Bortezomib/Lenalidomide Combination Therapy Evaluated in Relapsed/Refractory Mantle Cell Lymphoma

Editor’s note: This article describes the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to test the effectiveness of a mantle cell lymphoma treatment that combines the drugs bortezomib (Velcade) and lenalidomide (Revlimid). Specifically, the trial tested the treatment for patients whose cancer did not get better after previous treatments or whose cancer returned after treatment. The results of the clinical trial were “disappointing.” The combination treatment was less effective than either drug on its own.

“Although the majority of patients with mantle cell lymphoma respond to initial therapy, the duration of remission is typically short (1.5 to 3 years). Although bortezomib (Velcade) and lenalidomide (Revlimid) as single agents have been associated with response rates as high as 53% in patients with relapsed/refractory disease, Morrison et al reported an overall response rate of almost 40% with combination bortezomib/lenalidomide therapy in an article published in Leukemia & Lymphoma.

“The incidence of mantle cell lymphoma has increased dramatically over the past several decades. The median overall survival is 3 to 6 years with standard chemotherapy approaches, and fewer than 15% of patients are long-term survivors.

“Therefore, researchers continue to investigate newer therapeutic options for these patients. One such approach was the combination of bortezomib and lenalidomide, particularly in patients who experienced relapse from or were refractory to previous treatments. In the phase II CALGB 50501 trial, a team of investigators from the University of Minnesota, Duke University, Dana-Farber Cancer Institute, Ohio State University, Washington University, and Georgetown University attempted to evaluate the feasibility of combination treatment with bortezomib and lenalidomide in patients with relapsed or refractory mantle cell lymphoma.”


Dutch Phase II Study Supports Phase III Evaluation of Bevacizumab Plus Lomustine, but Not Bevacizumab Alone, in Recurrent Glioblastoma

The gist: Researchers conducted a clinical trial with volunteer patients to test two drugs, alone and in combination, for recurrent glioblastoma. The two drugs tested were bevacizumab (aka Avastin) and lomustine (aka CeeNU). The researchers found promising results for patients who took both bevacizumab and lomustine, and recommend that further clinical trials be conducted to continue to study the new combination treatment. The patients who participated in the study all had glioblastoma that was treated with temozolomide chemoradiotherapy, but recurred.

“Bevacizumab (Avastin) is frequently used in patients with recurrent glioblastoma, although it is unclear whether responses observed with such treatment result in improved overall survival. In the phase II Dutch BELOB study reported in The Lancet Oncology, Taal et al found that overall survival results supported phase III evaluation of the combination of bevacizumab and lomustine (CeeNU) but not bevacizumab monotherapy…

“In this open-label trial, 153 adult patients from 14 Dutch hospitals with a first recurrence of glioblastoma after temozolomide chemoradiotherapy were randomly assigned between December 2009 and November 2011 to receive oral lomustine at 110 mg/m2 once every 6 weeks, intravenous bevacizumab at 10 mg/kg once every 2 weeks, or combination treatment at the same doses. The primary endpoint outcome was overall survival at 9 months in the intent-to-treat population.

“A preplanned safety analysis after eight patients had received the combination regimen showed that three had grade 3 and two had grade 4 thrombocytopenia, with these toxicities requiring a reduction in bevacizumab dose intensity. The lomustine dose in the combination group was subsequently reduced to 90 mg/m2. In addition to the eight combination recipients getting the higher lomustine dose, 51 received bevacizumab alone, 47 received lomustine alone, and 47 received bevacizumab plus lomustine at 90 mg/m2.

“The investigators concluded, ‘The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.’ ”


Combined MEK, BRAF Inhibitors Promising in Melanoma

The gist: Researchers have conducted a clinical trial with volunteer patients to test a new melanoma treatment that combines the drugs cobimetinib and vemurafenib. The participants all had melanoma tumors with BRAFV600 mutations. People with BRAFV600 mutations often become resistant to treatment if they take a “BRAF inhibitor” like vemurafenib. The hope is that drugs like cobimetinib can be given alongside vemurafenib to circumvent resistance. The researchers found that the combination treatment was safe for these patients, and there was some promising evidence that the treatment was effective, but more follow-up will be needed.

“Combined treatment of BRAFV600-mutated melanoma with the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib was safe and tolerable, according to the results of a phase Ib study.

“Based on the promising antitumor activity seen with the combination, researchers led by Antoni Ribas, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues recommended further clinical development and testing of this combination.

“According to background information published with the study in Lancet Oncology, patients with BRAFV600-mutated metastatic melanoma often develop resistance to treatment with a BRAF inhibitor, ‘which frequently reactivates the MAPK pathway through MEK.’ Prior research has shown that sequential treatment with a MEK inhibitor after this progression does not result in meaningful antitumor activity.”


Unique Study Focuses on Combined Treatment Approach for Locally Advanced Pancreatic Cancer

The gist: With the participation of volunteer patients, researchers are testing a potential new treatment approach for locally advanced pancreatic cancer, which is difficult to treat. The treatment combines radiation, chemotherapy, and a specific drug known as a PARP inhibitor, which keeps cancer cells from being able to undo the damage caused by radiation and chemotherapy. The treatment is being tested in a clinical trial. The researchers are also interested in investigating certain molecules, or “biomarkers,” found in patients’ tumors that could be used to predict how well the new treatment will work for different patients.

“Investigators at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute are developing a novel, multistep investigational treatment for one of the most complex and difficult-to-treat forms of the disease, locally advanced pancreatic cancer.

“Locally advanced pancreatic cancer has the lowest survival rate of any solid tumor, with a cumulative five-year survival rate of only 4 percent for all stages of disease. Surgery is rarely an option for patients because tumors often involve vital blood vessels. Chemotherapy and radiotherapy given concurrently remain the mainstay treatment, yet to-date, no treatment has had a significant impact on improving outcomes.

” ‘To move the needle forward toward prolonged survival and better treatment outcomes, our research team created a combined investigational regimen for patients with locally advanced pancreatic cancer,’ said Richard Tuli, MD, PhD, a radiation oncologist in the Department of Radiation Oncology and a member of the Samuel Oschin Comprehensive Cancer Institute. ‘Coupled with this research treatment, we are also looking to identify patient biomarkers, or molecular signatures, that may provide clues to how, and why, some patients respond better than others.’ “


FDA Grants Breakthrough Status to Immunotherapy Combination for Pancreatic Cancer

The gist: A new pancreatic cancer treatment combines two drugs, known as CRS-207 and GVAX Pancreas. This combo treatment boosts a patient’s own immune system to fight cancer. It has been tested in volunteer patients in clinical trials, and has shown promising results for people with metastatic pancreatic cancer. The U.S. Food and Drug Administration (FDA) has now granted breakthrough therapy designation for CRS-207 plus GVAX Pancreas, meaning that review and approval will be accelerated so that the drug can more quickly reach patients in the U.S., outside of clinical trials.

“The FDA today granted breakthrough therapy designation to the combination of two immunotherapies — CRS-207 and GVAX Pancreas — for the treatment of metastatic pancreatic cancer, according to Aduro BioTech, the combination treatment’s manufacturer.

“The combination of GVAX, an irradiated, granulocyte-macrophage colony–stimulating factor vaccine, and CRS-207, an immunotherapy vaccine containing live-attenuated Listeria monocytogenes bacteria, induces a potent innate and T-cell–mediated immune response.

“ ‘We are extremely pleased to receive Breakthrough Therapy Designation and the high degree of FDA collaboration toward advancement of our program that it confers,’ Stephen T. Isaacs, chairman, president and CEO of Aduro, said in a press release. ‘This designation underscores the potential of our combination immunotherapy approach to make a difference in the lives of patients with pancreatic cancer, which remains a very difficult cancer to treat. We are encouraged by our phase 2 results and look forward to completing enrollment in our phase 2b ECLIPSE trial by end of 2015.’ “


GSK's Melanoma Study Stopped Early on Survival Boost

The gist: In the U.S. and Australia, oncologists are allowed to prescribe a treatment that combines the drugs Mekinist (trametinib) and Tafinlar (dabrafenib) for people with unresectable or metastatic melanoma whose tumors have a V600E or V600K mutation in the BRAF gene. European regulators would like to see more data on the benefits and risks of the treatment before approving it for European patients. The company that produces the treatment was conducting a clinical trial with volunteer patients to capture that data, but has now decided to halt the trial, which was comparing the combo treatment to the drug Zelboraf (vemurafenib). The trial found that the combo treatment has such a significant improvement on patient survival that the patients who had been taking vemurafenib for comparison should be allowed to switch to the combo treatment, and the trial ended early.

“GlaxoSmithKline has stopped a Phase III study of its combination therapy for advanced cutaneous melanoma ahead of schedule after it showed a significant survival benefit.

“The UK drug giant said an Independent Data Monitoring Committee (IDMC) has made the recommendation as it emerged patients with metastatic melanoma – carrying a BRAFV600 mutation – who took a combo of Mekinist (trametinib) and Tafinlar (dabrafenib) demonstrated an overall survival benefit compared to those taking vemarufenib.

“Safety signals were also good, remaining consistent with that for the MEK inhibitor and BRAF inhibitor observed to date, the firm said.”


Comparison of Gemcitabine Combined with Targeted Agent Therapy Versus Gemcitabine Monotherapy in the Management of Advanced Pancreatic Cancer

“This systematic evaluation compared the efficacy and safety profiles of gemcitabine combined with targeted agents (GEM + TA) versus gemcitabine administered as monotherapy or combined with placebo (GEM ± PLC) in locally advanced/metastatic pancreatic cancer (LA/MPC) patients. Based on the results from this analysis, the addition of targeted agents to a regimen of gemcitabine treatment does not bring survival benefits except 1–year survival rate to patients with LA/MPC.”

The gist: Researchers analyzed data from ten different clinical trials that tested whether the chemotherapy drug gemcitabine worked better for pancreatic cancer patients when combined with targeted therapy drugs. (Targeted therapies are drugs developed to fight tumors that have specific genetic mutations, as detected by molecular testing.) Not many benefits were found for the combination treatments, except that patients who took gemcitabine combined with targeted therapy were more likely be alive one year later than patients who only took gemcitabine.


Adding Ziv-Aflibercept to Topotecan Improves Progression-Free Survival but Increases Toxicity in Platinum-Treated Small Cell Lung Cancer

Editor’s note: A recent clinical trial with volunteer patients tested whether a treatment that combines a drug called ziv-aflibercept (Zaltrap) with the drug topotecan would be better than toptecan alone for people with small cell lung cancer (SCLC). All participating patients had previously been treated with platinum-based chemotherapy and had been treated for brain metastases. Patients were randomly assigned to be treated with either topotecan alone, or the topotecan/ziv-aflibercept combination. The researchers found that the combination treatment significantly increased the number of patients who survived three months or more without their disease worsening. However, the combo treatment had worse side effects and did not improve overall survival.

“The phase II Southwest Oncology Group (SWOG) S0802 trial reported in the Journal of Clinical Oncology by Allen et al showed that adding ziv-aflibercept (Zaltrap) to topotecan improved 3-month progression-free survival, but increased toxicity and had no effect on overall survival, in patients with platinum-treated small cell lung cancer (SCLC)…

“In the trial, 189 patients who had experienced disease progression after one line of platinum-based chemotherapy and had treated brain metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, and no recent vascular events or bleeding diatheses were randomly assigned to receive weekly topotecan at 4 mg/m2 with (n = 97) or without (n = 92) ziv-aflibercept at 6 mg/kg every 21 days. Patients were stratified as platinum-refractory (n = 55 vs 51) or platinum-sensitive (n = 42 vs 41). Progression-free survival at 3 months was the primary endpoint.”


Combining Targeted Therapy with Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

Editor’s note: Targeted therapies that fight tumors with specific genetic mutations opened up a new era in cancer treatment, but many patients become resistant to these treatments, and their cancer grows back. A new type of treatment called immunotherapy boosts a patient’s own immune system to fight cancer. Researchers are hopeful that combining targeted drugs with immunotherapy drugs could be highly effective. This article discusses the idea of combining immunotherapy with targeted drugs developed to treat melanomas with mutations in the GRAF gene. It is a scientific article, but may interest some patients and caregivers dealing with BRAF-mutant melanoma.

“Hu–Lieskovan S, et al. – In this review,the authors present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

  • “Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer.
  • “Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high.
  • “Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma.
  • “These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration.
  • “Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors.
  • “However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities.”