The annual meeting of the American Society of Clinical Oncology (ASCO) is nearing and Kantar Health has identified several pivotal abstracts that will be presented. The 2014 ASCO annual meeting promises to be packed with the latest data and trends from the world of oncology, and the meeting has the potential to alter treatment practices in several tumor types. The following is a brief discussion of the three abstracts that are likely to generate the most discussion and have the highest impact. For a full discussion of all 10 of our top abstracts, please see the associated article in the May issue of OBR Green.
Both Avastin® (bevacizumab, Genentech/Roche/Chugai) and Erbitux® (cetuximab, Bristol-Myers Squibb/Eli Lilly/Merck KGaA) are approved for the treatment of first-line metastatic colorectal cancer (mCRC) and have demonstrated progression-free survival (PFS) and overall survival (OS) benefits when added to standard chemotherapy in these patients; however, Erbitux is approved for use only in the subgroup of patients with wildtype KRAS. As with all new therapies that enter the same indication, physicians are left wondering how best to incorporate these agents into their practices. As multiple Phase III trials showed combining the agents are not effective, two trials set about to understand in which order these agents should be offered to patients.
At the 2013 ASCO annual meeting, the data from one of these trials, FIRE-3, was presented. FIRE-3 was designed to evaluate FOLFIRI plus either Erbitux or Avastin as first-line therapy, but was amended in 2008 to include only KRAS wildtype patients. The data suggested a non-significant benefit compared to Avastin in the primary endpoint (overall response rate; 62% versus 58%, p=0.183). A PFS benefit was not observed (HR 1.06, p=1.06), however, Erbitux was associated with a significant 3.7-month OS benefit compared to Avastin (HR 0.77, p=0.017).
The conflicting data found in FIRE-3 beg for a repeat, and thankfully we have one: CALGB 80403, for which the data will be presented in the ASCO 2014 plenary session. CALGB 80403 is a three-armed trial comparing Avastin plus physician’s choice of first-line chemotherapy (FOLFOX or FOLFIRI) versus Erbitux plus chemotherapy versus Avastin plus Erbitux plus chemotherapy in approximately 2,900 mCRC patients. The trial, which was initiated in November 2005, was later amended to include only KRAS wildtype patients. The primary endpoint is OS. Given past data, the combination arm may prove to be ineffective; however, the more important comparison will be the direct comparison of Avastin-based chemotherapy versus Erbitux-based chemotherapy.
Currently, U.S. physicians strongly favor Avastin-based regimens in first-line over Erbitux-based regimens in patients with KRAS wildtype mCRC, according to Kantar Health’s CancerMPact® Treatment Architecture data. This is largely based on order of entry, with Avastin receiving a first-line FDA approval eight years before Erbitux. Western European physicians slightly favor Erbitux-based regimens in first-line over Avastin-based regimens in patients with KRAS wildtype mCRC. This may be based on a preference for biomarker-driven treatment selection, which Erbitux affords. Both are also influenced by a lack of data to understand whether one of these agents is superior to the other. Since questions remain after the results of FIRE-3, the results of CALGB 80405 will ultimately be cited in comparisons between the two agents. Should the results of CALGB 80405 favor Avastin or show no significant difference between the two regimens, Kantar Health anticipates little impact on the current market.
The past several years have seen an explosion of new agents for the treatment of advanced melanoma: Yervoy® (ipilimumab, Bristol-Myers Squibb), Zelboraf® (vemurafenib, Genentech/Roche/Daiichi Sankyo), Tafinlar® (dabrafenib, GlaxoSmithKline) and Mekinist® (trametinib, GlaxoSmithKline). Moreover, other agents are waiting in the wings, as past ASCO meetings have highlighted the promise of Bristol-Myers Squibb’s anti-PD-1 monoclonal antibody nivolumab. However, at ASCO 2014 another anti-PD-1 monoclonal antibody, lambrolizumab (MK3475, Merck), will take center stage.
As Bristol-Myers Squibb initiated Phase III trials for nivolumab in December 2012 (for relapsed melanoma) and January 2013 (for first-line melanoma), it appeared that this agent would be the first to market. However, Merck announced in January that they started to file a rolling submission for lambrolizumab based on the results of a Phase II trial, which will be presented at this ASCO meeting, and they expect to complete this application in the first half of 2014. This Phase II trial compares lambrolizumab to standard cytotoxic chemotherapy in approximately 500 patients who have progressed after prior therapy, although it appears that data from only 411 patients will be presented at the ASCO 2014 presentation.
Given the high level of competition as mentioned above, it will be important to compare the efficacies and toxicity profiles. The co-primary endpoints for the lambrolizumab Phase II trial are PFS and OS, and given past Phase I data, Kantar Health feels that lambrolizumab will show a benefit compared to the control arm and therefore should be strong enough to support Merck’s rolling submission. The toxicity profile of lambrolizumab is expected to be manageable, based on data from the Phase I trial, with lambrolizumab having about 4% grade 1-2 pneumonitis.
Although Merck’s submission might allow lambrolizumab to beat nivolumab – one of lambrolizumab’s more direct competitors given their similar mechanisms of action – to market in relapsed or refractory patients, nivolumab still might ultimately prevail, as it is being examined in two Phase III trials in newly diagnosed melanoma patients. If one or both of these trials are successful, nivolumab could enjoy strong utilization in this setting – and as a consequence, keep lambrolizumab confined to later lines of therapy.
The primary question for lambrolizumab in this phase II trial, therefore, will be efficacy as this will be a guide in assessing lambrolizumab’s further prospects in other melanoma settings. Will it be strong enough to offer hope against front-line Yervoy and, in the future, nivolumab?
Both Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) and idelalisib (Gilead) are generating a lot of excitement as potential treatment options in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Arzerra® (ofatumumab, Genmab/GlaxoSmithKline) is currently approved for use in refractory CLL patients in both the United States and Europe. Although Arzerra was the second-most utilized agent in the United States in CLL patients after their second relapse, it was still only used in 14% of U.S. CLL patients, according to Kantar Health’s CancerMPact® Treatment Architecture data. This utilization rate highlights the unmet need for more therapies and helps partly explain the level of excitement for new therapies such as Imbruvica and idelalisib.
Imbruvica, an inhibitor of the Bruton’s Tyrosine Kinase (BTK), has already garnered accelerated approvals as a monotherapy for both mantle cell lymphoma and CLL based on Phase II data. While work on these two applications were ongoing with the FDA, Pharmacyclics initiated a Phase III trial (RESONATE) that compares Imbruvica versus Arzerra in 391 patients with relapsed/refractory CLL or small lymphocytic lymphoma. In January 2014, the companies announced that the trial met its primary endpoint of PFS as well as a secondary OS endpoint.
The data from this trial, to be presented at this ASCO conference, will be closely monitored. How much difference will there be in these two efficacy endpoints for Imbruvica and Arzerra? In the Phase Ib/II trial from which the application for accelerated approval for Imbruvica was made, the overall response rate (ORR) was 71%, and the 12-month PFS rate was 86%. These data compare favorably against current treatment options, including Arzerra, which showed a 58% ORR in CLL patients previously treated with fludarabine and Campath® (alemtuzumab, Genzyme), warranting the accelerated approval. However, these data come after release of Phase III data for the PI3Kδ inhibitor idelalisib, in which the added efficacy of idelalisib to Rituxan® (MabThera® in Europe, rituximab, Biogen Idec/Roche) was evaluated in 220 relapsed or refractory CLL patients. Idelalisib significantly improved PFS (HR 0.15, p<0.0001) and OS (HR 0.28, p-0.018). Although physicians have been equally excited about both idelalisib and Imbruvica, they will look closely at the efficacy data from RESONATE to help guide them as they select which agent to use or in which patient subtype to offer a particular agent.
If doctors cannot choose which regimen to use strictly on comparisons of efficacy, then the adverse event profile will be monitored. In the Phase Ib/II trial, Imbruvica was relatively well tolerated with less than 10% incidence of grade 4 neutropenia, anemia and thrombocytopenia. It is expected that no untoward signals will be reported.
If these efficacy and tolerability data trends continue to be seen in RESONATE, Imbruvica will continue to justify the strong level of excitement directed toward it.
 Ribas, Abstract 9009, ASCO 2013
 O’Brien, Lancet Oncol, 15: 48-58, 2014.
 O’Brien, Abstract 983, ASH 2011.
 Wierda, J Clin Oncol, 28:1749-1755, 2010.
 Furman, Abstract LBA6, ASH 2013