“An immunotherapy combination for untreated melanoma reduced the risk of death or progression by more than half as compared with a drug currently used as a standard of care, a large randomized trial showed.
“Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months — more than four times greater than the PFS of patients who received only ipilimumab — among patients whose tumors tested positive for programmed death receptor ligand 1 (PD-L1), the target of nivolumab.
“The PFS improvement came at a price of increased toxicity, as grade 3/4 adverse events occurred twice as often with the combination as with ipilimumab monotherapy, but even patients who discontinued treatment because of side effects did better with the combination, as reported here at the American Society of Clinical Oncology meeting.”
Memorial Sloan Kettering Cancer Center | May 31, 2015
“Treating advanced melanoma patients with either a combination of the immunotherapy drugs nivolumab (Opdivo™) and ipilimumab (Yervoy™) or nivolumab alone significantly increases progression-free survival (PFS) over using ipilimumab alone, according to new findings from researchers at Memorial Sloan Kettering Cancer Center (MSK) simultaneously presented today at the American Society of Clinical Oncology (ASCO) annual meeting and published online in the New England Journal of Medicine (NEJM). Examining specific characteristics of each patient’s tumor has also given researchers clearer understanding of which patients should receive the combination.
“These initial findings from the phase III clinical trial confirm the results of the phase II trial, presented just weeks ago at the American Association of Cancer Research annual meeting in Philadelphia and published by MSK researchers online in NEJM.”
“Melanoma is predicted to result in approximately 10,000 deaths in 2015. The majority of these deaths are due to advanced stage disease that has spread or metastasized to other sites. The prognosis for patients with metastatic melanoma remains poor, with 5-year survival rates of 63 percent in patients who have metastatic disease in regional lymph nodes, and only 17 percent in patients who have metastatic disease in distant sites. Moffitt Cancer Center researchers participated in an international phase 3 study that demonstrated that a drug called ipilimumab improves the relapse-free survival of advanced stage melanoma patients rendered free of disease surgically but at high risk for relapse.
“Ipilimumab is approved for the treatment of melanoma that cannot be surgically removed or that has metastasized to different sites. Ipilimumab targets a protein called cytotoxic T lymphocytic antigen-4 (CTLA-4) that is found on a type of immune cell called a T cell. CTLA-4 keeps the immune system in check to avoid autoimmune disease by downregulating T cell activity. Tumors take advantage of CTLA-4 activity to avoid immune detection. By targeting CTLA-4, ipilimumab restimulates the immune system to target tumor cells.
“Researchers wanted to determine if ipilimumab could improve the survival of advanced-stage melanoma patients if it was given after the surgical removal of both their primary melanoma tumors and their regional lymph nodes.”
It has become routine practice to prescribe targeted drugs to patients with metastatic non-small cell lung cancer (NSCLC), whose tumors harbor molecular alterations in EGFR, ALK, and ROS. However, the majority of patients with NSCLC have no targetable mutations and lack good treatment options. Enter immunotherapy drugs, specifically ‘immune checkpoint blockade antibodies,’ to which many refer simply as ‘anti-PD-1 drugs,’ or simply ‘PD-1 drugs.’ In this post, I provide some updates on the efficacy of anti-PD-1 and anti-PD-L1 drugs in lung cancer. Continue reading…
The drugs pembrolizumab (Keytruda) and nivolumab (Opdivo) were approved by the U.S. Food and Drug Administration (FDA) in 2014 and 2015, respectively. These two competing blockbuster drugs are already changing the outlook in metastatic melanoma, previously considered to be a fatal disease. Known as ‘immune checkpoint inhibitors,’ they work by releasing ‘brakes’ on a patient’s own immune system, freeing it to attack tumors. In the wake of their success, researchers are now taking immune checkpoint inhibition in new directions. Continue reading…
“As single agents, immune checkpoints blockers nivolumab (Opdivo) and ipilimumab (Yervoy) both have demonstrated improvements in overall survival for patients with metastatic melanoma. However, when taken together, these agents have demonstrated even more impressive findings.
“Earlier reported findings from a phase I dose-escalation study demonstrated that the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab demonstrated encouraging antitumor activity. Additionally, an ongoing phase III clinical trial is assessing nivolumab or ipilimumab plus nivolumab versus ipilimumab alone in previously untreated patients with advanced melanoma (CheckMate-067; NCT01844505).
“At the 2015 AACR Annual Meeting, F. Stephen Hodi, MD, presented findings from the phase II CheckMate-069 trial, further validating the efficacy seen with the combination in earlier studies and providing hints at what could be expected in the phase III trial. In this analysis, nivolumab plus ipilimumab delayed disease progression by 60% compared with 11% in patients who were given ipilimumab alone (HR = 0.40; 95% CI, 0.23-0.68; P .001). With the combination, the ORR was 61% in BRAF wild-type (WT) patients and 52% in BRAF-positive patients.
“Included in the phase II CheckMate-069 study were 142 treatment-naïve patients with advanced melanoma with a median patient age of 65 years. Patients were randomized to receive ipilimumab at 3 mg/kg with either nivolumab at 1 mg/kg (n = 95) or placebo (n = 47) every 3 weeks for four doses. This was followed by nivolumab or placebo every 2 weeks until progression or unacceptable toxicity.”
“Talimogene laherparepvec combined with ipilimumab demonstrated tolerability at the planned doses without dose-limiting toxicities in patients with unresected, stage IIIB to IV melanoma, according to study results presented at the HemOnc Today Melanoma and Cutaneous Malignancies meeting in New York.
“The combination also demonstrated higher overall and complete response rates than typical for either agent alone, results showed.
“Talimogene laherparepvec (T-VEC, Amgen) — a systemically active oncolytic immunotherapy derived from herpes simplex virus type 1 — yielded a higher durable response (≥ 6 months) than granulocyte-macrophage colony-stimulating factor (GM-CSF) in a phase 3 melanoma trial, according to study background.
“Igor Puzanov, MD, MSCI, FACP, of the division of hematology-oncology at Vanderbilt University Medical Center, and colleagues sought to evaluate the safety and efficacy of T-VEC in combination with ipilimumab (Yervoy, Bristol-Myers Squibb).”
“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.”
“Results of an EORTC trial appearing in The Lancet Oncology show that adjuvant Ipilimumab significantly improves recurrence-free survival in patients with completely resected stage III melanoma at high risk of disease recurrence, but that this treatment was also associated with a high rate of immune-related adverse events.
“Prof Alexander M M Eggermont of the Gustave Roussy Cancer Campus and lead author of this study says, ‘Ipilimumab has already been approved as a treatment for patients with advanced melanoma. Our intention with this study was to assess Ipilimumab as an adjuvant treatment for patients with completely resected stage III melanoma at high risk of recurrence. In my experience, this marks both the first clinical trial of an approved drug with an effect on survival in advanced melanoma in the adjuvant setting, and, in this same setting, the first to study an immune checkpoint inhibitor in the adjuvant setting. Our results show that Ipilimumab is active in the adjuvant setting, but the side-effects are considerable.’
“Between 2008 and 2011, the double-blind, phase III EORTC trial 18071 accrued 951 patients who were randomly assigned to receive either Ipilimumab (475 patients) or placebo (476 patients). All patients were included in the intention-to-treat analyses. At a median follow-up of 2.74 years, the median recurrence-free survival was 26.1 months (95% confidence interval (CI) 19.3 – 39.3) in the Ipilimumab group and 17.1 months (95% CI 13.4 – 21.6) in the placebo group (hazard ratio 0.75; 95% CI 0.64 – 0.90; p = 0.0013). The 3-year recurrence-free survival rate was 46.5% (95% CI 41.5 – 51.3) in the Ipilimumab group and 34.8% (30.1 – 39.5) in the placebo group.”