May 2014 Edition Vol.11, Issue 5

What’s in Store at ASCO 2014? Kantar Health Offers a Preview

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[1]) but failed to show a benefit when added to carboplatin and paclitaxel in the CA225-099 trial (HR 0.89, p=0.17[2]). 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[3] 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.[4]

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,[5] 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.[6] 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.[7]

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%,[8] and the 12-month PFS rate was 86%.[9] 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),[10] 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).[11] 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.

Kantar Health’s oncology-related offers include Oncology Conference Insight, client-directed oncology conference coverage that analyzes the most important research at significant oncology meetings; and

CancerMPact® Treatment Architecture, which assesses the current clinical management of cancer patients by site and stage for all treatment modalities.

If you would like us to act as catalysts for you, contact us at

[1] Pirker, Lancet, 373: 1525-1531, 2009

[2] Lynch, J Clin Oncol, 28: 911-917, 2010

[3] Wilke, Abstract LBA7, ASCO Gastrointestinal Cancers Symposium, 2013

[4] Sarnaik, Clin Cancer Res, 17: 896-906, 2011.

[5] Fletcher, Am J Clin Oncol, 16: 359-62, 1993

[6] O’Brien, J Clin Oncol, 31: 676-683, 2013.

[7] Topp, Abstract 6500, ASCO 2012.

[8] O’Brien, Lancet Oncol, 15: 48-58, 2014.

[9] O’Brien, Abstract 983, ASH 2011.

[10] Wierda, J Clin Oncol, 28:1749-1755, 2010.

[11] Furman, Abstract LBA6, ASH 2013


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