverse order, and patients completed preference questionnaires at the end of each treatment period. This unique design allowed direct evaluation of drug preference among patients who had been equally exposed to both agents. The results, presented at today’s Oral Genitourinary Cancers session, were overwhelming – 70% of patients who completed both treatments and questionnaires preferred Votrient whereas only 22% preferred Sutent (8% stated no preference). Overall quality of life and all queried toxicities were cited as favoring Votrient with fatigue standing out from the patients’ perspective. Despite the overwhelming nature of these results favoring Votrient, the lack of head-to-head efficacy data still weighs on physicians minds, with Dr. Escudier and an audience member both commenting that they plan to wait on the results of the COMPARZ study (NCT00720941) before acting on the PISCES results. COMPARZ, a head-to-head study against the market leader, can be viewed as a bold move by GSK in retrospect given the positive results from PISCES. However, at the time COMPARZ was initiated, efficacy was viewed as the most important issue in RCC. However, with the results of PISCES, Votrient will likely be rewarded even if non-inferior efficacy is demonstrated in COMPARZ particularly with physicians who are already convinced that Votrient and Sutent have similar efficacy. Stay tuned for the COMPARZ data in late 2012 or 2013.
Recognizing your weaknesses and threats, and leveraging your strengths and opportunities is one of the first things taught in business school and should be incorporated into any strategic development plan. GSK is going out guns blazing in a valiant attempt to position Votrient as the preferred first-line agent for advanced RCC. How will other new entrants in this competitive field fare? Next in line for probable approval is tivozanib (AVEO/Astellas), for which the results of their pivotal Phase III TIVO-1 trial were presented immediately prior to the PISCES data. AVEO initially planned to position tivozanib as a preferred agent based on biology – greater affinity for VEGFR-1,-2, and -3 with a longer half-life were supposed to produce superior efficacy and better tolerability and allow it to penetrate the RCC market. Based on the data presented today, tivozanib is clearly superior to Nexavar in terms of both efficacy and tolerability – but is that enough? Tivozanib is clearly (upon regulatory approval) “an” option in advanced RCC, but it’s far from “the” option. Manufacturers attempting to enter the RCC could take a lesson from GSK in terms of boldness, innovation, and proactive behavior. At this point, manufacturers should consider a patient preference study similar to GSK’s PISCES. Regulatory approval does not guarantee market share – newer agents will need to demonstrate compelling benefits against appropriate standards of care that will convince physicians, patients, and payers alike that they are the drug to beat.
By Gordon Gochenauer, Director, Commercial Development, Kantar Health
The winning streak for Avastin continues with successful results reported with Avastin in pivotal trials for ovarian cancer at 2011 and 2012 ASCO. The AURELIA study was the first randomized study to evaluate the clinical efficacy of Avastin in combination with chemotherapy in platinum-resistant patients. Eligible patients were randomized to receive chemotherapy (paclitaxel, topotecan or liposomal doxorubicin) alone or in combination with Avastin (15 mg/kg). The trial was designed to achieve a HR of 0.7 (anticipated PFS improvement from 4 to 5.7 months) and the results did not disappoint. Avastin plus chemotherapy achieved significant improvement in primary endpoint of median progression-free survival (mPFS= 6.7 months in Avastin plus chemotherapy versus 3.4 months in control arm; HR 0.48, p<0.001). In addition, the ORR was also significantly improved for the Avastin plus chemotherapy arm compared to the chemotherapy alone arm (ORR: 30.9% versus 12.6%; p2 hypertension (20%), proteinuria (10.6%) and thromboembolic events (5%). There were slightly higher reports of peripheral sensory neuropathy and hand-foot syndrome observed in Avastin plus chemotherapy arm but this was attributed to the fact that patients in the combination arm remained on therapy for longer time compared to the chemotherapy alone arm.
With the caveats of cross-trial comparison, Avastin plus chemotherapy does look better than current standards. Unfortunately the authors of the presentation did not provide any of the efficacy results according to each chemotherapy agent used in the study. Disappointingly, no information on the increasingly important secondary endpoint, overall survival, was provided. The overall survival data from AURELIA study are anticipated in 2013 and Roche/Genentech have indicated that they will file for approval in ovarian cancer with the FDA based on the survival results.
Although the trial achieved its primary endpoint, the discussant (Dr. Seiden) was skeptical that Avastin would achieve a survival benefit. Dr. Seiden correlated the PFS data from AURELIA with that observed in the GOG-0218 trial (first-line Avastin plus chemotherapy), which demonstrated a 2.8 month PFS benefit (comparable to 3.3 months observed with AURELIA) but failed to demonstrate a survival benefit. In spite of Dr. Seiden’s skepticism on the survival benefit, the fact is that Avastin did achieve a significant PFS benefit and physicians are willing to accept PFS benefit in ovarian cancer. As mentioned before, Avastin is not yet approved in the United States; however, it does have a category 2A recommendation in the NCCN guidelines. It is preferred in almost one-third of platinum-resistant patients either as a monotherapy or in combination with other agent according to Kantar Health’s CancerMPact Treatment Architecture U.S. physician survey. The newly reported results from AURELIA are likely to augment further adoption of this combination in United States; although questions of which is the best combination partner will remain unanswered until further subset analysis are reported. The situation is slightly different in Europe with the EMA already granting Avastin a label in first-line setting. Its indication in Europe will likely be expanded to include platinum-resistant patients and platinum-sensitive patients (based on improving PFS in the previously reported OCEANS trial). Kantar Health’s Treatment Architecture Western Europe physician survey from the first quarter of 2012 reports 10% utilization of Avastin in platinum-sensitive patients and approximately 20% in platinum-resistant patients according to CancerMPact Treatment Architecture. Unlike breast cancer, Avastin seems to have been able to demonstrate a consistent and more robust PFS benefit in ovarian cancer; whether this translates into an OS benefit will be revealed in 2013.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health