What’s in Store for ASCO 2016? Kantar Health Offers a Preview
By Tari Awipi, PhD, Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, PhD, Vice President, Clinical & Scientific Assessment, Kantar Health
The 2016 American Society of Clinical Oncology (ASCO) annual meeting is approaching, and it promises to be packed with the latest data and trends from the world of oncology. Kantar Health has identified nine pivotal abstracts that could have a significant impact on patient management and generate the most discussion. Of note, only two of these presentations are for new entities in the oncology space – the majority of new advancements to be presented at ASCO will involve new opportunities for existing therapeutics.
Vyxeos as induction for older patients with untreated high-risk (secondary) AML
Management of acute myeloid leukemia (AML) has been largely unchanged over several decades, with first-line induction therapy typically consisting of a combination regimen of cytarabine plus an anthracycline (7+3 most commonly).1 This is a very intensive regimen, and while it is effective at inducing remissions in a high proportion of patients, several subsets of AML patients exist with unmet needs. In patients with high-risk AML, which includes cytogenetic abnormalities as well as those with secondary AML (including those who progressed from myelodysplastic syndrome (MDS)), prognosis is poor. These patients have been the target of recent clinical development in AML. At ASCO 2016 we will see the pivotal results for a novel chemotherapeutic, Vyxeos™ (CPX-351, Celator Pharmaceuticals), which could transform care for a subset of patients. Vyxeos is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio that was designed to maintain an optimized ratio of the two drugs together to maximize efficacy outcomes.
Celator chose to study Vyxeos in the first-line setting in a subpopulation of patients at higher unmet need, specifically those with secondary AML and/or poor cytogenetics. In this patient population, a Phase III trial (NCT01696084) compared Vyxeos versus 7+3 as first induction therapy. In March 2016, Celator announced that this trial had met the primary endpoint of prolonging overall survival (OS), with a 3.6-month improvement favoring the Vyxeos arm (9.6 months vs. 6.0 months, HR 0.69, p=0.005), and landmark analysis suggested the benefit with Vyxeos was maintained over time. Based on these data, Celator plans to file for regulatory approval in the U.S. and Europe in the third quarter of 2016 and first quarter of 2017, respectively. These are welcome results for this patient population, and the first presentation of results at ASCO 2016 will be critical to fully assess the opportunity for this agent. The shape of the OS curve will be informative, as will the data on remission rates, duration of remission, and safety – all of which were stated or suggested to be improved in the company press release.
Nexavar in combination with transarterial chemoembolization in patients with unresectable hepatocellular carcinoma (TACE-2)
Nexavar® (sorafenib, Onyx/Amgen/Bayer) has become the established standard of care in unresectable/metastatic hepatocellular carcinoma (HCC). Although it has transformed the treatment landscape of advanced disease, management of earlier-stage disease remains unchanged, save for the occasional, unsupported off-label use of Nexavar in these patients. Several treatment options exist rather uniquely in HCC for the management of patients with localized disease. Among them is transarterial chemoembolization (TACE). Following Nexavar’s approval in advanced disease, a number of studies have been conducted to explore its utility in earlier-stage disease, including in combination with TACE for patients with localized HCC.
Two randomized studies have already explored the use of Nexavar in combination with TACE, both with mixed but overall negative results. The international randomized Phase II SPACE trial reported a 20% improvement in disease-free survival but no difference in OS.2 A companion study in Japanese and Korean patients also failed to meet its primary endpoint of significantly prolonging time to progression.3
While two failed trials would normally be the end of the story, some intriguing and as-yet unanswered questions remain that could support an opportunity for Nexavar in this treatment setting. The most interesting theory is based on preclinical studies looking at angiogenic factors, which emerged to suggest that the timing of VEGFR inhibition in relation to TACE may be critical to the success of Nexavar in this setting. The two completed trials may not have been designed with optimal Nexavar exposure, and ongoing Phase III trials with a different administration schedule may be better optimized to affect the course of the disease. The first of these trials, the TACE-2 study that is being conducted by University College London and the National Cancer Institute, will be reported for the first time at ASCO 2016; a second study being conducted by the Eastern Cooperative Oncology Group (E1208) is still ongoing.
The TACE-2 trial, which was initiated in November 2010, randomized patients to Nexavar or placebo as initial treatment, followed by TACE within two to five weeks after the start of Nexavar. The importance of timing of Nexavar pre-/post-TACE remains an academic theory at this point, but the results of the TACE-2 trial will be the first to put it to the test. If this trial demonstrates a strong progression-free survival (PFS) advantage favoring use of Nexavar with TACE, this could become a new standard of care for patients with unresectable but localized HCC. If the TACE-2 trial is not positive, this may be the final attempt of this combination.
Afinitor as consolidation in patients with DLBCL (PILLAR2)
Improvements in therapies have led to an increased number of non-Hodgkin’s lymphoma (NHL) patients in remission. For aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL), however, there have been minimal advances in treatment in the past decade. Although the R-CHOP regimen can induce complete remissions in the vast majority of newly diagnosed patients, relapse may still occur for many of these patients. In patients with poor prognosis, as defined by the International Prognostic Index (IPI), the relapse rate is even higher and accordingly OS is reduced.4 This has led to development of agents in a new maintenance/consolidation setting in order to prolong time to relapse. To date, no drug has been approved in this indication, creating an excellent opportunity for Novartis to have a first-in-class compound in this space with Afinitor® (everolimus). Development of Afinitor in DLBCL is supported by preclinical evidence showing that activation of the PI3K/mTOR signaling pathway is implicated in lymphoma pathogenesis, Phase II data for Afinitor in relapsed DLBCL,5 as well as clinical data that led to Food and Drug Administration (FDA) approval of the mTOR inhibitor Torisel® (temsirolimus, Pfizer) in relapsed/refractory mantle cell lymphoma.
Novartis launched the Phase III PILLAR2 trial (NCT00790036) in November of 2008. The randomized interventional trial compares Afinitor to placebo in poor-risk (IPI score 3, 4 or 5) DLBCL patients who have achieved a complete remission following first-line rituximab-based chemotherapy. Even in these poor-risk patients, disease-free survival is measured in years, which may be to blame, in part, for the prolonged nature of this trial (eight years from initiation to read-out), although slow accrual also appeared to be a culprit. Nevertheless, results from PILLAR-2 will finally be presented at ASCO 2016, providing a first look at whether post-remission consolidation in general, and with Afinitor in particular, can improve disease-free survival in these poor-risk DLBCL patients. If these results are positive, it could lead to the sixth FDA-approved oncology indication for Afinitor and its first foray into hematologic malignancies. Given the unmet need that exists for poor-risk DLBCL patients, the possibilities in the consolidation setting are very exciting, and we eagerly anticipate seeing the results from PILLAR2.
Darzalex plus VelDex in patients with relapsed or refractory multiple myeloma (CASTOR)
Darzalex™ (daratumumab, Genmab/Janssen) was recently approved as a first-in-class anti-CD38 monoclonal antibody in fourth-line multiple myeloma. This approval was based on the results of the pivotal Phase II SIRIUS study, in which single-agent Darzalex resulted in an objective response rate (ORR) of 29.2% in patients who had received a median of five prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.6 Although the SIRIUS trial offered an important opportunity to gain accelerated approval for Darzalex, the true opportunity lies in earlier lines of therapy. As such, Janssen initiated two Phase III studies of Darzalex in combination with the standard of care in second-line myeloma. The first of these studies to report is CASTOR, which compares the combination of Darzalex, Velcade® (bortezomib, Millennium/Janssen) and dexamethasone (VelDex) versus VelDex in patients previously treated with at least one prior line of therapy. In March 2016, Genmab announced that the trial met the primary endpoint of improving PFS in an interim analysis (p≤0.0001), prompting the independent data monitoring committee to recommend early stoppage of the trial.
Although it is highly treatable, multiple myeloma is rarely curable, and patients often become resistant to therapy. As such, data from this trial would be very well received if the combination provides a meaningful improvement in time to relapse or minimizes resistance. Darzalex itself is still very new to the market, and as the first human anti-CD38 monoclonal antibody it has the potential to change the landscape. In the second-line setting, Darzalex will be competing directly with Empliciti™ (elotuzumab, AbbVie/Bristol-Myers Squibb) and Kyprolis® (carfilzomib, Amgen), both of which were approved in the past year as part of triplet regimens (both in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone, RevDex). Both regimens produced very strong PFS benefits in comparison with doublet therapy (RevDex). Key for Darzalex will be demonstrating a level of PFS benefit that is at least comparable to that observed with the Empliciti or Kyprolis triplets, and/or other safety or efficacy differentiators, to overcome the fact that it will be third to market in this setting. The importance of this study on the myeloma landscape is further highlighted by the fact that the ASCO committee has slated this presentation for the Plenary Session.
Jevtana versus docetaxel in patients with metastatic CRPC (FIRSTANA)
Jevtana® (cabazitaxel, Sanofi) is a next-generation taxane that is already approved in docetaxel-pretreated metastatic castration-resistant prostate cancer (CRPC). Although Jevtana significantly improved PFS and OS in its pivotal trial in this setting, its commercial success has suffered due to the introduction of the next-generation hormonal agents – Xtandi® (enzalutamide, Medivation/Astellas) and Zytiga® (abiraterone, Janssen) – which were initially approved in the post-docetaxel setting as well. Seeking to move into an earlier line of therapy, and eager to displace now-generic docetaxel, Sanofi initiated FIRSTANA (NCT01308567), a three-arm Phase III study of Jevtana/prednisone (two different dose arms) versus docetaxel/prednisone in chemotherapy-naïve metastatic CRPC. At the time this trial was started, the standard of care in front-line symptomatic metastatic CRPC was docetaxel/prednisone. However, since then, the standard of care has changed dramatically, and over one-half of symptomatic (and two-thirds of asymptomatic) patients now receive Xtandi or Zytiga as a first-line therapy.1
The evolution of the prostate cancer landscape puts the FIRSTANA trial results in a new light. Taxane-based therapy is still used in approximately one-third of first-line metastatic CRPC patients as well as in some second- and third-line patients. If Jevtana can demonstrate superior efficacy and/or improved tolerability compared with docetaxel, it may be able to capture the taxane market. The safety profile will be key to watch for in the ASCO presentation to understand how well Jevtana can be tolerated in the first-line setting and also whether its toxicity profile can be tempered without sacrificing efficacy when given at a lower dose. Sanofi has not spoken publicly about the status of this trial, so ASCO will provide the first look at the FIRSTANA results.
Immunotherapy in head and neck cancer
Of course, what discussion of exciting trends would be complete without examination of the PD-1 inhibitors Opdivo™ (nivolumab, Bristol-Myers Squibb/ONO) and Keytruda® (pembrolizumab, Merck)? Since first being approved by the FDA in 2014, these compounds have begun to dominate the market and have been in fierce competition with each other at every step of the way. While the “financial toxicity” associated with these agents is an often discussed detractor, the strong improvements in OS and relatively lower toxicity profile have pushed these compounds to the forefront of treatment in a very short time.
In a Clinical Science Symposium titled “Harnessing the Immune System in Head and Neck Cancer: Evolving Standards in Metastatic Disease” (Monday 11:30 a.m. -1:00 p.m.), a series of abstracts will examine the role of these and similar compounds in patients with squamous cell carcinoma of the head and neck (SCCHN).
First up is Opdivo with updated/reprised data from the Phase III CheckMate 141 trial that compared Opdivo versus investigator’s choice of therapy in patients with SCCHN with tumor progression on or within six months of platinum therapy. Results from this trial showed a significant OS benefit favoring Opdivo (7.5 months vs. 5.1 months, HR 0.70, p=0.0101), which ultimately led to the FDA awarding it Breakthrough Therapy designation in April 2016. These results were presented initially at the 2016 annual meeting of the American Association for Cancer Research (AACR),7 but this reprisal at ASCO will bring the data into view for a much wider audience of clinicians.
Keytruda will follow with a series of abstracts anchored around the first presentation of results from the single-arm KEYNOTE-055 trial that examine efficacy of Keytruda after platinum and Erbitux (cetuximab, Lilly/Merck KGaA) failure. Results of this study haven’t been reported, but Merck has already filed for approval and the FDA took quick action, setting a priority review PDUFA date of August 9, 2016, by which to act on the application. In the Phase I KEYNOTE-012 study, single-agent Keytruda produced a response rate of 24.8% in a largely third-line or later population,8 and an update on this trial will be reported in this same session at ASCO 2016. Kantar Health will be watching to see whether this level of efficacy can be maintained in the KEYNOTE-055 trial. Also of importance is information on the potential role of the PD-L1 biomarker as a predictor of response to Keytruda in recurrent/metastatic SCCHN, which will be discussed in a third presentation in this session. Biomarkers are a possible point of distinction between the two compounds (as is the case for these two agents in non-small cell lung cancer, NSCLC), and gaining clarity surrounding the informative benefits and necessity of PD-L1 testing in SCCHN will be well worth noting.
As is already the case in melanoma and NSCLC, Opdivo and Keytruda will be each other’s primary competitors in SCCHN. With Opdivo having randomized trial data with an OS advantage but Keytruda potentially being first to market with an accelerated approval strategy, the strength of the data from these trials and any additional data that could distinguish one from the other will be critically important to each drug’s success and something to watch for with a keen eye at ASCO 2016.
Binimetinib in NRAS-mutant advanced/metastatic melanoma (NEMO)
Binimetinib (MEK162, Array BioPharma) is a MEK inhibitor with demonstrated preclinical and clinical activity against BRAF-V600E and NRAS mutant melanoma.9 Positive Phase II results prompted a global Phase III trial (NEMO; NCT01763164) in patients with advanced, unresectable or metastatic NRAS Q61 mutation-positive melanoma (which occurs in an estimated 20% of patients). In a press release from February 2015,10 Array announced that this study met its primary endpoint of improving PFS compared with dacarbazine (2.8 months vs. 1.5 months, HR 0.62, p<0.001). These results are highly significant and should aid in gaining the drug FDA approval. Adding to the excitement, binimetinib would be first to market with this niche biomarker indication. However, the improvement in PFS (only a 1.3-month difference at the median) may be viewed poorly given that other MEK inhibitors (Mekinist, trametinib, Novartis) and BRAF inhibitors have demonstrated PFS gains of three to four months in BRAF mutant melanoma). Additionally, although binimetinib has the chance to be the first drug approved to treat NRAS mutant melanoma, it will still face hefty competition from the PD-1 inhibitors Keytruda and Opdivo, and the PFS benefit reported for NEMO may not be enough to overtake immunotherapy in this indication. It’s unclear yet whether the modest gains observed in NEMO reflect a nuance of NRAS mutant disease, whether it reflects on the activity of binimetinib, or both. Key to helping understand these issues will be analysis of secondary endpoints that we hope will be presented at ASCO, including response rate, OS and safety. The final data may have to be very strong for this drug to be impactful in the first-line setting.
Kadcyla + Perjeta as neoadjuvant therapy in early-stage HER2-positive breast cancer (KRISTINE)
In the treatment of HER2+ breast cancer, Genentech/Roche compounds have become the standards of care in most treatment settings – Herceptin® (trastuzumab) in the adjuvant setting, the combination of Herceptin plus Perjeta® (pertuzumab) in first-line metastatic disease, and Kadcyla® (ado-trastuzumab emtansine) in second-line metastatic disease.1 Most recently, Perjeta became part of the first regimen to be FDA-approved for use in the neoadjuvant setting based on a significant improvement in pathologic complete response rate (pCR) for the combination of Perjeta + Herceptin + docetaxel. Roche also has been seeking to advance the development of Kadcyla beyond the relapsed/refractory setting, with several Phase III trials initiated in various settings. The highly anticipated MARIANNE trial was somewhat of a shocking disappointment in December 2014 when it failed to show a benefit for the use of Kadcyla + Perjeta in first-line metastatic disease.11 Similar studies continue in early-stage disease and initial results from the first of these trials, KRISTINE, will be reported at ASCO 2016. KRISTINE (NCT02131064) evaluates the efficacy of Kadcyla + Perjeta in comparison with Herceptin + Perjeta + chemotherapy in the peri-operative setting, with patients receiving six cycles of neoadjuvant (pre-operative) treatment followed by surgery; following surgery, patients will receive adjuvant Kadcyla + Perjeta versus Herceptin + Perjeta.
Results of this study have not been announced publicly, so it’s unknown whether the presentation at ASCO will be positive or negative. The MARIANNE trial in first-line metastatic disease showed no difference in PFS, OS, or ORR among the three study arms. However, a Phase Ib/IIa open label study evaluated Kadcyla and docetaxel with or without the addition of Perjeta as neoadjuvant therapy in 70 previously untreated HER2+ locally advanced breast cancer patients (NCT00934856). The pCR rate was relatively similar in patients who received the Perjeta/Kadcyla/docetaxel regimen (60.6%) compared with those who received Kadcyla/docetaxel (56.8%).12 Although the pCR rates in these two arms were similar, both are notably higher than the pCR rate upon which Perjeta + Herceptin + docetaxel was FDA-approved in the neoadjuvant setting (39%).13 Importantly, the Kadcyla + Perjeta combination demonstrated improved safety and quality of life in the MARIANNE trial. The tolerability of this combination will be a key to watch in the KRISTINE trial, as safety takes on even greater importance in potentially curative early-stage disease.
With the failure of the MARIANNE trial, Roche is looking for success in trials in early-stage disease to build on the early success that Kadcyla has experienced. Ongoing trials in the adjuvant setting are the most highly anticipated but are several years off; the results of the KRISTINE trial will be important to watch in terms of potential for short-term advancement of Kadcyla, as well as possible foreshadowing of results to come from the adjuvant KATHERINE and KAITLIN trials.
In sum, many potential game-changers are awaiting us at this meeting. As in years past, ASCO 2016 should prove very exciting!
About the Contributors
Kantar Health is a leading global healthcare advisory firm and trusted advisor to the world’s largest pharmaceutical, biotech, and medical device and diagnostic companies. It combines evidence-based research capabilities with deep scientific, therapeutic and clinical knowledge, commercial development know-how, and marketing expertise to help clients launch products and differentiate their brands in the marketplace.
Kantar Health provides both the research and consulting services you need to support your business decisions across the product lifecycle for cancer therapies. Our oncology expert status has been earned because of the proprietary material we publish on cancer epidemiology, trends in oncology market access, oncology pipeline potential and treatment trends that help our clients with their business issues.
If you would like us to act as catalysts for you, contact us at www.kantarhealth.com.
- Kantar Health, CancerMPact® Treatment Architecture, accessed from www.cancermpact.com, May 2, 2016.
- Lencioni R, Llovet JM, Han G, et al.; “Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial;” Proc Amer Soc Clin Oncol Gastrointest Canc Symp, Abstract LBA154, 2012.
- Kudo M, Imanaka K, Chida N, et al., “Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma.” Eur J Cancer. 47:2117-27, 2011.
- The International Non-Hodgkin's Lymphoma Prognostic Factors Project; “A Predictive Model for Aggressive Non-Hodgkin's Lymphoma;” N Engl J Med 1993; 329:987-994.
- DARZALEX® (daratumumab) FDA-approved label. Accessed at www.darzalex.com, May 2, 2016.
- Reeder CB, Gornet MK, Habermann TM, et al.; “A Phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma;” Leukemia, 25(2): 342-347, 2011.
- Gillison ML, Blumenschein G, Fayette J, et al.; “Nivolumab (nivo) vs investigator’s choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): CheckMate-141”, [Abstract CT099]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract CT099.
- Seiwert TY, Haddad RI, Gupta S, et al.; “Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort;” J Clin Oncol 33, 2015 (suppl; abstr LBA6008).
- Ascierto PA, Schadendorf D, Berking C, et al.; “MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study;” Lancet Oncol, 14 (3): 249-256, 2013.
- Array BioPharma Reports Financial Results For The Second Quarter Of Fiscal 2016 [Press release]. Boulder, CO Array BioPharma; February 2, 2016.
- Ellis PA, Barrios CH, Eiermann W, et al.; “Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study;” J Clin Oncol 33, 2015 (suppl; abstr 507).
- Martin M, Dewar J, Albanell J, et al., “Neoadjuvant trastuzumab emtansine and docetaxel, with or without pertuzumab, in patients with HER2-positive early-stage breast cancer: Results from a phase 1b/2a study,” Proc San Antonio Breast Canc Symp, Abstract P4-12-07, 2013.
- Perjeta® (pertuzumab) FDA-approved label. Accessed at www.perjeta.com, May 2, 2016.