“A single dose of a programmed cell death protein 1 (PD-1) inhibitor before resection for melanoma may predict clinical outcomes for patients. Researchers from the Abramson Cancer Center at the University of Pennsylvania—who documented this finding in the largest cohort of patients to be treated with anti–PD-1 drugs before surgery—also showed that immune responses brought on by this therapy can peak as early as 7 days after treatment—much earlier than previous studies have shown. These findings were published by Huang et al in Nature Medicine.”
“A phase I trial found promising activity and good tolerability with the combination of pembrolizumab and a stimulant of Toll-like receptor 9 (TLR9) known as SD-101 in patients with unresectable or metastatic melanoma, particularly in those who had not received prior anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapy.
“PD-1/PD-L1 inhibition has improved outcomes in metastatic melanoma, and studies have indicated that combination therapy can increase immune responses further. “Despite the improvement in response rates with combination immunotherapy, a large unmet need remains,” wrote study authors led by Antoni Ribas, MD, PhD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center.”
“The use of steroids at baseline was associated with inferior survival outcomes in patients with advanced non-small cell lung cancer who were starting either PD-1 or PD-L1 blockade therapy, according to retrospective data presented at ASCO Annual Meeting.
” ‘Treatment with PD-1 and PD-L1 inhibitors is now standard therapy for nearly all patients with advanced non-small cell lung cancer,’ Kathryn C. Arbour, MD, a fellow at Memorial Sloan Kettering Cancer Center, said during her presentation. ‘The potential impact of steroids in patients with PD-1 or PD-L1 blockade has been an open question. Steroids are frequently used as a supportive medication in cancer care and can provide rapid relief of numerous cancer-related symptoms, including dyspnea, anorexia, pain, fatigue and symptoms associated with brain metastases. However … [physicians] routinely recognize that there can be substantial toxicities associated with long-term steroid use.’ ”
“Immunotherapies targeting PD-1 and PD-L1 have become standards-of-care across all lines of therapy for patients with metastatic non-small cell lung cancer (NSCLC) who do not have targetable driver mutations. Furthermore, the PD-L1 inhibitor durvalumab was recently approved as consolidation therapy after chemoradiation in locally advanced NSCLC. Based on the improved outcomes seen with these agents in advanced NSCLC, they are now being evaluated in early stage NSCLC where effective therapies are needed, as many patients (particularly those beyond stage IB) relapse after surgery, despite neoadjuvant/adjuvant chemotherapy.”
Immune checkpoint inhibitor drugs that target the proteins PD-1 and PD-L1 are by now well established in the treatment of non-small cell lung cancer (NSCLC). In 2015, the U.S. Food and Drug Administration (FDA) approved nivolumab (Opdivo), an anti-PD-1 drug, for treatment of patients with metastatic NSCLC who progressed or relapsed after platinum-based chemotherapy. Atezolizumab (Tecentriq), an anti-PD-L1 drug, was approved in 2016 for treatment of NSCLC patients in the same situation. In October 2016, the FDA approved Pembrolizumab (Keytruda), a competing anti-PD-1 antibody, as first-line treatment in metastatic NSCLC patients whose tumors have high expression levels of the PD-L1 protein.
With these approvals, the stage was set to move these drugs into combination treatments that may increase their efficacy. Not surprisingly, combinations with chemotherapy have now been explored, among other possibilities. Continue reading…
“Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced results from KEYNOTE-189, a pivotal Phase 3 trial evaluating KEYTRUDA®, Merck’s anti-PD-1 therapy, in combination with pemetrexed (ALIMTA®) and cisplatin or carboplatin for the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC). Findings showed that the KEYTRUDA-pemetrexed-platinum chemotherapy combination significantly improved overall survival (OS), reducing the risk of death by half compared with chemotherapy alone (HR=0.49 [95% CI, 0.38-0.64]; p<0.00001). In pre-specified exploratory analyses, an OS benefit was observed regardless of PD-L1 expression in the three PD-L1 categories that were evaluated, including: patients whose tumors were negative for PD-L1 (HR=0.59 [95% CI, 0.38-0.92]); patients whose tumors had PD-L1 tumor proportion scores (TPS) of 1-49 percent (HR=0.55 [95% CI, 0.34-0.90]); and patients who had a TPS of greater than or equal to 50 percent (HR=0.42 [95% CI, 0.26-0.68]). The addition of KEYTRUDA to pemetrexed plus platinum chemotherapy also achieved a significant improvement in progression-free survival (PFS), with a reduction in the risk of progression or death of nearly half for patients in the KEYTRUDA combination arm, compared with chemotherapy alone (HR=0.52 [95% CI, 0.43-0.64]; p<0.00001). A PFS improvement in the KEYTRUDA combination group was observed in patients whose tumors were negative for PD-L1 (HR=0.75 [95% CI, 0.53-1.05]); patients with a TPS of 1-49 percent (HR=0.55 [95% CI, 0.37-0.81]); and patients with a TPS greater than or equal to 50 percent (HR=0.36 [95% CI, 0.25-0.52]). These results are being presented today in a plenary session at the American Association for Cancer Research (AACR) Annual Meeting 2018 (Abstract #CT075), with simultaneous publication in The New England Journal of Medicine.”
“The FDA has granted a priority review to a supplemental biologics license application (sBLA) for Opdivo (nivolumab) for the treatment of patients with small cell lung cancer (SCLC) with disease progression following two or more lines of therapy, according to Bristol-Myers Squibb, the manufacturer of the PD-1 inhibitor.
“The sBLA is based on data from the phase 1/2 CheckMate-032 trial, in which single-agent Opdivo led to a median overall survival (OS) of 4.4 months and a one-year OS rate of 33 percent in patients with progressive SCLC following one or more prior lines of therapy. Under the priority review, the FDA is scheduled to make its decision by Aug. 16, 2018.”
Drugs that activate the immune system to attack cancer in a process known as immune checkpoint blockade (ICB) are a focus of intense investigation. A number of them are already approved by the U.S. Food and Drug Administration (FDA) for various cancers; namely, the anti-CTLA4 antibody ipilimumab (Yervoy), two anti-PD-1 antibodies: pembrolizumab (Keytruda) and nivolumab (Opdivo), and three anti-PD-L1 drugs: atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These ICB drugs have the potential to induce durable cancer regressions, but the majority of cancer patients just do not respond to them at all.
Biomarkers, signature molecules in the blood or other tissue, can sometimes be used to predict a patient’s response to a given treatment. But no reliable biomarkers exist for ICB, and this is a serious concern. Patients who may really benefit from ICB could be overlooked, and patients who are not likely to respond may receive useless (and very expensive) ICB treatment.
Most potential response predictors that have already been identified are not yet useful for one or all of the following reasons: they are not extensively validated, their significance is still uncertain and may differ from one cancer (or even one patient) to another, or they are technically challenging for routine use. These markers are addressed below. Continue reading…
“Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the pivotal Phase 3 KEYNOTE-042 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC, including nonsquamous or squamous histologies) met its primary endpoint of overall survival (OS). An interim analysis conducted by the independent Data Monitoring Committee (DMC) demonstrated that treatment with KEYTRUDA resulted in significantly longer OS than platinum-based chemotherapy (carboplatin plus paclitaxel or carboplatin plus pemetrexed) in patients with a PD-L1 tumor proportion score (TPS) of ≥1 percent. As part of a pre-specified analysis plan, OS was sequentially tested and was significantly improved in patients with a TPS of ≥50 percent, with a TPS of ≥20 percent and then in the entire study population with a TPS of ≥1 percent. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported monotherapy studies involving patients with advanced NSCLC.”