What’s in Store at ASCO 2014? Kantar Health Offers a Preview
By Arnold DuBell, Ph.D., M.B.A.
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. A brief synopsis of the 10 abstracts that we think are likely to generate the most discussion and have the highest impact are discussed.
Orteronel in Asymptomatic/Minimally Symptomatic CRPC
Orteronel (TAK-700; Millennium, a wholly owned subsidiary of Takeda) inhibits the steroidal enzyme 17-α-hydroxylase/C17,20 lyase; however, it is overshadowed by Zytiga® (abiraterone acetate, Johnson & Johnson), which has a similar mechanism of action and is already approved for prostate cancer. Moreover, orteronel suffered a setback in July 2013 when Takeda announced that the ELM-PC 5 (C21005) trial, which compared orteronel plus prednisone to prednisone plus placebo in about 1,000 metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed during or following chemotherapy, did not meet the primary endpoint of improved overall survival (OS).
Takeda has several other ongoing trials for orteronel, including ELM-PC 4 (C21004), which is comparing orteronel plus prednisone to placebo plus prednisone in more than 1,400 patients with chemotherapy-naïve mCRPC. Data from this trial will be presented at ASCO this year. The degree of benefit will be important to view, as orteronel will need to show a large OS benefit in order to compete with both Zytiga and Xtandi® (enzalutamide, Medivation/Astellas).
Zytiga is currently one of the most utilized agents in chemotherapy-naïve asymptomatic CRPC patients, as about one-third of patients in both the U.S. and Western Europe are treated with this agent, according to Kantar Health’s CancerMPact® Treatment Architecture 2013 data. This use was based on the strong data from the COU-AA-302 trial that showed a radiographic progression-free survival (rPFS) benefit for Zytiga compared to placebo (HR 0.69, p<0.0001) but had an OS benefit that did not cross the prespecified boundary for significance (HR 0.75, p=0.01). In the PREVAIL trial, Xtandi improved both rPFS (HR 0.19, p<0.0001) and OS (HR 0.70, p<0.0001) relative to placebo (please note that data from PREVAIL will be presented immediately following the ELM-PC 4 presentation).
Safety considerations will take a backseat to questions about efficacy. Phase II trials indicated increased fatigue, hypokalemia, hyperglycemia and diarrhea, which are similar to those seen with Zytiga. However, physicians’ ears will perk up if other toxicities are noted.
Although Zytiga was approved by the U.S. Food and Drug Administration (FDA) without showing an OS advantage, Xtandi has shown an OS benefit – and that threshold will most likely be the standard by which orteronel will be judged. A strong showing in this trial also will help overcome any lessened enthusiasm that may be harbored by physicians after news of the failed ELM-PC 5 was released last year.
CALGB 80405: Will this definitively determine the appropriate sequence of targeted therapies in metastatic CRC?
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 OS benefits when added to standard chemotherapy in these patients. Avastin is approved for use in all first-line patients, while 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 at best (and harmful in the extreme), 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 a German trial designed to evaluate FOLFIRI plus either Erbitux or Avastin (at 5 mg/kg every two weeks) as first-line therapy; it was amended in 2008 to include only KRAS wildtype patients. Data presented at ASCO 2013 suggested a non-significant benefit compared to Avastin in the overall response rate, which was the primary endpoint (62% versus 58%, p=0.183). Moreover, 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 Kaplan-Meier OS curves were especially intriguing, as the curves for each arm began to separate only after 18 months, well after the 10-month PFS median, and the curves continued to separate past the median OS, where the superiority of Erbitux becomes far more pronounced and is evidently durable.
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 North American three-armed trial comparing Avastin (also at 5 mg/kg every two weeks) 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 first-line mCRC patients. The trial, which was initiated in November 2005, was later amended to include only KRAS wildtype patients. The primary endpoint is overall survival. 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.
Quality of life data from CALGB 80405 were released at ASCO 2013. No differences were found among the three treatment groups on global health/quality of life (p=0.164) as well as other EORTC QLQ-C30 scales (physical functioning, role functioning, social functioning, emotional functioning, or cognitive functioning). As might be expected given the toxicity profile associated with EGFR inhibitors such as Erbitux, differences were seen in the Dermatology-Specific Quality of Life Scores “Skin Symptoms” (p<0.001), “limitations in social activities due to skin condition” (p=0.008) and “concern about appearance” (p<0.0001). Therefore, an examination of the toxicity profiles will be of lessened interest, allowing a full consideration of efficacy to guide treatment practice.
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, in particular how Erbitux can generate a strong OS benefit compared with Avastin but not show a PFS benefit, 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. Therefore, any impact on the market will be driven by results showing superiority of an Erbitux-based regimen, although the impact will be limited to KRAS wildtype patients.
 Ryan, N Engl J Med, 368: 138-148, 2013.
 Beer, Abstract LBA1, Genitourinary Cancers Symposium, 2014
 Heinemann, Abstract LBA3506, ASCO 2013.
 Naughton, Abstract 3611, ASCO 2013.
What’s in Store at ASCO 2014? Kantar Health Offers a Preview (continued)
ALTTO: The last hope for adjuvant Tykerb?
GlaxoSmithKline has been diligently working towards getting Tykerb® (Tyverb® in Europe, lapatinib) established in the adjuvant HER2-positive breast cancer setting. Toward that goal, Tykerb has been evaluated either against Herceptin® (trastuzumab, Genentech/Roche/Chugai) or in combination with Herceptin and chemotherapy in an adjuvant trial (ALTTO) and three neoadjuvant trials (NeoALTTO; NSABP B-41; CALGB 40601). In the NSABP B-41 and CALGB 40601 studies, Tykerb was unable to show statistical significance in improving the pathologic complete response (pCR) rate. A statistically significant pCR benefit for the combination of Tykerb, Herceptin and chemotherapy was observed in the NeoALTTO trial. Given the lack of consistent data, the last hope to promote Tykerb for early-stage breast cancer will be the results of ALTTO, which will be presented in a plenary session at this year’s ASCO.
The ALTTO trial randomized more than 8,000 patients to one of four arms: Tykerb, Herceptin, Tykerb plus Herceptin, or Tykerb following Herceptin. All treatments followed anthracycline-based chemotherapy, and as a further evaluation patients could be treated concurrently with paclitaxel or docetaxel plus carboplatin. The comparison between the two single-agent arms was designed to evaluate non-inferiority between the arms, while all other comparisons were designed to evaluate whether either combination was superior to Herceptin alone. In September 2011, GlaxoSmithKline closed accrual on the Tykerb (with or without chemotherapy) arm as it was determined the arm would not show non-inferiority to Herceptin. The primary endpoint for these comparisons is disease-free survival.
Tykerb’s past struggles in the neoadjuvant setting foreshadow difficulty in the adjuvant ALTTO trial. However, the other difficulty is that breast cancer therapies have rapidly evolved since the May 2007 initiation of ALTTO. The combination of Perjeta® (pertuzumab, Genentech/Roche/Chugai) with Herceptin and docetaxel has proved beneficial relative to Herceptin plus docetaxel as a front-line metastatic therapy in HER2-positive patients, and the combination is currently being evaluated in the APHINITY trial, which should report in 2016. Therefore, not only does Tykerb need to show a statistically significant advantage either in combination with Herceptin or following Herceptin, but it will need to show a clinically relevant benefit or it will be turned aside by physicians once APHINITY data are available.
The other issue with Tykerb is toxicity, which will need to be closely monitored when the results of ALTTO are presented. Unlike Herceptin, which is an anti-HER2 monoclonal antibody, Tykerb is a dual HER2/EGFR tyrosine kinase inhibitor. Similar to other EGFR TKIs, Tykerb administration was associated with increased incidence of grade 3-4 diarrhea. Although these toxicities can be managed generally well in metastatic patients, will the increased duration of therapy associated with adjuvant treatment also hinder Tykerb’s prospects?
In spite of all the history, there is still hope for Tykerb. We will know the outcome for its prospects in the adjuvant treatment during the ASCO plenary session.
Panobinostat plus VelDex in Relapsed/Refractory Multiple Myeloma
Panobinostat (LBH589; Novartis) is a multitargeted pan-deacetylase inhibitor in development for multiple myeloma. Originally planned to be tested as a monotherapy, Novartis ultimately chose to position the agent in combination with VelDex in relapsed or refractory myeloma. The vehicle for this development is the randomized Phase III PANORAMA-1 trial, which is comparing panobinostat plus VelDex versus placebo plus VelDex in more than 750 previously treated multiple myeloma patients.
In December 2013, Novartis announced via press release that PANORAMA-1 met its primary endpoint of significantly improving PFS. The data supporting this press release will be presented at ASCO on Monday, June 2, 2014, and it will be important to learn the extent of the efficacy benefit. If approved, panobinostat will be thrown into a highly competitive segment, as both the proteasome inhibitor Kyprolis® (carfilzomib, Amgen) and the immunomodulatory agent Pomalyst® (pomalidomide, Celgene) have been already approved by the FDA for use in these patients. A perceived lesser benefit relative to other agents typically pushes agents to later lines of therapy, but in the case of panobinostat the trial design (combining with VelDex) perceived lesser benefit might mean that panobinostat is just used very sparingly instead.
One thing in favor of panobinostat relative to its potential competition in this setting is that it has a different mechanism of action than its competition. However, this also implies a different toxicity profile, so toxicity in PANORAMA-1 will be closely monitored. Will the toxicities noted in Phase II trials (thrombocytopenia, neutropenia, anemia, asthenia and respiratory tract infections) be viewed favorably relative to the toxicity profiles of the approved agents?
Prior to Novartis’ press release, the enthusiasm level for this agent was slightly lower compared to the recently approved Kyprolis and Pomalyst. However, Novartis got our attention with the news of statistically significant data in spite of the lack of quantitation associated with that press release. The data at ASCO will now have the chance to get us further excited.
Lambrolizumab in relapsed/refractory advanced melanoma
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, GlaxoSmithSkline) and Mekinist® (trametinib, GlaxoSmithSkline). 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 will take center stage.
Lambrolizumab (MK3475, Merck) is a humanized monoclonal IgG4 antibody against PD-1. In a Phase I trial the response rate in advanced melanoma patients, who may or may not have been treated with prior Yervoy, treated with the highest dose level of lambrolizumab (10 mg/kg) was 52%, including a 10% complete response rate. Although cross-study comparisons should be viewed carefully, such a comparison with the fully human monoclonal antibody nivolumab suggest that the antibodies could have similar activities in melanoma patients, as a Phase I trial for nivolumab indicated that the best response rate for nivolumab monotherapy (at the 3 mg/kg dose) was 41%.
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 the past data (plus the poor activity of cytotoxic chemotherapy in these patients), 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 profiles, based on data from the Phase I trials, also appear similar, with both agents having similar levels of grade 1-2 pneumonitis (about 4% for each).
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. Nivolumab is being examined in two Phase III trials in newly diagnosed melanoma patients (as monotherapy or in combination with Yervoy). 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?
 Blackwell, J Clin Oncol, 28: 1124-1130, 2010.
 Ribas, Abstract 9009, ASCO 2013
 Sznoll, Abstract CRA9006, ASCO 2013
What’s in Store at ASCO 2014? Kantar Health Offers a Preview (continued)
Necitumumab plus gemcitabine and cisplatin in newly diagnosed squamous NSCLC
As treatment of lung cancer patients has become more driven by histology or biomarkers, one group of patients had been left out: non-small cell lung cancer (NSCLC) patients whose tumors have squamous histology. Eli Lilly has already stated via press release in August 2013 that necitumumab, their second-generation anti-EGFR monoclonal antibody (mAb), significantly improved OS when combined with gemcitabine and cisplatin as a first-line treatment in 1,093 patients with squamous NSCLC (SQUIRE). Lilly plans to submit regulatory applications for necitumumab in late 2014; they had noted in their rationale for the filing delay that they needed to validate manufacturing protocols. This press release did not provide quantitation for the OS benefit found in SQUIRE, but such data will finally be available at ASCO 2014.
The press release noted that the more common adverse events were rash and hypomagnesemia, and that there was a smaller incidence of thromboembolism. The extent and severity of the latter adverse event will be interesting to observe as it was the stated cause of the failure of Eli Lilly’s other trial for necitumumab in lung cancer – INSPIRE, which evaluated the efficacy of Alimta® (pemetrexed, Eli Lilly) plus cisplatin with or without necitumumab in NSCLC patients with non-squamous histology. Was toxicity managed better in the patients enrolled in SQUIRE compared with those enrolled in INSPIRE, or is there something about the biology of squamous NSCLC that reduces the risk for this toxicity?
The critical endpoint to watch will be the degree of OS for necitumumab relative to gemcitabine-cisplatin alone in SQUIRE. As noted above, necitumumab is a second-generation anti-EGFR mAb, and past history of a first-generation anti-EGFR mAb, Erbitux, provides a note of caution. Erbitux had been tested in the first-line setting in two Phase III trials: FLEX and CA225-099. Erbitux was shown to provide a modest yet significant benefit in the FLEX study when added to cisplatin and vinorelbine (HR 0.871, p=0.044) but failed to show a benefit when added to carboplatin and paclitaxel in the CA225-099 trial (HR 0.89, p=0.17). Given the history of these inconsistent yet minimal results for Erbitux, it will be important for necitumumab to show a strong benefit that would be considered clinically relevant.
Cyramza plus docetaxel in relapsed or refractory NSCLC patients
Another Eli Lilly agent that will be closely reviewed will be the anti-VEGFR2 monoclonal antibody/anti-angiogenic agent Cyramza® (ramucirumab). It was recently approved by the U.S. FDA for use in gastric cancer – and a second favorable trial in gastric cancer, RAINBOW, has already been presented at the ASCO Gastrointestinal Cancers Symposium and additional subgroup analyses will be presented at this year’s ASCO (Abstracts 4005 and 4058). Eli Lilly announced in February 2014 that the REVEL trial, a Phase III trial of Cyramza plus docetaxel in more than 1,200 locally advanced or metastatic NSCLC patients after the failure of prior platinum-based chemotherapy, reached its primary endpoint of OS. Eli Lilly also noted that Cyramza achieved its PFS secondary endpoint; however, no details were provided with quantitation for either the overall- or progression-free-survival benefit, but such data will be presented at this ASCO conference.
Docetaxel is an oft-utilized second-line agent for patients with lung cancer, so the primary efficacy question related to this data will be if the survival benefit is clinically relevant. The press release noted that the more common grade 3 or higher toxicities were hematologic (neutropenia, leukopenia and febrile neutropenia), fatigue/asthenia and hypertension. This is not surprising as hematologic toxicities are often observed with docetaxel monotherapy. Although Cyramza did not cause major toxicity concerns when combined with paclitaxel in gastric cancer (RAINBOW trial), it will still be interesting to see whether the toxicities reported in the press release appear to be additive or if they are driven primarily by docetaxel.
There were no histological or genetic exclusion criteria for entrance into REVEL. However, as Avastin, another anti-angiogenic agent, is limited to only non-squamous patients for reasons of toxicity, it will be interesting to see at least histological subgroup analysis of the REVEL data. Moreover, Genentech and Roche have sponsored the Phase III trial AvaALL (NCT01351415) evaluating the use of second-line Avastin in patients treated with first-line Avastin; this trial is still enrolling patients. Therefore, an important question, which may not be addressed at this ASCO presentation, will be the efficacy benefit of Cyramza in patients treated with first-line Avastin plus standard chemotherapy. This was a similar question that Sanofi faced in developing Zaltrap® (ziv-aflibercept) as a second-line treatment option for metastatic mCRC.
Unfortunately, several of these questions may remain unanswered at ASCO. But the initial presentation of the data will be a start. Cyramza should be approved in this indication, and could be quickly adopted into clinical practice. The answers to the questions posed here could address whether this first-mover advantage will be sufficient.
Yervoy versus placebo in Stage III High-Risk Melanoma
Yervoy is currently approved for both first- and second-line treatment of advanced (unresectable or metastatic) melanoma. It was approved by the FDA in March 2011 for all melanoma patients. Yervoy was also approved by the European Medicines Agency in July 2011 (for the second-line setting) and in November 2013 (for the first-line setting). The median OS and relapse-free survival were not able to be calculated after a follow-up of 29.5 months in a Phase II trial in patients with resected stage IIIc/IV high-risk melanoma treated with Yervoy monotherapy.
Based on these hopeful Phase II data, the EORTC sponsored an international Phase III trial (CA184-029; EORTC 18071) comparing Yervoy to placebo as adjuvant therapy for 950 completely resected melanoma patients, and data from this trial will be reported at ASCO. The primary endpoint is relapse-free survival, and secondary endpoints include OS, metastasis-free survival and safety. Safety will be a key endpoint as some of the immune-related toxicities associated with Yervoy in the two metastatic Phase III trials – diarrhea, rash, pruritus and colitis – might prove difficult for patients with earlier-stage disease.
However, there are currently few good options for these patients other than interferon therapy such as Intron A® (IFN alfa-2b, Merck) or Roferon® (IFN alfa-2a, Roche), or cytotoxic chemotherapy. Cytotoxic chemotherapy is utilized in approximately one-third of all patients treated with adjuvant therapy, according to Kantar Health’s CancerMPact® Treatment Architecture data. Chemotherapy is generally not very active in these patients, and its continued use further highlights the limited available options for these patients. Five-year relapse-free survival rates for interferon therapy ranges from 30%-45%, so a rate greater than that for Yervoy could solidify its use once approved by regulators.
A second ongoing trial sponsored by the Eastern Cooperative Oncology Group (ECOG; E1609) will directly compare Yervoy to Intron A in patients with resected high-risk Stage III or IV melanoma, and positive data from the ECOG trial will further strengthen the Yervoy’s position in this setting. However, one step at a time: a statistically significant result in the EORTC 18071 trial at this ASCO meeting will be used by Bristol-Myers Squibb as a means of a line extension for Yervoy, and these results will be eagerly awaited.
Blinatumomab in Ph- Relapsed/Refractory ALL
There are currently no targeted therapies for the treatment of relapsed/refractory Philadelphia Chromosome (Ph)-negative acute lymphocytic leukemia (ALL). Moreover, given the toxicities associated with the available chemotherapy options, only 38% of U.S. patients are treated with second-line therapy, according to the 2013 data from Kantar Health’s CancerMPact® Treatment Architecture reports. Current standard of care in relapsed/refractory Ph- ALL patients results in median OS time of less than a year. This could change based on data from the Phase II MT103-211 of blinatumomab (Amgen) in relapsed or refractory ALL patients after at least three intense chemotherapy blocks. Amgen has advised that this will be a pivotal trial, so if the data are strong we can expect Amgen to file blinatumomab for accelerated approval.
Blinatumomab is a bispecific monoclonal antibody developed using Micromet’s “BiTE” (Bispecific T-cell Engager) technology. The concept behind the bispecific antibody is that by binding the tumor cell through CD19 expressed on B-cells (including ALL blasts), and T-cells through CD3, the antibody brings the T-cells into closer contact with the tumor cells, thereby promoting T-cell mediated lysis of the tumor cells. In a Phase II study conducted in 36 B-cell relapsed/refractory ALL patients (33% enrolled patients had two or more relapses), blinatumomab achieved 44% complete hematologic remission (CR) rate and 28% complete response rate with partial hematologic recovery (CRh), for a 72% CR/CRh rate.
The primary endpoint of the MT103-211 trial is CR and CRh rates within the first two treatment cycles. Two of the secondary endpoints include the proportion of patients eligible for allogeneic stem cell transplantation (SCT), and OS. Given the current treatment outcomes, it will be important to note if blinatumomab treatment results in survival times approaching one year in length or if the CR rate is similar to that observed in the previous Phase II trial (that is, a CR/CRh rate of 75% or higher). If so, then blinatumomab should receive its accelerated approval. Also, as one key to successful therapy in ALL is treating patients with allogeneic SCT, another guide to deeming this trial a success will be seeing that higher percentages of patients become eligible for allogeneic SCT.
In late 2013 Amgen initiated a Phase III trial (00103311; NCT02013167) that will randomize patients to either blinatumomab or physician’s choice of chemotherapy. The endpoint of this trial is OS and will most likely only serve the need to convert an accelerated approval to a full approval. An approval will not come fast enough for this setting with high unmet need. The data from this potentially breakthrough Phase II trial therefore ushers in the era of targeted immune therapy as a new treatment option for ALL patients.
Imbruvica versus Arzerra in Relapsed/Refractory CLL
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.
In the same session at ASCO, long-term follow-up data from the Phase Ib/II trial for Imbruvica will be presented (Abstract 7014) prior to the data release for RESONATE. As this data for Imbruvica is released and will hopefully be followed by similar data for idelalisib, these long-term data will become more important: Can Imbruvica and idelalisib be given long-term, and if so, are there any cumulative toxicity issues of note? Are there any biomarkers which might explain which patients respond more favorably to either agent?
About the Contributor
Arnold DuBell, Ph.D., M.B.A., is a Consultant, Clinical and Scientific Assessment at Kantar Health.
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.
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