The OBR Blog

May 13, 2015 - 08:05 pm Posted in Featured comments0 Comments

As preparations for ASCO’s annual meeting heat up, a pre-meeting Presscast highlighted four abstracts of special interest to be presented in greater detail at the meeting in Chicago. All four are based on data from Phase III trials:

  • In the ELOQUENT-2 trial, a new monoclonal antibody — elotuzumab — extended remission when added to standard therapy for relapsed/refractory multiple myeloma
  • A phase 3 double-blind randomized trial showed that daily use of a vitamin B3 pill (nicotinamide) reduces incidence of new non-melanoma skin cancers (basal cell and squamous cell cancers), as well as pre-cancerous actinic keratoses in people at high risk for skin cancer
  • Data from two Phase III Children’s Oncology Group Studies show that a specific genetic abnormality enables more intensive therapy to be given to children with Wilms Tumor, thereby improving outcomes in this high-risk group
  • Results from STAMPEDE show that docetaxel — but not zoledronic acid — extended overall survival when given with hormone therapy to men with newly diagnosed, metastatic, hormone-naive prostate cancer

“Trials like these are engines of progress for people with cancer of all ages. In just four studies, we see the potential to spare thousands of people the stress and complications of a new cancer diagnosis, and to extend the lives of children and adults facing cancer in its most daunting forms. At ASCO’s meeting in Chicago, we’ll continue to see the transformative power of investments in cancer research and care,” stated ASCO President Peter Paul Yu, MD, FACP, FASCO, in an official press release.

Elotuzumab in Multiple Myeloma
Interim results of a Phase III trial show that adding the monoclonal antibody elotuzumab to standard therapy with lenalidomide/dexamethasone reduced the risk of cancer progression and death by 30% in patients with relapsed/refractory multiple myeloma.

“This therapy combines the precision of a targeted, immune-based therapy with traditional myeloma therapy. The results are very encouraging, giving renewed hope to patients who have relapsed,” stated ASCO President-Elect Julie M. Vose, MD, who was not involved in this trial.

“Elotuzumab acts on the tumor cell and enhances the activity of natural killer cells, providing a sort of ‘double whammy’,” said lead author Sagar Lonial, MD, Winship Cancer Institute of Emory University School of Medicine, Atlanta, GA. “We are excited about the progression-free survival results attributable to this novel first-in-class antibody.”

This is the largest study of a targeted monoclonal antibody in multiple myeloma and the first Phase III study to show the benefit of this approach in multiple myeloma. The study randomized 646 patients with relapsed/refractory multiple myeloma to standard therapy with lenalidomide/dexamethasone or standard therapy plus elotuzumab. At a median follow-up of 24 months, progression-free survival (PFS) was 41% in the triple therapy arm versus 27% in the standard therapy arm (P=.0004).

“It is striking that these curves remain separated at 2 years, which speaks to the power of an immune approach as part of treatment of multiple myeloma,” Dr. Lonial commented.

Importantly, patients at high risk due to genetic abnormalities — del(19p) and t(4;14) — had similar benefit from elotuzumab as in the overall study. These patients typically have less benefit from conventional therapies, Dr. Lonial said.

Overall elotuzumab was well tolerated with no significant increases in adverse events. About 10% of patients experienced a mild infusion reaction with the first few doses of the monoclonal antibody. Elotuzumab has been granted a Breakthrough Designation by the U.S. FDA.

Vitamin B3 Supplement (Nicotinamide) and Skin Cancer
An oral form of vitamin B3 (nicotinamide) taken twice daily for 12 months reduced the rate of new skin cancers by 23% compared to placebo in people at high risk for these cancers. This simple, inexpensive pill is safe, affordable, and available over the counter, making it widely available for people at risk.

“When we stopped treatment, there was no difference between the two arms, suggesting that continuous treatment is needed. I should emphasize that these results pertain to high-risk patients who have had other skin cancers, not the general public,” said lead author Diona Damian, MBBS, PhD, Dermatology University of Sydney, Australia.

“The pill does not take the place of sunscreen use and regular skin check-ups for people at high risk,” she emphasized.

The study included 386 patients who had at least two non-melanoma skin cancers over the past 5 years and were therefore deemed high risk. Patients were randomized to daily nicotinamide or placebo for 12 months. Dr. Damian said the patient mix reflected those seen in a typical skin cancer clinic. Average age was 66 years and two thirds were men, many with ongoing chronic comorbidities.

Nicotinamide reduced the rates of new basal cell cancer and squamous cell cancer diagnoses by 23% compared with placebo. Nicotinamide reduced the rates of actinic keratoses (pre-cancers) by 11% at 3 months and by 20% at 9 months of treatment compared with placebo.

This preventive treatment has no side effects, Dr. Damian said.

High-Risk Wilms Tumor
Intensifying therapy for children with Wilms Tumor improves outcome in patients with a chromosomal abnormality associated with poorer prognosis, according to results of two Phase III trials conducted by the Children’s Oncology Group.

Previous studies of patients with the genetic abnormality treated with conventional regimens showed 4-year relapse-free survival rates of 74.9% for stage I/II disease and 65.9% for stage III/IV disease. Intensified, or augmented therapy, increased the rates to 83.9% and 91.5%, respectively.

“Augmentation of therapy for favorable histology Wilms Tumor with LOH improves outcomes, particularly for stage III/IV disease. We are encouraged that augmentation can overcome a known adverse biomarker,” said lead author David B. Dix, MD, British Columbia Children’s Hospital, Vancouver, Canada.

The AREN0533 and ARENO532 studies evaluated whether augmenting therapy would improve event-free survival for patients with favorable Wilms histology and the genetic abnormality (tumor-specific loss of heterozygosity [LOH] of chromosomes 1p and 16q). Augmentation strategies were as follows:

  • Stage I/II patients received doxorubicin in addition to vincristine/dactinomycin, and
  • Stage III/IV patients received all three drugs alternating with cyclophosphamide/etoposide and radiotherapy
  • At a median follow-up of 3.6 years, of a total of 1134 patients, 35 stage I/II patients and 52 stage III/IV patients had combined LOH 1p and 16q; these patients formed the basis of the analysis. Grade 3 or higher hematologic toxicity was the most common adverse event observed with the augmented regimen given to stage III/IV patients, occurring in 60%. The analysis did not establish superiority of either augmented regimen.

    LOH 1p, 16q testing is considered the standard of care at the Children’s Oncology Group Biopathology Center and several other centers, Dr. Dix noted.

    Docetaxel for Hormone-Naive Advanced Prostate Cancer
    The STAMPEDE trial found that the addition of docetaxel to standard hormone therapy improved overall survival (OS) by a median of 10 months in men with newly diagnosed advanced prostate cancer who were previously naive to hormone therapy; however, the addition of zoledronic acid to standard therapy had no effect on survival in this group of men and the combination of docetaxel plus zoledronic acid was not superior to docetaxel alone.

    “Docetaxel chemotherapy should be routine in men with newly diagnosed metastatic prostate cancer about to start hormones for the first time. There is some uncertainty regarding the survival benefit in men with non-metastatic prostate cancer, but docetaxel should be offered upfront to these men to prolong failure free survival,” said lead author Nicholas David James, MD, PhD, University of Warwick in Coventry, U.K. ” It’s clear that zoledronic acid does not benefit these patients and should not be offered as upfront treatment for advanced prostate cancer.”

    STAMPEDE is the largest randomized clinical trial conducted to date of treatment for prostate cancer, including more than 6500 men enrolled since 2005. The innovative, ongoing, multi-arm study has an adaptive trial design, modifying the standard of care (SOC) control, arm as new patients are continuously enrolled. Ineffective treatments are dropped and new arms are added to assess the efficacy of newer treatments. The control, or standard of care (SOC) arm, has evolved over time.

    Results to be presented at ASCO 2015 focus on 2962 hormone-naive men assigned to one of 4 of STAMPEDE’S 9 different treatment arms: SOC, SOC with docetaxel for 6 cycles, SOC with zoledronic acid for 2 years, and SOC with both docetaxel and zoledronic acid.

    By Don Sharpe

    May 07, 2015 - 02:05 pm Posted in Featured comments0 Comments

    By Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health and Len Kusdra, PhD, Analyst, Clinical & Scientific Assessment, Kantar Health

    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 its 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

    1) Independent Data Monitoring Committee Unanimously Recommends Unblinding of IMBRUVICA® (ibrutinib) Phase III Combination HELIOS Trial Based on Interim Analysis Showing Significant Improvement in Progression-Free Survival in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma [press release]. Sunnyvale, CA: Pharmacyclics; March 16, 2015.
    2) Byrd et al., N Engl J Med. 2014; 371: 213-223.
    3) Maio et al., J Clin Oncol. 2015;33(10):1191-1196.
    4) Ribas et al., N Engl J Med. 2015;372:320-330.
    5) Wolchok et al., N Engl J Med. 2013;269(2:122-133.
    6) Finn et al., Lancet Oncol. 2015;16(1:25-35.
    7) Pfizer Announces PALOMA-3 Trial For IBRANCE® (Palbociclib) Stopped Early Due To Efficacy Seen In Patients With HR+, HER2- Metastatic Breast Cancer Whose Disease Has Progressed Following Endocrine Therapy [press release]. New York, NY : Pfizer ; April 15, 2015.

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