Nivolumab and Ipilimumab Combination Active as First-Line Therapy for Advanced NSCLC

“Nivolumab (Opdivo) and ipilimumab (Yervoy), a chemotherapy-free regimen, showed activity as a first-line therapy for patients who have advanced non-small cell lung cancer (NSCLC), according to a preliminary clinical trial that was presented at this year’s World Conference on Lung Cancer.

“Four different regimens of nivolumab, the PD-1 inhibitor, and ipilimumab, the anti-CTLA-4 antibody, led to response rates of 13% to 39% in 148 patients with no prior exposure to systemic therapy. The combination produced deep and durable responses, with a low rate of treatment-emergent grade 3/4 adverse events (AEs) leading to discontinuation.

“ ‘Clinical activity was observed regardless of tumor PD-L1 expression,’ said lead investigator Naiyer A. Rizvi, MD, director of Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center. ‘We have preliminary evidence of greater activity in tumors that have 1% or greater PD-L1 expression. The median disease control rate [response plus stable disease] was not reached in any arm, regardless of PD-L1 expression.’ “

New Cohorts from CheckMate -012 Assess Optimal Dosing of Opdivo+Yervoy in the First-Line Treatment of Patients with Advanced Non-Small Cell Lung Cancer

“Bristol-Myers Squibb Company (NYSE:BMY) today announced updated results from the Opdivo (nivolumab)+Yervoy (ipilimumab) arms in CheckMate -012, a multi-arm Phase 1b trial evaluating Opdivo in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC). In this study, Opdivo was administered as monotherapy or as part of a combination with other agents, including Yervoy, at different doses and schedules. Results from other cohorts in CheckMate -012 have been previously-unreported. These updated results include findings from the administration of four new dosing schedules of Opdivo+Yervoy (n=148), which resulted in confirmed objective response rates (ORR) ranging from 13% to 39% depending on the administered regimen. Median duration of response was not reached in any of these arms with a median follow-up of 6.2 months to 16.6 months, and median progression-free survival (PFS) ranged from 4.9 months to 10.6 months.”

Ipilimumab Side Effects in Real World, and What to Do

“Adverse events related to immune activation with ipilimumab (Yervoy, Bristol-Myers Squibb Company) may be higher than clinical trials have previously suggested, according to a study of real-world clinical data from patients treated at Memorial Sloan Kettering Cancer Center, in New York City. The study was published online August 17 in the Journal of Clinical Oncology.

“Ipilimumab was the first of the novel immunotherapies launched for melanoma, and so far it is the only one that is an anticytotoxic T-cell lymphocyte-4 (anti-CTLA-4) antibody. It can cause immune activation and adverse reactions, such as diarrhea, rash, hepatitis, and pituitary inflammation. These reactions are often treated with steroids; severe reactions may require treatment with an anti–tumor necrosis factor alpha (anti-tNFα), such as infliximab (Remicade, Janssen Biotech, Inc).

” ‘Among our small group of physicians highly experienced with ipilimumab, we felt that 35% of the patients required systemic steroids to treat adverse events,’ commented lead author Paul Chapman, MD, a specialist in metastatic melanoma at Memorial Sloan Kettering Cancer Center.”

Video: Efficacy of PD-1/PD-L1 Inhibitors in Melanoma

“Jason J. Luke, MD, FACP, assistant professor of medicine, The University of Chicago, discusses the efficacy of PD-1/PD-L1 inhibitors in melanoma. The combination of these inhibitors, nivolumab and ipilimumab, was used to treat patients with previously untreated, unresectable or metastatic melanoma, in the Checkmate 069 study.

“Luke says PD-L1 is very complex and difficult when developing immunohistochemical assays. Since several pharmaceutical companies conduct different assays that test various things, a particular patient may be positive in one case, but not in another. For this reason, patients become very confused.

“Luke also mentions that there is no validated method across the board, so it is difficult to determine the next steps going forward.”

What Determines Whether a Melanoma Patient Will Respond to Checkpoint Blockade Drugs?

Of all cancer types, melanoma is the most investigated in terms of its potential to be treated through immune system-based approaches. More immunotherapy drugs are approved for melanoma than for any other type of cancer, and more are in development. Recent additions to the immunotherapy arsenal are the ‘anti-PD-1’ immune checkpoint blockade drugs pembrolizumab (Keytruda) and nivolumab (Opdivo). Continue reading…

ECOG-ACRIN Opens Trial of Treatment Sequencing in Advanced Melanoma

“A new phase III cancer treatment trial has opened for patient enrollment that examines two treatments that work in completely different ways yet have both been shown in previous clinical trials to be effective in treating patients with advanced melanoma, the ECOG-ACRIN Cancer Research Group announced today.

“Half of the patients in the trial will be randomly assigned to begin treatment with an investigational combination of two immunotherapy drugs, given together, that work by unleashing parts of the immune system to kill tumor cells. If the treatment stops working and the disease gets worse, patients will receive a second, different treatment of two other drugs, also given together, that work by blocking molecular pathways that drive tumor cell growth and survival.

“For the other half of the patients in the trial, the scenario will be reversed. They will be randomly assigned to begin treatment with the two molecularly targeted drugs, and if those drugs stop working and the disease gets worse, they will be treated with the investigational immunotherapy combination.

“Researchers in the ECOG-ACRIN Melanoma Committee are conducting trial EA6134 to find out which sequence of treatments provides the best outcome for patients.”

Pembrolizumab Increases Progression-Free Survival vs Chemotherapy in Ipilimumab-Refractory Advanced Melanoma

“In a randomized phase II KEYNOTE-002 trial reported in The Lancet Oncology, Ribas et al found that treatment with the anti–PD-1 antibody pembrolizumab (Keytruda) prolonged progression-free survival vs investigator-choice chemotherapy in patients with advanced melanoma progressing on ipilimumab (Yervoy) and, if BRAF V600 mutant–positive, a BRAF or MEK inhibitor.

“The open-label trial included 540 patients from 12 countries with progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant–positive, previous treatment with a BRAF or MEK inhibitor or both. Patients were randomly assigned 1:1:1 between November 2012 and November 2013 to receive pembrolizumab 2 mg/kg (n = 180) or 10 mg/kg (n = 181) every 3 weeks or investigator-choice chemotherapy (n = 179, including 42 to paclitaxel plus carboplatin, 28 to paclitaxel, 13 to carboplatin, 45 to dacarbazine, and 43 to temozolomide)…

“The investigators concluded: ‘These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.’ “

Promising New Drug Combo Offers Hope for People Battling Melanoma

“Summer inspires many people to think about their vacation plans; it makes Montaser Shaheen, MD, think about melanoma. Shaheen is a medical oncologist at the University of New Mexico Cancer Center. He and colleagues from around the country recently published a paper in the New England Journal of Medicine about a promising new treatment for melanoma. Shaheen ran the UNM Cancer Center’s portion of the clinical trial from which the paper’s data was collected. He hopes to be able to offer the melanoma treatment to more people.

“Melanoma doesn’t strike often but it can be deadly when it does: it accounts for only two percent of all skin cancers but causes most skin cancer deaths. Once it has spread from the original tumor site, melanoma is particularly difficult to treat. Chemotherapy, the standard treatment, causes the tumor to shrink in only about 10 percent of the people treated.

“The treatment Shaheen and his colleagues tested in the clinical trial caused tumors to shrink in 61 percent of the people treated. In another 22 percent, the tumors disappeared completely. ‘This is a revolutionary therapy,’ Shaheen says. ‘The efficacy is dramatic for melanoma. More than 70 percent [of people treated] benefit.’ “

Top Takeaways from ASCO: Melanoma

“The results of a phase 3 trial presented during the Plenary Session at the ASCO Annual Meeting comparing combination nivolumab-ipilimumab treatment to nivolumab alone and ipilimumab alone was one of the most pivotal presentations on melanoma at the 2015 ASCO Annual Meeting.

“A second key melanoma study examined survival of patients undergoing SLNB who did or did not receive CLND. Several physicians shared their insights on the Top Takeaways from these findings with

“Jedd D. Wolchok, MD, PhD, chief of melanoma and immunotherapeutics service and the Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, presented the results of the CheckMate 067 study during the Plenary Session that compared the use of nivolumab alone to ipilimumab alone as well as to nivolumab plus ipilimumab. Nivolumab is a programmed death 1 (PD-1) checkpoint inhibitor and ipilimumab is a cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoint inhibitor.

“ ‘The most important data that came out — which is very clear — is that there’s no doubt now in anyone’s mind that anti-PD-1 beats anti-CTLA-4. Whether its nivolumab or pembrolizumab, it’s better than giving ipilimumab front-line,’ Sanjiv S. Agarwala, MD, chief of oncology and hematology at St. Luke’s Cancer Center, professor at Temple University School of Medicine and a HemOnc Today Editorial Board member, told Pembrolizumab is another anti-PD-1 immunotherapy indicated for melanoma.”