With the annual meeting of the American Society of Clinical Oncology (ASCO) quickly approaching (June 3-7, Chicago), the 2016 event is sure to live up to its reputation for delivering market-changing data and trends from the world of oncology. Below, Kantar Health spotlights four potentially noteworthy abstracts that are likely to generate much discussion and significantly influence patient care. For a complete assemblage of all nine of Kantar Health’s top abstracts of interest, please see the associated article in the May issue of OBR Green.
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. Abstract 7000, Saturday, June 4, 3:00 p.m.
Immunotherapy in head and neck cancer
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.
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),2 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,3 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. Abstracts 6009-6012, Monday, June 6, 11:30 a.m.
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.4 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 progression-free survival (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. Abstract LBA4, Sunday, June 5, 3:10 p.m.
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.5 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%).6 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%).7 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. Additionally, 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. Abstract 500, Monday, June 6, 1:15 p.m.
- Kantar Health, CancerMPact® Treatment Architecture, accessed from www.cancermpact.com, May 2, 2016.
- 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).
- 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.
- 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.