May 2015 Edition Vol.11, Issue 5

What’s in Store at ASCO 2015? Kantar Health Offers a Preview

What’s in Store at ASCO 2015? Kantar Health Offers a Preview

By Len Kusdra, PhD, and Stephanie Hawthorne, PhD

The 2015 American Society of Clinical Oncology (ASCO) Annual Meeting is nearing, and it promises to be packed with the latest data and trends from the world of oncology as well as the potential to alter treatment practices in several tumor types. Kantar Health has identified 10 pivotal abstracts that are likely to generate the most discussion and have the highest impact, which are summarized below.

 

Opdivo in pretreated non-small cell lung cancer – CheckMate-017 and -057 trials

Histology and biomarker status have increasingly become a guiding factor in the treatment of non-small cell lung cancer (NSCLC). Various subsets have been shown not only to have different etiologies but also differential responses to treatment. In patients with EGFR or ALK mutations, tyrosine kinase inhibitors have established themselves as the standard of care; in patients with non-squamous histology lacking one of these biomarkers, significant improvements in overall survival (OS) have been achieved with Avastin® (bevacizumab, Genentech/Roche) and with Alimta® (pemetrexed, Eli Lilly), although relapsed disease has limited options; for patients with squamous cell NSCLC, effective treatment options have been severely lacking. 

Enter the immune checkpoint inhibitors. Since their initial appearance in melanoma with the approval of the CTLA-4 inhibitor Yervoy® (ipilimumab, Bristol-Myers Squibb/Ono Pharmaceuticals) in 2011, clinical development of two PD-1 inhibitors, Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) and Keytruda® (pembrolizumab, Merck) has expanded at a rapid pace into other tumors, including renal cell carcinoma, bladder cancer, breast cancer, gastric cancer, head and neck cancer, Hodgkin’s lymphoma, and NSCLC, leading to aggressive competition of these two inhibitors.

In January 2015, Opdivo proved its mettle in NSCLC when Bristol-Myers Squibb announced that the open-label Phase III CheckMate-017 (NCT01642004) trial comparing Opdivo with docetaxel in squamous cell patients who had progressed after prior platinum-based therapy was stopped early after the independent data monitoring committee (IDMC) determined that the primary OS endpoint was met.1  On the heels of this news, results from the single-arm Phase II CheckMate-063 (NCT01721759) trial assessing Opdivo in patients with advanced, refractory squamous NSCLC were published in March 2015, showing an overall response rate of 15% in 177 patients treated with Opdivo.2 These data were enough to convince the FDA to grant Opdivo accelerated approval for the treatment of relapsed squamous cell NSCLC in March 2015.

CheckMate-017 enrolled 272 patients who were randomized 1:1 to receive Opdivo or docetaxel as second-line therapy. The results of this trial have not been publicly reported in their entirety, although the OS data was included in the FDA label that accompanied the NSCLC approval, showing a 3.2 month improvement in median OS.

The presentation of this trial at ASCO will allow us to take a more rigorous look at the survival curve, as well as secondary metrics such as progression-free survival (PFS) and toxicity. Of particular interest will be the frequency of pneumonitis, which was observed in 6% of NSCLC patients treated with Opdivo in the CheckMate-063 study and is a toxicity that can be particularly concerning in a lung cancer population. Biomarker analysis, if provided, will also be of interest as the debate continues as to whether PD-L1-positivity is a meaningful predictive biomarker for these checkpoint inhibitors.  

More recently, BMS’s second Phase III trial in NSCLC, CheckMate-057 (NCT01673867) in second-line non-squamous NSCLC, was stopped early upon recommendation of the IDMC because the study had met its primary endpoint of improving OS.3 Similar in design to the CheckMate-017 trial in squamous NSCLC, CheckMate-057 is a Phase III, open-label, randomized study of Opdivo versus docetaxel in previously treated patients with advanced or metastatic non-squamous NSCLC. The positive results from CheckMate-057 means the path toward an expanded label for Opdivo in NSCLC is on track. With Keytruda having also filed for approval in this setting in late April 2015, the race to be first in class in NSCLC is heated, although Opdivo has the lead at the moment. 

 

Imbruvica plus R-Treanda in relapsed/refractory chronic lymphocytic leukemia (CLL) – HELIOS trial

The development of new agents in CLL management has increased in the past few years with the introduction of agents with diverse mechanisms of action (MOA). The recent entrants to this field are the PI3K inhibitor Zydelig® (idelalisib, Gilead) and the BTK inhibitor Imbruvica® (ibrutinib, Pharmacyclics/Janssen). Janssen has been aggressively developing Imbruvica across a number of settings in B-cell malignancies, including CLL and non-Hodgkin’s lymphoma (NHL). This strategy has paid off with Imbruvica’s approval as monotherapy in CLL patients with del17P, in previously treated CLL patients, in Waldenström’s macroglobulinemia, and in previously treated mantle cell lymphoma, where it has an accelerated approval status. The approval in CLL was based on Phase II data4,5 as well as results from the Phase III RESONATE trial (NCT01578707), which pitted Imbruvica against Arzerra® (ofatumumab, Novartis) in the relapsed/refractory setting.6

Pharmacyclics and Janssen have an aggressive and broad development program in place for Imbruvica, including the multiple indications already approved and several lifecycle management studies to expand its use in target indications. In CLL, the company is looking beyond its approval as monotherapy ― spurred by the late-stage development of its strongest competitor, Zydelig. Pharmacyclics hopes that by combining Imbruvica with the standard of care chemotherapy backbone in second-line ― Rituxan® (rituximab, Genentech/Roche) and Treanda® (bendamustine, Teva/Mundipharma) ― the R-Treanda combination will yield a stronger effect compared with Rituxan-Treanda in the relapsed/refractory setting.

In March 2015, Janssen announced that an IDMC unanimously recommended unblinding the HELIOS trial (NCT01611090), an international Phase III, placebo-controlled trial comparing the efficacy of Imbruvica in combination with R-Treanda versus placebo plus R-Treanda in relapsed/refractory CLL and small lymphocytic lymphoma (SLL).7  The trial was initiated in September 2012 and enrolled 578 CLL and SLL patients who had received at least one prior line of systemic therapy. The IDMC’s recommendation came as a result of the study having met its primary endpoint, demonstrating a significant improvement in PFS with Imbruvica in combination with R-Treanda.

Imbruvica has generated a lot of excitement among physicians who treat hematological malignancies, not only evidenced by AbbVie’s proposed bid to acquire Pharmacyclics and Imbruvica’s development portfolio but also reflected in clinical practice. According to Kantar Health’s CancerMPact® Treatment Architecture data,8 Imbruvica is the most commonly utilized regimen in U.S. CLL patients in both second- and third-line treatment; this level of adoption contributed significantly to Imbruvica’s $492 million in net product revenue in 2014. Imbruvica seems to be outpacing its closest competitor, Zydelig, which is utilized in a minority of CLL patients in the same settings. Imbruvica received accelerated approval in CLL in February 2014, five months ahead of Zydelig’s approval, which contributed to its rapid uptake. The strong utilization of Imbruvica is also impressive because it was approved as monotherapy while Zydelig was approved in combination with Rituxan, an agent that remains a cornerstone in CLL therapy.

Successful lifecycle management of Imbruvica dictates expansion into earlier lines of therapy and new indications. The HELIOS trial is the first big step in that direction because R-Treanda is the most commonly used chemotherapy regimen in first- and second-line CLL. The unblinding of the study suggests a significant level of benefit; the PFS curves will be the key metric to watch for at ASCO.

In the Phase III RESONATE trial that compared Imbruvica with Arzerra in relapsed/refractory CLL, the hazard ratio for PFS was 0.215 and for OS was 0.434.9 It remains to be seen whether the addition of Imbruvica to R-Treanda can elicit this same magnitude of benefit, or whether the level of improvement will be more muted when used in combination with an active regimen.

The safety profile in the HELIOS trial also will be looked at during the presentation, in particular the incidence of neutropenia. Treanda was associated with Grade 3/4 neutropenia in 43% of patients in its Phase III trial in relapsed/refractory CLL, and neutropenia was also the most common Grade 3/4 adverse event that occurred in the Imbruvica arm of RESONATE (16% of patients). Some myelosuppression may be inherent to leukemia, but it will be important to confirm that the combination of drugs won’t exacerbate this toxicity, particularly in a disease that is associated with a more elderly population.

 

Alimta in Stage III NSCLC – PROCLAIM Trial

While studies have shown that concurrent chemoradiotherapy provides a survival benefit in patients with advanced NSCLC10 and has become standard practice, clear guidance is lacking on the choice of regimen to use with radiation. Additionally, no definitive consensus exists as to whether the addition of a post-chemoradiotherapy regimen as part of a consolidation phase would further enhance the efficacy. While several studies have suggested that the addition of consolidation chemotherapy in patients who respond to chemoradiotherapy can improve survival compared with chemoradiotherapy alone, a more recent U.S. Phase III trial showed no significant differences in survival for patients receiving consolidation docetaxel versus observation but with significant added toxicity associated with consolidation docetaxel.11  As such, the concept of consolidation therapy following chemoradiation remains up for debate.

The PROCLAIM study seeks to improve or refine the regimen choice among stage III patients receiving chemoradiotherapy plus consolidation chemotherapy by comparing an Alimta-based (pemetrexed, Eli Lilly) chemoradiotherapy regimen and Alimta consolidation versus physician’s choice chemoradiotherapy and consolidation. The primary endpoint is OS. PROCLAIM was initiated in September 2008, but no results have yet been published. That will change when data from the PROCLAIM study will be presented at ASCO on May 30.

Given the relative silence from Eli Lilly, it is unknown how the data will play out in this trial. Alimta is currently approved for use in first-line, maintenance following first-line, and second-line treatment of non-squamous NSCLC. Positive data in PROCLAIM could help physicians understand the optimal regimen for use in this treatment setting. However, several issues are at play here that beg to be addressed.

Currently, only about 50% of patients receive consolidation therapy,8 underscoring the need to assess whether consolidation provides a therapeutic benefit. This would have been important information, but with the lack of an observation arm following chemoradiotherapy this question will remain unanswered. An additional caveat is that the control arm in this study does not entirely reflect current standard of care.

While etoposide plus cisplatin is a recognized option as part of concurrent chemoradiotherapy, it is used in only 20% of U.S. patients currently; carboplatin plus paclitaxel is a more commonly used regimen in this setting.8 However, compelling OS data may sway not only physicians who administer consolidation therapy to change their regimen choice but may also increase use among those physicians who do not currently utilize consolidation therapy.

If the trial fails to show a benefit in favor of Alimta, treatment of stage III NSCLC will remain unchanged from current practice, at least in the short term, as we await results of the pivotal PACIFIC trial of the PD-L1 inhibitor durvalumab (MEDI-4736, MedImmune/AstraZeneca) in this setting.

 

Opdivo plus Yervoy in first-line metastatic melanoma – CheckMate-067 trial

Historically, prognosis for metastatic melanoma has been poor, with OS of less than a year and treatment usually involving toxic and mostly ineffective agents. This changed with the approval of Yervoy in 2011, which improved OS to a little more than one year and was the first agent to significantly improve prognosis. Yervoy also provided evidence of potentially curative effects, with five-year survival of nearly 20%.12

Despite these advances, Yervoy is not without shortcomings, primarily its association with severe immune-related adverse events (irAEs), liver toxicity and gastrointestinal side effects occurring in over a quarter of patients, requiring close monitoring and supportive care with steroid and immunosuppressant treatment. Additionally, while Yervoy induces long-term survival in a fraction of patients, the majority does not enjoy such a benefit, leaving room for agents that can induce a higher level and longer duration of response and survival. 

Since Yervoy’s approval, the development of checkpoint inhibitors has proceeded rapidly, creating great excitement in the oncology field with the development of PD-1/-L1 inhibitors. The two frontrunners are the PD-1 inhibitors Keytruda and Opdivo, which are now FDA approved for the treatment of unresectable/metastatic melanoma following Yervoy treatment and a BRAF inhibitor (in patients with a BRAF mutation). Additionally, the National Comprehensive Cancer Network (NCCN) recommends both drugs for use in first-line metastatic melanoma (category 1 for Opdivo, category 2A for Keytruda).13

In cross-trial comparisons, Opdivo looks to be more efficacious than Yervoy and has decreased frequency of irAEs. With this favorable profile, Opdivo will compete to displace Yervoy as the standard of care in metastatic melanoma. However, BMS hopes that a combined approach ― Yervoy plus Opdivo ― will act in synergy to further improve outcomes over each agent alone. Based on a high response rate in early clinical trials, the company initiated the Phase III CheckMate-067 trial (NCT01844505) in 2013 to evaluate the impact of the combination of Yervoy and Opdivo on PFS and OS versus either single agent. On May 31, initial data from CheckMate-067 will be presented at ASCO.

Yervoy has quickly become standard of practice in both patients with BRAF-mutant and wildtype metastatic melanoma, enjoying high utilization among U.S. physicians.5 Positive results from CheckMate-067 will solidify the combination of Yervoy plus Opdivo as the standard of care replacing checkpoint inhibitor monotherapy, thus staving off competition from Merck’s Keytruda, which demonstrated a significant OS benefit over Yervoy at the American Association for Cancer Research (AACR) Annual Meeting last month.14 In addition, given the efficacy of Yervoy and Opdivo in both BRAF-mutant and wildtype patients, long-term survival with the combination has great potential to replace the use of tyrosine kinase inhibitors in first-line for BRAF-mutant patients.

Early clinical trials observed a high response rate (40%) with the combination.15 Will that hold up in CheckMate-067, and will it translate into PFS and OS benefit? In the CheckMate-066 trial, Opdivo monotherapy produced a one-year OS rate of 72.9% (too soon to estimate five-year OS), and in Yervoy’s pivotal first-line trial one-year OS was 47.3%.12 Where will the curves fall for the combination? Unfortunately, it’s too early to get a feel for long-term survival (the trial has been ongoing for only two years), but even the early timepoints of the curve will be informative to appreciate how much the curves are diverging. 

Secondary endpoints to pay attention to include safety and biomarker analyses. Given the current debate on PD-L1 marker status and its correlation to response, it will be interesting to see what the subgroup analysis of CheckMate-67 will reveal. Will PD-L1 expression on either the tumor or on tumor-infiltrating lymphocytes meaningfully affect benefit, as some studies have suggested? If so, what are the criteria by which PD-L1 positivity will be measured? Another important endpoint to assess will be toxicity. Given that Yervoy and Opdivo have both distinct and overlapping toxicity profiles, it will be important to assess the severity and frequency of these side effects to determine whether the combination will be manageable and the benefit outweighs the risk.

If this combination benefit in CheckMate-067 is appreciable, physicians will certainly be excited to adopt the combination into clinical practice. One hurdle to success of the combination is cost; at the doses studied in combination in CheckMate-067 it amounts to approximately $245,000 for a full year of treatment.  It is unclear whether BMS will push the limit of treatment pricing in the oncology space or whether they will devise a new pricing scheme for the combination to make it more financially tolerable. 

A full understanding of whether this combination can justify its price tag is unlikely to be answered at ASCO 2015, but instead will be measured as survival data matures and we are able to see where the curves plateau.  Time will tell, but the early data at ASCO 2015 will set the stage for this high-impact discussion.

 

Ibrance plus Faslodex in pretreated HR+ metastatic breast cancer – PALOMA-3 trial

Endocrine therapy is the mainstay for the management of patients with metastatic hormone receptor positive (HR+) breast cancer. Given its relatively mild toxicity profile, physicians prefer to administer hormone therapy as long as possible before resorting to more toxic chemotherapy. While endocrine therapy is very effective in extending the lives of these patients, most will eventually progress. The 2012 approval of Afinitor® (everolimus, Novartis) in combination with exemestane in postmenopausal HR+ patients provided proof of principle that combining a hormonal agent with a targeted agent could prolong patients’ survival and maintain hormone therapy for a longer period of time.  Since then other companies have been developing targeted agents to be used in combination with endocrine therapy for the treatment of HR+ breast cancer. On June 1, we will hear about Ibrance® (palbociclib), Pfizer’s entrant in this setting.

Ibrance is a dual CDK4/6 inhibitor that has been shown to inhibit components of the pathway that drives cell division, leading to cell cycle arrest and subsequent cell death. Results from the randomized Phase II PALOMA-1 trial (NCT00721409) showed that the combination of Ibrance with letrozole significantly improved PFS compared with letrozole and placebo (20.2 months versus 10.2 months, HR 0·488, p=0·0004) in the first-line setting.16

The impressive results led to Ibrance’s accelerated approval in February 2015. At ASCO, we will hear results from the first Phase III trial to report data for Ibrance. PALOMA-3 (NCT01942135) is a double-blind, placebo-controlled trial testing the efficacy of Ibrance in combination with Faslodex® (fulvestrant, AstraZeneca) versus Faslodex alone for the treatment of patients with HR+, HER2- metastatic breast cancer who had progressed on prior endocrine therapy.

Signs point to encouraging results as Pfizer announced it had stopped the trial early because it had met its primary endpoint of improvement in PFS as assessed by the IDMC.17 PALOMA-3 is in a second-line setting, so the number of months benefit may be muted in comparison to PALOMA-1, but will the relative magnitude of benefit (a 51% reduction in the risk of progression or death in PALOMA-116) be retained? Another aspect of the data that will be interesting to note is whether Ibrance will be equally active in an HR+ population as it is in the ER+ population that was enrolled in PALOMA-1. 

The use of these agents in combination with hormone therapy raises the risk of increased side effects in a treatment setting that has long been sheltered from significant toxicity. Indeed, significant side effects have accompanied both Afinitor and Ibrance combinations. Hematological adverse events were seen in a significant portion of patients in the PALOMA-1 trial. Clearly, this is a parameter that will be closely examined during the PALOMA-3 presentation and will be weighed against the efficacy benefit. If the efficacy benefit in PALOMA-3 is not as large as seen in the first-line setting, the balance between efficacy and toxicity will be more important.

Building on its recent accelerated approval in front-line in the U.S., PALOMA-3 results will broaden Ibrance’s utilization opportunities, giving physicians flexibility to combine with letrozole or Faslodex and data to support use in the first- or second-line settings. In addition, PALOMA-3 will support regulatory filings outside the U.S., making Ibrance the second targeted agent to be approved in combination with hormone therapy in metastatic HR+/HER2- breast cancer. 

 

Gazyva plus Treanda in relapsed/refractory indolent NHL – GADOLIN trial

Since its approval in 2006, Rituxan has become the backbone of virtually every treatment regimen in NHL. Although highly effective and often used across multiple lines of therapy, approximately 20% of indolent NHL patients are considered refractory to Rituxan following first-line therapy.8 For these patients, treatment historically has been chemotherapy alone, most commonly Treanda, although use of Zydelig in this patient segment has been growing since its July 2014 FDA approval in relapsed/refractory follicular lymphoma.

Gazyva® (obinutuzumab, Genentech/Roche) is a third-generation, humanized anti-CD20 IgG1 monoclonal antibody that has been glycoengineered to enhance its antibody-dependent cellular cytotoxicity (ADCC). It has been shown to bind with high affinity to the CD20 type II epitope, resulting in the induction of ADCC that is five- to 100-fold greater than observed with Rituxan and shown to be more potent at inducing cell death.18

Given the looming patent expiration of Rituxan, Roche hopes to stave off biosimilar competition by establishing Gazyva as a replacement to Rituxan given the promising activity and potentially lower toxicity of Gazyva compared with Rituxan. Genentech and Roche believe in Gazyva’s favorable efficacy and toxicity profile and have implemented an aggressive development strategy, with concurrent initiation of multiple pivotal Phase III trials in CLL, indolent NHL and diffuse large B-cell lymphoma (DLBCL).

In unfit newly diagnosed CLL patients, Gazyva has already proven itself to be superior to Rituxan in terms of efficacy. CLL11 was the first Phase III trial of Gazyva to report, but Roche is conducting at least four additional Phase III trials of Gazyva in B-cell malignancies.

GADOLIN (NCT01059630) is an open-label, multicenter, randomized, Phase III study investigating the efficacy and safety of Gazyva in combination with Treanda compared with Treanda alone in patients with Rituxan-refractory indolent NHL. Roche previously announced that the IDMC determined that the study had met its primary endpoint of improving PFS in the Gazyva plus Treanda arm compared with Treanda alone. No unexpected adverse events were seen with Gazyva.19 Data from the study will be submitted to the FDA and EMA for approval consideration. With positive results from the GADOLIN trial, regulatory approval is not far behind.

Several elements of the GADOLIN trial will be important to assess at ASCO. First and foremost will be the precise magnitude of PFS benefit. In unfit CLL patients, Gazyva plus chlorambucil more than doubled response rate and PFS compared with chlorambucil. In GADOLIN, however, Treanda is a much more active comparator, and the trial is enrolling patients who are considered refractory to prior CD20 inhibition. Can Gazyva achieve the same level of benefit in this treatment setting? Having met the endpoint at the interim analysis suggests the magnitude of benefit will be large, but the proof will be in the Kaplan-Meier curves. In addition, the toxicity profile of the Gazyva plus Treanda combination will be important to watch.

In the CLL11 trial, Gazyva was associated with increased incidence of infusion-related reactions, neutropenia and thrombocytopenia; these last two are also characteristically seen with Treanda. Will the combination of these two agents raise any red flags in terms of tolerability? 

Although the GADOLIN trial is not comparing Gazyva directly with Rituxan, this data in Rituxan-refractory indolent NHL, combined with the data from the CLL11 trial, will be important initial stepping stones to allow Gazyva to replace Rituxan.

 

Neratinib as post-Herceptin adjuvant therapy in locally advanced HER2+ breast cancer – ExteNET trial

Neratinib is an irreversible tyrosine kinase inhibitor targeting EGFR and HER2, originally developed by Wyeth, then by Pfizer and now by PUMA Biotechnology. In July 2014, PUMA announced top-line results from the ExteNET trial (NCT00878709), which evaluated neratinib versus placebo as additional adjuvant therapy after adjuvant chemotherapy and Herceptin in 2,821 early-stage HER2+ breast cancer patients. The primary endpoint of disease-free survival (DFS) was met, with neratinib providing a 33% improvement in DFS versus placebo (HR 0.67, p=0.0046). The secondary endpoint of the trial was DFS including ductal carcinoma in situ (DFS-DCIS), and treatment with neratinib resulted in a 37% improvement in DFS-DCIS versus placebo (HR 0.63, p=0.0009).20 Two-year follow-up data will be presented at ASCO on June 1.

This turn of events certainly has helped PUMA, whose stock soared upon announcement of positive results. PUMA’s decision to study neratinib in the post-Herceptin adjuvant space was a unique but probably wise decision. Herceptin is a highly active agent and has proven difficult to both displace and improve upon, as evidenced by the failure of the ALLTO trial (NCT00490139), in which Tykerb® (lapatinib, GSK) failed to improve DFS when compared with Herceptin and when combined with Herceptin in the adjuvant setting.21

Neratinib will be the first agent to enter the post-Herceptin adjuvant space, a novel indication that essentially prolongs the duration of anti-HER2 therapy for these patients. Although the company-stated degree of DFS benefit is promising, it is somewhat concerning that nine months after topline results were announced the public has yet to see the data. Additionally, PUMA had originally guided that it planned to file for regulatory approval of neratinib in the extended adjuvant setting in the first half of 2015 but has delayed the filing until the first quarter of 2016.

ASCO will be the first time this data can be critically analyzed, and several elements will be important to assess. Has the degree of DFS benefit eroded with time, potentially delaying the presentation and filing plans? Are concerning safety signals associated with neratinib? Based on prior data for neratinib and this class of agent in general, diarrhea is common, which may be particularly tough to tolerate when the duration of therapy is a full year and the patient may otherwise be considered disease-free and potentially cured; treatment discontinuation rates attributable to toxicity will certainly be a telling piece of data.

A secondary endpoint of particular interest will be the effect of neratinib on rate of disease recurrence to the brain; in the metastatic setting, neratinib significantly reduced the rate of CNS metastases compared with Herceptin.22 Can a similar benefit be observed in the locally advanced setting? Given the unique treatment setting that neratinib is seeking to create, the efficacy and safety data will be scrutinized to determine the opportunity that exists for it to enter the landscape.

 

Kyprolis/dexamethasone versus Velcade/dexamethasone in relapsed multiple myeloma – ENDEAVOR trial

The past couple of years have seen the entrance of several new agents in the treatment of multiple myeloma, including immunomodulatory agents (IMiDs) such as Thalomid® (thalidomide, Celgene), Revlimid® (lenalidomide, Celgene), and Pomalyst® (pomalidomide, Celgene) and proteasome inhibitors such as Velcade® (bortezomib, Millennium/Takeda/Johnson & Johnson) and Kyprolis® (carfilzomib, Onyx/Amgen/Ono Pharmaceuticals).

As a result, outcomes for patients have improved, but relapsed or refractory patients still need more effective options. Kyprolis is a second-generation proteasome inhibitor that was granted accelerated approval by the FDA in July 2012 for use as a single agent in myeloma patients who had progressed on prior Velcade and Revlimid. More recently, results from the Phase III ASPIRE trial (NCT01080391) showed that the addition of Kyprolis to the RevDex (Revlimid plus dexamethasone) regimen significantly improved PFS and response rates, with a trend toward improved OS,23 although the FOCUS trial comparing Kyprolis to best supportive care failed to show a PFS or OS benefit.24

Kyprolis is currently used predominantly in the third-line setting, although Onyx and Amgen have their eye on earlier treatment settings. To do so, the companies hope to establish Kyprolis as the preferred proteasome inhibitor, replacing Velcade as the agent of choice for this class. In that vein, the ENDEAVOR trial will be pivotal, and first results will be presented on June 2.

ENDEAVOR (NCT01568866) is a randomized, open-label Phase III trial designed to test head-to-head the efficacy of Kyprolis plus dexamethasone (Kd) vs. Velcade plus dexamethasone (Vd) in 929 multiple myeloma patients who had relapsed after at least one but no more than three prior therapies. Amgen announced earlier this year that the trial had met its primary endpoint of PFS improvement, doubling the time patients lived without disease progression for Kd compared to Vd.25

Of interest will be subgroup analysis to understand whether any patient characteristics confer a better response to therapy with one agent over the other. Most interesting will be whether any patient subsets derive greater benefit from Velcade. Because the trial allows patients to have been pretreated with a proteasome inhibitor, the level of benefit with Kyprolis in Velcade-pretreated patients will be important; if any patients were enrolled who had received prior Kyprolis, the activity of both arms in that patient group will be interesting.  

Another important aspect of this trial will be the safety profile. A lower incidence of neuropathy has been touted as an advantage of Kyprolis over intravenous (IV) Velcade; however, subcutaneous (SC) Velcade seems to have a lower incidence of neuropathy. Because the Velcade arm in ENDEAVOR allows use of either IV or SC at the physician’s discretion, this design should allow comparison of neuropathy incidence between the most commonly used formulations of these two proteasome inhibitors.

The company press release noted that the incidence of neuropathy was lower in the Kyprolis arm, but the degree of benefit will wait to be seen at ASCO. The company also noted that the rates of cardiac and renal toxicity, hypertension and dyspnea were higher in the Kyprolis arm versus the Velcade arm, which is concerning in and of itself but perhaps more concerning because the trial excluded patients with left ventricle ejection fraction of less than 40%, a history of cardiovascular disease or poor creatinine clearance.

Cardiac toxicity was a subject of debate when the Oncology Drug Advisory Committee (ODAC) considered Kyprolis’ original application for accelerated approval, so no doubt cardiac and renal events will be closely assessed in ENDEAVOR’s results. Although PFS is doubled in the Kyprolis arm, if the level of these toxicities is too alarming, physicians could shy away from using the drug. 

 

Elotuzumab plus Revlimid/dexamethasone in relapsed/refractory multiple myeloma – ELOQUENT-2 trial

Treatment of multiple myeloma is largely limited to two classes of agents: IMiDs and proteasome inhibitors. Few other MOAs exist in myeloma management, with the only other option being the recently approved Farydak® (panobinostat, Novartis), an HDAC inhibitor. Several other agents with novel MOAs are now in development. Elotuzumab (co-developed by Bristol-Myers Squibb and AbbVie) is a humanized monoclonal antibody that is directed at SLAMF7 (also called CS1). Elotuzumab has generated excitement in the field not only for its encouraging efficacy and mild toxicity profile in earlier trials but also for its novel MOA.

This excitement is reflected in the FDA granting it breakthrough therapy status. Both companies hope that its novel MOA will help differentiate it in a field that has been dominated by IMiDs and proteasome inhibitors. Elotuzumab is being studied in the front-line setting (ELOQUENT-1 trial, NCT01335399) for transplant-ineligible patients, and on June 2 we will hear details about their study in the relapsed/refractory setting, ELOQUENT-2 (NCT01239797). ELOQUENT-2 is a global, open-label, Phase III trial comparing Revlimid plus dexamethasone (RevDex) with or without elotuzumab in patients who had received one to three prior regimens.

Given the high response rate (92%) seen in its Phase I/II trial in relapsed/refractory patients and its mild toxicity,26 hopes are high for elotuzumab’s performance in ELOQUENT-2. Specifically, can elotuzumab maintain the high level of response and translate it into a clinically meaningful PFS benefit? OS data may not be mature. Positive results from ELOQUENT-2, combined with its breakthrough therapy status, could lead to rapid approval of elotuzumab.

The lack of communication from the companies raises some doubt about the outcome of the study because positive results would have been expected to be announced in a press release or other forum. The magnitude of benefit will be important. Farydak’s approval in the same setting was controversial, with the 3.9-month improvement in PFS arguably offset by the increased incidence of severe adverse events. If the addition of elotuzumab to RevDex doesn’t present a risk-to-benefit ratio that exceeds that of Farydak and matches or exceeds that of Kyprolis (discussed above), then elotuzumab will be relegated to later lines of therapy or may even face regulatory challenges.

 

Of course, let’s not forget the ever-spreading development of checkpoint inhibitors. ASCO will see several first reports on the activity of the PD-1 and PD-L1 inhibitors in new indications:

  • Esophageal cancer (Keytruda, Abstract 4010)
  • Glioblastoma (Opdivo and Yervoy, Abstract 3010)
  • Hepatocellular carcinoma (Opdivo, Abstract LBA101)
  • Ovarian cancer (avelumab, Abstract 5509; Keytruda, Abstract 5510; Opdivo, Abstract 5570)
  • Small cell lung cancer (Keytruda, Abstract 7502; Opdivo and Yervoy, Abstract 7503)

Follow-up data will also be presented in several tumor types in which the activity of this class has been previously reported (bladder, gastric cancer, head and neck, and non-small cell lung cancers, melanoma, and renal cell carcinoma). The PD-1 pathway will also be the focus of this year’s David A. Karnofsky Memorial Lecture, given by Dr. Suzanne Topalian on May 30.

Other new immunotherapy MOAs will be reported, including a focus on chimeric antigen receptor T-cell therapies (CAR-T) in a Clinical Science Symposium dedicated to this class of agents, occurring June 1, from 3-4:30pm.

Finally, immunotherapy, while high-profile, is not the only therapeutic class in development. ASCO will bring new data for a host of other novel MOAs too numerous to list here. Given the number of high-profile trials and incremental advances being reported at ASCO, it’s sure to be an exciting week in Chicago!

About the Contributor

Len Kusdra, PhD is Analyst, Clinical and Scientific Assessment, at Kantar Health. Stephanie Hawthorne, PhD is Senior Director, 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.

One of Kantar Health’s oncology-related offers is Oncology Market Access US (OMA US), which provides strategic and tactical insights into the evolving oncology landscape. Combining Kantar Health’s commercial and clinical expertise in oncology, OMA US provides cutting-edge information and analysis on critical reimbursement, coverage and competitive issues in the U.S. oncology marketplace.

If you would like us to act as catalysts for you, contact us at www.kantarhealth.com/contactus.

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