Celldex Therapeutics Announces Initiation of Phase 1/2 Study of Varlilumab in Combination with Ipilimumab and CDX-1401 in Metastatic Melanoma

“Celldex Therapeutics, Inc. (CLDX) today announced the initiation of a Phase 1/2 safety pilot and expansion study examining the investigational combination of varlilumab and ipilimumab (Yervoy(R); Bristol-Myers Squibb) in patients with Stage III or IV metastatic melanoma. Varlilumab is Celldex’s fully human monoclonal antibody that targets CD27, a critical co-stimulatory molecule in the immune activation cascade. Ipilimumab, a recombinant, human monoclonal antibody that blocks CTLA-4, is FDA approved for the treatment of unresectable or metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, Celldex’s off-the-shelf antibody-based dendritic cell vaccine that targets tumors expressing the NY-ESO-1 oncoprotein.

“The three agents in this study were specifically selected because they uniquely intervene at key points of immune regulation and because Celldex has observed enhanced activity in preclinical studies when varlilumab is combined with either checkpoint inhibitors or with vaccines. In addition, this study will also build on previous clinical data from the CDX-1401 experience that suggests that CDX-1401 may predispose patients to better outcome on checkpoint inhibitors, including ipilimumab. “We believe sophisticated combination approaches centered on immunotherapy hold significant promise for the treatment of cancer and, to this end, are committed to exploring novel combinations across a broad array of mechanisms and indications. This latest trial marks the third Phase 1/2 combination study that varlilumab has entered and the first three-drug combination study,” said Thomas Davis, MD, Executive Vice President and Chief Medical Officer of Celldex Therapeutics.”


Nivolumab Beats Chemotherapy in Melanoma That Has Not Responded to Ipilimumab

“In the phase III CheckMate 037 trial reported in The Lancet Oncology, Weber et al found that treatment with the PD-1 inhibitor nivolumab (Opdivo) resulted in a significantly greater response rate vs chemotherapy as second- or later-line treatment in patients with advanced melanoma progressing after anti–CTLA-4 treatment. Findings in this trial supported the accelerated approval of nivolumab in this setting in December 2014.

“In this open-label trial, 405 patients with unresectable or metastatic melanoma from 90 sites in 14 countries were randomly assigned 2:1 between December 2010 and January 2014 to receive nivolumab (n = 272) or chemotherapy (n = 133). Patients had to have progressed after treatment with ipilimumab (Yervoy) or with ipilimumab and a BRAF inhibitor if they were BRAF V600 mutation–positive. Nivolumab was given at 3 mg/kg intravenously every 2 weeks. Dose delay but not reduction was permitted in nivolumab patients. Investigator’s choice of chemotherapy consisted of dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve = 6 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints of the trial are objective response and overall survival. In the current report of the first interim analysis, objective response was assessed after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks…

“The investigators concluded: ‘Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.’ ”


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.’ “


Ipilimumab Confers Long-Term Survival in Advanced Melanoma

“Ipilimumab was associated with long-term OS rates that plateaued after 3 years in patients with unresectable or metastatic melanoma, according to results from a pooled analysis of phase 2 and phase 3 trials.

“ ‘We observed an apparent plateau in the survival curve regardless of prior therapy, ipilimumab dose or treatment regimen,’ Dirk Schadendorf, MD, of the department of dermatology at the University Hospital Essen, Germany, and colleagues wrote. ‘In all analyses, including those with OS data from patients in the expanded access treatment protocol, the survival curves seemed to consistently begin around year 3 and extended up to 10 years in some patients.’

“Schadendorf and colleagues sought to provide an estimate of the long-term OS benefit associated with ipilimumab (Yervoy, Bristol-Myers Squibb), which was approved in 2011 for the treatment of unresectable or metastatic melanoma.

“Researchers evaluated data from 1,861 patients with advanced melanoma who were enrolled in 10 prospective and two retrospective clinical trials. Approximately two-thirds (n = 1,257) of the patients had received prior treatment.”


Keytruda Performs Much Better than Yervoy in a Phase III Trial

“Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the randomized, pivotal Phase 3 study (KEYNOTE-006) investigating KEYTRUDA® (pembrolizumab) compared to ipilimumab in the first-line treatment of patients with advanced melanoma has met its two primary endpoints of progression-free survival and overall survival. The trial will be stopped early based on the recommendation of the study’s independent Data Monitoring Committee. In KEYNOTE-006, KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in overall survival and progression-free survival compared to ipilimumab. The safety profile of KEYTRUDA in this trial was similar to the safety profile previously reported in advanced melanoma. KEYTRUDA is the first anti-PD-1 therapy to demonstrate a survival advantage compared to the standard of care for the first-line treatment of advanced melanoma. These data will be presented in the opening plenary session at the American Association of Cancer Research (AACR) Annual Meeting in Philadelphia, April 18-22.

” ‘Evidence from our clinical program for KEYTRUDA will help to define the appropriate treatment of advanced melanoma,’ said Dr. Roger Perlmutter, president, Merck Research Laboratories. ‘We greatly appreciate the efforts of our investigators and their patients in this important study, and we look forward to the presentation of overall survival data from KEYNOTE-006 at the AACR annual meeting.’ “


Nivolumab Works in Melanoma Patients for Whom Previous Treatments Did Not

“More patients with advanced melanoma who had progressed on ipilimumab with or without a BRAF inhibitor were able to achieve an objective response when treated with the PD-1 immune checkpoint inhibitor nivolumab than with alternative chemotherapy options, according to the interim analysis results of the CheckMate 037 trial published recently in Lancet Oncology.

“In fact, the rate of objective response was about threefold greater with nivolumab compared with investigator’s choice of chemotherapy; however, no difference in progression-free survival in the intention-to-treat population was noted.

“These results were the basis of the December 2014 US Food and Drug Administration accelerated approval of nivolumab for this patient population.

“ ‘Findings from our study show that nivolumab leads to clinically meaningful improvements in the proportion of patients achieving an objective response and provide a manageable safety profile when compared with chemotherapy,’ wrote Jeffrey S. Weber, MD, of Moffitt Cancer Center, Tampa, Florida, and colleagues. ‘Nivolumab can now be considered as a new treatment option for patients that have progressed after ipilimumab, or a BRAF inhibitor and ipilimumab if their melanoma is BRAF V600–mutated.’ ”


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.”


Combining Radiation and Immune Therapies Could Be a Good Option for Melanoma Treatment

“Treating metastatic melanoma with a triple threat—including radiation therapy and two immunotherapies that target the CTLA4 and PD-1 pathways—could elicit an optimal response in more patients, one that will boost the immune system’s attack on the disease, suggests a new study from a multidisciplinary team of researchers from Penn’s Abramson Cancer Center published today in Nature.

“The study, led by senior authors Andy J. Minn, MD, PhD, assistant professor of Radiation Oncology, Robert Vonderheide, MD, DPhil, the Hanna Wise Professor in Cancer Research, Amit Maity, MD, PhD, professor of Radiation Oncology, and E. John Wherry, PhD, professor of Microbiology and director of the Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania, reports for the first time on the response and resistance to radiation combined with ipilimumab (an antibody against CTLA4) in both patients and mice.

“In the phase I clinical study, known as the ‘RadVax’ trial, the team found that combining ipilimumab with radiation was safe and shrank tumors in a subset of 22 metastatic melanoma patients (18 percent). The concurrent mouse study shed light on a mechanism of resistance, known as the PD-L1 pathway, found in many patients whose cancers progressed, suggesting that an antibody against PD-L1 or its partner PD-1 is an ideal third treatment to improve response and immunity.”


Ipilimumab Is on the Way to Approval for Stage III Melanoma Treatment

“The FDA has accepted a supplemental Biologics License Application (sBLA) for ipilimumab (Yervoy) as an adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection, according to Bristol-Myers Squibb, the company developing the drug. The FDA is scheduled to make a decision on adjuvant ipilimumab by October 28, 2015.

“The acceptance of the sBLA is based on results from the phase III EORTC 18071 trial, which was presented at the 2014 ASCO Annual Meeting. This study showed a 25% improvement in recurrence-free survival (RFS) in patients treated with ipilimumab versus placebo (HR = 0.75; 95% CI, 0.64–0.90).

“ ‘This is a promising treatment—we saw substantially fewer recurrences among patients who are at high risk of relapse,’ Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France, said in an 2014 ASCO Annual Meeting press release. ‘We’ve seen many impressive new treatments for advanced melanoma in recent years. This trial with ipilimumab is the first to show we may be able to give these new drugs earlier in the course of disease, where they can do more good and potentially cure more patients.’ ”