Immunotherapy Combination Active in Advanced Melanoma

“Combined treatment with the T-cell checkpoint pathway inhibitors nivolumab and ipilimumab produced significantly higher rates of response and progression-free survival among patients with advanced melanoma (regardless of BRAF mutation status) than did treatment with ipilimumab alone, according to the phase I results of a trial published in the New England Journal of Medicine and presented at the 2015 American Association for Cancer Research (AACR) Annual Meeting.

“ ‘On the basis of the high degree of tumor reduction in the current study, with a high rate of complete responses, a favorable clinical benefit can be anticipated with longer follow-up,’ wrote study author F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute, and colleagues.

“The phase I dose-escalation study included 142 patients with treatment-naive metastatic melanoma. Patients were randomly assigned 2:1 to ipilimumab 3 mg/kg with nivolumab 1 mg/kg or placebo every 3 weeks for four doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks.

“In patients with BRAF wild-type tumors, combined treatment resulted in an objective response rate of 61% compared with 11% in those assigned ipilimumab alone (P < .001). Complete responses occurred in 22% of patients assigned to the combined immunotherapy treatment and none of the patients assigned to monotherapy.”


New Combo of Immunotherapy Drugs Is Safe, Shrinks Tumors in Metastatic Melanoma Patients

“Once again, researchers at Penn’s Abramson Cancer Center have extended the reach of the immune system in the fight against metastatic melanoma, this time by combining the checkpoint inhibitor tremelimumab with an anti-CD40 monoclonal antibody drug. The first-of-its-kind study found the dual treatments to be safe and elicit a clinical response in patients, according to new results from a phase I trial to be presented at the AACR Annual Meeting 2015 on Sunday, April 19.

“Researchers include first author David L. Bajor, MD, instructor of Medicine in the division of Hematology/Oncology, and senior author Robert H. Vonderheide, MD, DPhil the Hanna Wise Professor in Cancer Research.

” ‘We’ve had wonderful success with immunotherapies, but we are barely scratching the surface,’ Bajor said. ‘Checkpoint inhibitors are just the beginning. When they are thoughtfully combined with immune-stimulating compounds like CD40 or drugs targeting other facets of the immune system we hope to be able to increase the response rate to previously approved therapies.’

“Known as a checkpoint inhibitor, tremelimumab is an investigational monoclonal antibody that ‘cuts the brakes’ of the immune system by targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a protein that can switch off a patient’s immune response. Anti-CD40 drugs (in this trial, CP- 870,893) antagonize the CD40 receptor, and effectively ‘push the gas’ on the immune system to make it work harder.”


Review Highlights Potential of Cancer Immunotherapy plus Targeted Therapy

“The prospect of combining genomically targeted therapies with drugs that free the immune system to attack cancer suggests ‘we are finally poised to deliver curative therapies to cancer patients,’ researchers at The University of Texas MD Anderson Cancer Center note in a review in the April 9 edition of Cell.

” ‘To support this goal and accelerate these efforts, changes in directions of research support and funding may be required,’ co-authors Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology, and Jim Allison, Ph.D., chair of Immunology, said in the review.

“The review, titled ‘Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential,’ covers the strengths and weaknesses of the two forms of therapy and notes how their combination could be particularly potent.”


Lion Biotechnologies Announces Positive Data From a TIL-Ipilimumab Combination Study in Melanoma

“Lion Biotechnologies, Inc. (Nasdaq: LBIO), a biotechnology company that is developing novel cancer immunotherapies based on tumor infiltrating lymphocytes (TIL), today announced that researchers from Moffitt Cancer Center reported positive results from a pilot trial of TIL and ipilimumab in patients with metastatic melanoma. The data from the trial, which Lion partially sponsored, were presented at the Society of Surgical Oncology 2015 meeting in Houston, TX on Friday, March 27, 2015.

“The Phase 1 trial was conducted at Moffitt Cancer Center in 12 patients with metastatic melanoma, with the objective of determining the safety and feasibility of combining TIL therapy with the CTLA-4 checkpoint inhibitor, ipilimumab. Patients were treated with ipilimumab one week prior to tumor harvest for TIL expansion, a second time while their TIL were being expanded, and two more times following TIL transfer.

“Of the 12 patients enrolled in the trial, 11 went on to receive their autologous TIL, with five out of the 11 TIL-treated patients (46%) responding to treatment (one complete response and four partial responses), consistent with response rates from previous TIL studies in metastatic melanoma. Notably, the researchers observed that following a single infusion of ipilimumab, TIL grew to higher numbers than historically had been observed in previous studies, in which ipilimumab was not administered prior to tumor harvest. In addition, only one of the 12 enrolled patients (8%) was ineligible for TIL transfer, indicating relatively high patient adherence to trial protocol.

” ‘Ipilimumab has potential to enhance the effectiveness of TIL therapy by boosting the concentration of tumor-reactive T cells in the tumors of patients prior to TIL harvest, and by controlling disease before TIL transfer,’ said Sangeetha Prabhakaran, MD, the study’s presenting author. ‘Based on the results of this study, we conclude that TIL-ipilimumab combination treatment is both safe and feasible. Furthermore, this approach serves as a model for future efforts to combine TIL with PD-1/PD-L1 blockade and other emerging immune checkpoint inhibitors.’ “


Triple Combo: Two Targeted Drugs Plus Immunotherapy Show Promise in BRAF-Mutant Melanoma

“Results of a new study by UCLA researchers has found that a groundbreaking new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous BRAF + MEK inhibitor or BRAF inhibitor + immunotherapy combos alone, and with increased immune response and fewer side effects.

“An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 will die of the disease. About 50 percent of these men and women (or 35,000 a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.

“In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patients’ own immune system to enhance immunotherapy, and reduce the probability of the melanoma eventually developing resistance.

“This is a significant advance compared to previous drug combination findings, in which a combined BRAF inhibitor (vemurafenib) with immunotherapy (ipilimumab) caused serious liver toxicity in some patients, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.”


Lenalidomide Combination Fails to Improve Survival in Castration-Resistant Prostate Cancer

“The addition of lenalidomide to docetaxel and prednisone was associated with a significantly greater mortality rate in patients with metastatic castration-resistant prostate cancer, according to phase 3 study results.

“Daniel P. Petrylak, MD,professor of oncology and urology at Yale School of Medicine and a HemOnc Today Editorial Board member, and colleagues evaluated data from 1,046 chemotherapy-naive patients with metastatic castration-resistant prostate cancer.

“Researchers randomly assigned 525 patients to receive docetaxel and prednisone plus lenalidomide (Revlimid, Celgene). The other 521 patients received docetaxel and prednisone plus placebo.

“After a median follow-up of 8 months, 221 patients had died (lenalidomide arm, n = 129; placebo arm, n = 92). The number of deaths that occurred during treatment or within 28 days of receiving the final dose was similar in both groups (lenalidomide, n = 18; placebo, n = 13).”


Breast Cancer Cocktail Buys More Than a Year of Life

“A cocktail of three breast cancer drugs buys patients an extra 16 months of life — a good news story so unusual, doctors have rushed to make it standard therapy, researchers said Wednesday.

“The combination includes two so-called magic bullet drugs plus standard chemotherapy. It helps patients with advanced HER-2 positive breast cancer — a hard-to-treat type that’s more often than not a death sentence.

” ‘I can’t think of something that improves survival by this much. Often, we debate over changing practice for something that extends survival by a few months, so 15.7 months that is so impressive. And really that’s exactly what I see in the clinic,’ says Dr. Jennifer Keating Litton of the University of Texas MD Anderson Cancer Center. She was not involved in the trial.”


Drug Combo Shows Promise for Treating Metastatic Melanoma

The gist: In a clinical trial, a treatment that combines the drugs ipilimumab (Yervoy) and fotemustine showed promise for treating patients with metastatic melanoma.

“The combination of ipilimumab and fotemustine demonstrated long-term efficacy in patients with metastatic melanoma, according to extended follow-up results of a phase 2 study.

“The NIBIT-M1 study evaluated the combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and fotemustine as first- or second-line treatment for patients with metastatic melanoma.

“Initial results suggested promising activity of the combination in this population, including those with or without brain metastases.

“For the current analysis, Anna Maria Di Giacomo, MD, of the department of medical oncology and immunotherapy at the University Hospital of Siena, Italy, and colleagues assessed 3-year outcomes.”


Immune System-Boosting Drug Combo to Begin Testing in Patients in New Clinical Trial

The gist: A new drug combination will be tested in patients with advanced non-small cell lung cancer (NSCLC), metastatic melanoma (MEL), colorectal cancer (CRC), ovarian cancer, or head and neck squamous cell carcinoma (SCCHN). The treatment combines the drugs varlilumab and nivolumab (Opdivo). Both drugs are immunotherapies; they activate a patient’s own immune system to fight cancer. The trial will test the safety of the combo and see how well it works.

“Celldex Therapeutics, Inc. (NASDAQ: CLDX) and Bristol Myers-Squibb (NYSE: BMY) today announced the initiation of a Phase 1/2 dose escalation and cohort expansion study examining the investigational combination of varlilumab, Celldex’s CD27 targeting investigational immune-activating antibody and Bristol-Myers Squibb’s immunotherapy Opdivo (nivolumab). The study will be conducted in adult patients with advanced non-small cell lung cancer (NSCLC), metastatic melanoma (MEL), colorectal cancer (CRC), ovarian cancer, and head and neck squamous cell carcinoma (SCCHN). Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. This study will evaluate the safety and tolerability of the combination and address the hypothesis that the combination of these two mechanisms enhance the anti-tumor activity compared to either agent alone. Celldex is responsible for conducting the study and development costs will be shared.”