Kantar Health Blog

Kantar Health Offers a Preview of the Pivotal Abstracts at ASCO 2015

by Stephanie Hawthorne | May 6, 2015
Stephanie Hawthorne

Co-authored by Len Kusdra, PhD

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 2015 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 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.

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

Pharmacyclics and Janssen have been aggressively developing Imbruvica® (ibrutinib) 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 (accelerated approval). In CLL, the company is looking beyond its approval as monotherapy and hopes that combining Imbruvica with the standard-of-care chemotherapy backbone in second-line ― Rituxan® (rituximab, Genentech/Roche) and Treanda® (bendamustine, Teva/Mundipharma) ― will yield a stronger effect compared with Rituxan-Treanda in the relapsed/refractory setting.

In March 2015, Janssen announced that the independent data monitoring committee (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).1 The IDMC’s recommendation came as a result of the study having met it primary endpoint, demonstrating a significant improvement in progression-free survival (PFS) with Imbruvica in combination with R-Treanda.

The HELIOS trial is a step toward expanding Imbruvica into earlier lines of therapy, since R-Treanda is a commonly used chemotherapy regimen in first- and second-line CLL. In the Phase III RESONATE trial that compared Imbruvica with Arzerra® (ofatumumab, Novartis) in relapsed/refractory CLL, the hazard ratio for PFS was 0.215 and for overall survival (OS) was 0.434.2 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. In that respect, the PFS curves will be an important metric to examine at ASCO.

The safety profile in the HELIOS trial also will be key 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.

Abstract LBA7005, Saturday May 30, 2:27 PM

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

Historically, prognosis for metastatic melanoma has been poor, with median OS of less than a year and treatment usually involving toxic and mostly ineffective agents. This changed with the approval of Yervoy® (ipilimumab, Bristol-Myers Squibb) in 2011, which improved OS and provided evidence of potentially curative effects, measured as a 20% five-year survival rate.3

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, particularly with PD-1/-L1 inhibitors. Keytruda® (pembrolizumab, Merck & Co) and Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) are the frontrunners and are now FDA approved for the treatment of unresectable/metastatic melanoma following Yervoy and a BRAF inhibitor (in patients with a BRAF mutation).

Keytruda has recently shown superiority to Yervoy in a head-to-head comparison of the two monotherapies in metastatic melanoma.4 BMS is taking an alternative approach, with 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) 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.

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. In addition, efficacy of Yervoy and Opdivo in both BRAF-mutant and wildtype patients may lead to the combination replacing tyrosine kinase inhibitors for BRAF-mutant patients if the response rates and long-term survival are sufficiently convincing.

Early clinical trials reported a high response rate (40%) with the combination.5 Will that hold up in CheckMate-067, and will it translate into PFS and OS benefits? 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%.3 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 it will be interesting to assess whether PD-L1 expression on either the tumor or on tumor-infiltrating lymphocytes will meaningfully affect benefit, and if so how PD-L1 positivity will be measured. Additionally, Yervoy and Opdivo have both distinct and overlapping toxicity profiles, so it will be important to determine whether the combination will be manageable and the benefit outweighs the risk.

Abstract LBA1, Sunday, May 31, 1:35 PM

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

Endocrine therapy is the mainstay of management for patients with metastatic hormone receptor positive (HR+) breast cancer. Long-term hormone therapy is preferred before resorting to more toxic chemotherapy, and while endocrine therapy is very effective in extending disease control in these patients, most will eventually progress. 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 in the first-line setting,6 which led to Ibrance’s accelerated approval in February 2015. At ASCO, we will hear results from the Phase III PALOMA-3 trial (NCT01942135), which compares Ibrance in combination with Faslodex® (fulvestrant, AstraZeneca) versus Faslodex alone for the treatment of patients with HR+, HER2- metastatic breast cancer patients who have progressed on prior endocrine therapy.

The trial was stopped early because it had met its primary endpoint of improvement in PFS as assessed by the IDMC.7 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-16) 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. 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. 

Abstract LBA502, Monday, June 1, 8:24 AM

Kantar Health’s Top Abstracts of Interest at ASCO 2015

Agent

Manufacturer

Indication

Abstract

Date and Time

Opdivo

Bristol-Myers Squibb/Ono

NSCLC, non-squamous, second line

LBA109

Saturday, 8:51 AM

Imbruvica

Pharmacyclics/ Johnson & Johnson

CLL, relapsed/refractory

LBA7005

Saturday, 2:27 PM

Alimta

Eli Lilly

NSCLC, Stage III chemoradiation

7506

Saturday, 5:00 PM

Opdivo + Yervoy

Bristol-Myers Squibb/Ono

Melanoma, first line

LBA1

Sunday, 1:35 PM

Opdivo

Bristol-Myers Squibb/Ono

NSCLC, squamous, second line

8009

Sunday, 4:30 PM

Ibrance

Pfizer

Breast, HR+ relapsed/refractory

LBA502

Monday, 8:24 AM

Gazyva

Genentech/ Roche

Indolent NHL, relapsed/refractory

LBA8502

Monday, 10:09 AM

neratinib

PUMA Biotechnology

Breast, HER2+ adjuvant

508

Monday, 10:24 AM

elotuzumab

Bristol-Myers Squibb/AbbVie

Multiple myeloma, relapsed/refractory

8508

Tuesday, 9:45 AM

Kyprolis

Onyx/Amgen

Multiple myeloma, relapsed/refractory

8509

Tuesday, 9:57 AM

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