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American Association for Cancer Research 2018
This year’s American Association for Cancer Research (AACR) annual meeting hosted more than 22,000 oncology professionals in Chicago from April 14 to 18. Below we review sessions on immunotherapies for non–small-cell lung cancer and pancreatic cancer.
KEYNOTE-189: Randomized, Double-Blind Phase 3 Study of Pembrolizumab or Placebo Plus Pemetrexed and Platinum as First-Line Therapy for Metastatic NSCLC
- Leena Gandhi, MD, PhD, NYU Langone Health, New York, New York
In patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC), first-line pembrolizumab (Keytruda, Merck) with chemotherapy led to significantly longer long-term survival than treatment with placebo plus pemetrexed (Alimta, Lilly USA, LLC) and platinum in the KEYNOTE-189 trial.
Chemotherapy, Dr. Gandhi noted, has complex and pleiotropic effects on antitumor immune responses that both promote and impair them. Among the latter, it can negatively affect immune regulatory receptors, ligands, and cytokines, leading to reduced circulating lymphocytes and increased circulating monocytes and myeloid-derived suppressor cells. Anti-programmed death-1 (PD-1) agents, however, enhance positive immune effects of chemotherapy (e.g., antigen shedding, enhanced T-cell function, innate immunity activation), and reduce negative immune chemotherapy effects.
KEYNOTE-189 investigators enrolled 616 patients with metastatic nonsquamous NSCLC to the double-blind phase 3 study who had not received prior treatment for metastatic disease. They were randomized 2:1 to pemetrexed and a platinum-based chemotherapy agent plus either pembrolizumab or placebo. Patients were stratified based on programmed death ligand 1 (PD-L1) tumor proportion score (1% or greater than 1%), among other factors. The dual primary endpoints were overall survival (OS) and progression-free survival (PFS).
After a median follow-up of 10.5 months, patients in the test arm were 51% less likely to die than those in the control arm. Those with high PD-L1 scores were 58% less likely to die. Median OS was not reached in the test arm and was 11.3 months in the control arm. Median PFS was 8.8 months in the pembrolizumab arm and 4.9 months in the control arm.
Control arm patients who progressed were allowed to crossover to pembrolizumab. “Despite a 50% crossover rate, there was still a very clear survival benefit, suggesting that combination therapy up front may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness,” Dr. Gandhi commented.
Adverse events led to discontinuation at rates of 13.8% in the test arm and 7.9% among controls. The rates for immune-related adverse events were 22.7% in the test arm and 11.9% in the control arm. Dr. Gandhi added, “Toxicities were as expected other than an increase in the rate of acute kidney injury in the pembrolizumab arm (5.2% versus 0.5%).”
Dr. Gandhi called the results “practice changing,” noting that improvements in overall response rate, PFS, and OS were observed across all groups regardless of PD-L1 expression. The halving of mortality risk, she said, was “an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR [epidermal growth factor receptor] or ALK [anaplastic lymphoma kinase] alterations.”
Nivolumab Plus Ipilimumab Versus Platinum-Doublet Chemotherapy as First-Line Treatment for Advanced NSCLC: Initial Results From CheckMate 227
A first-line combination of nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) improved progression-free survival (PFS) in patients with advanced non–small-cell lung cancer (NSCLC) with high tumor mutational burden (TMB) in the CheckMate 227 trial. High TMB is defined as greater than 10 mutations per megabase (mut/Mb).
The standard-of-care, first-line treatment for patients with advanced NSCLC has been platinum-doublet chemotherapy or pembrolizumab (Keytruda, Merck) in patients with a tumor programmed death ligand 1 (PD-L1) expression of 50% or greater, Dr. Hellmann noted. Both nivolumab and ipilimumab are immune checkpoint inhibitors, but they have distinct and complementary mechanisms of action. The combination has demonstrated improved overall survival (OS) in phase 3 studies of melanoma and renal cell carcinoma, as well as in first-line treatment of NSCLC in CheckMate 012. In addition, efficacy was enhanced among patients with 1% or greater tumor PD-L1 expression.
CheckMate 227, a large, open-label, randomized phase 3 trial of nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy (PT-DC) versus PT-DC, included 1,759 patients with stage 4 or recurrent NSCLC who had not received prior treatment. Based on data emerging to support the importance of TMB, investigators amended the trial to include a coprimary endpoint comparing the regimens among PD-L1-selected patients with high TMB.
Of 299 patients (median age, 64 years) in the trial with high TMB, 139 received nivolumab plus ipilimumab and 160 received chemotherapy. Patients receiving the immunotherapy combination, after a mean follow-up of 11.5 months, were 42% less likely to have disease progression than those who received PT-DC. PFS nearly tripled to 43% for the combination versus 13% for chemotherapy. Median PFS was 7.2 months in the combination arm and 5.4 months in the chemotherapy arm (P = 0.0002). One-year duration of response was 68% for the combination and 25% for chemotherapy. Furthermore, the objective response rate was 45.3% for the nivolumab/ipilimumab combination and 26.9% for PT-DC.
Preliminary median OS was 23.0 months versus 16.4 months for the nivolumab/ipilimumab combination and chemotherapy, respectively; one-year OS rates were 67% and 58%, respectively. “Early analysis of overall survival is encouraging,” Dr. Hellmann commented.
The combination was well tolerated, he said, with no new safety concerns. The grade 3–4 treatment-related toxicity rate was 31% for the combination and 36% for chemotherapy. Twenty-nine patients discontinued treatment for adverse events in the combination arm compared with 13 in the chemotherapy arm. The leading reasons in the combination arm were rash, diarrhea, fatigue, decreased appetite, and nausea.
Dr. Hellmann concluded, “These results validate TMB as an important and independent biomarker to be routinely tested in treatment-naïve advanced NSCLC. They also introduce nivolumab plus ipilimumab as a new option for first-line NSCLC with TMB of 10 mut/Mb or greater.”
Associations Between Antihypertensive Medications, sRAGE, and Risk of Pancreatic Cancer: Results From the Women’s Health Initiative Study
Use of short-acting calcium-channel blocker (CCB) antihypertensive medications was associated with increased pancreatic cancer risk in a Women’s Health Initiative (WHI) study.
Five-year survival rates of about 8.2% have remained relatively unchanged over recent years for patients with pancreatic cancer, Dr. Wang said. The study of WHI data sought to determine if an observation that higher levels of circulating soluble receptor for advanced glycation end-products (sRAGE) are associated with a lower risk of pancreatic cancer would be confirmed among patients taking antihypertensive medications shown to increase sRAGE concentrations. Previous research has suggested that sRAGE has an anti-inflammatory effect on the body.
The WHI prospective cohort study included 145,551 postmenopausal women with no prevalent cancer at baseline. The authors looked at data from women taking beta blockers, diuretics, angiotensin-converting enzyme inhibitors, and CCBs, and determined hazard ratios for pancreatic cancer risk. Up to a cutoff of August 29, 2014, pancreatic cancer was found in 841 women. Among these, serum levels of sRAGE were obtained in 489 along with those of 977 noncancer controls. Among women taking CCBs, 30.8% were taking short-acting agents and 69.8% long-acting agents.
Compared with women who had used other non-CCB antihypertensive drugs, analysis showed incident pancreatic risk was 66% higher in those women who had ever used short-acting CCBs, and 107% higher in those using short-acting CCBs for three or more years. No increase in risk was detected in women using other antihypertensive medications, including long-acting CCBs. sRAGE levels were significantly lower in those women who had ever taken short-acting CCBs compared with the other women (P = 0.009). Versus women taking other antihypertensive medications, sRAGE levels were also lower (P = 0.032). The finding, Dr. Wang said, is important because chronic inflammation is “a well-recognized risk factor for pancreatic as well as many other cancers.”
Dr. Wang commented, “Our findings on short-acting CCB use and pancreatic cancer risk are novel and of potential broad medical and public health significance if confirmed. Short-acting CCBs are still prescribed to manage hypertension, which is one of the components of metabolic syndrome, and metabolic syndrome is a possible risk factor for pancreatic cancer.”
While further research will be necessary to confirm the finding and to explain it, the authors speculated that blocking calcium channels with short-acting CCBs may reduce sRAGE release and its anti-inflammatory effects.
Asked in an AACR press conference if women now taking short-acting CCBs should switch to other medications, Dr. Wang recommended consultation with a physician on a case-by-case basis. She urged further research looking at sRAGE in men and African-Americans, groups with higher pancreatic cancer risk.