carcinoma

Pembrolizumab in combination with chemotherapy improves progression free survival for women with advanced or recurrent endometrial cancer

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NRG Oncology Phase III clinical trial, NRG-GY018, evaluating pembrolizumab in combination with standard of care chemotherapy (carboplatin and paclitaxel) met its primary endpoint of progression free survival (PFS) for the treatment of patients with stage III-IV or recurrent endometrial carcinoma, regardless of mismatch repair status. A pre-specified interim analysis, conducted by an independent Data Monitoring Committee, demonstrates that pembrolizumab in combination with chemotherapy has a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in both study cohorts, mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR). The full results of this trial will be presented at an upcoming scientific conference.

NRG-GY018, a randomized, blinded, placebo-controlled study, accrued 819 women with stage III-IV or recurrent endometrial cancer. Two independent cohorts were evaluated, patients with endometrial cancers that are dMMR and patients with endometrial cancers that are pMMR. Patients were randomly assigned to receive pembrolizumab combined with carboplatin and paclitaxel (for a planned six, 3-week cycles), followed by pembrolizumab maintenance (for up to fourteen, 6 week cycles) or placebo combined with carboplatin and paclitaxel, followed by placebo maintenance.

Patients with advanced stage or recurrent endometrial cancer, the most common type of gynecologic cancer in the U.S., face a poor prognosis with limited treatment options. This is particularly notable in patients who progress after prior platinum-based adjuvant therapy with disease not amenable to curative surgery or radiation. In this study, pembrolizumab in combination with carboplatin and paclitaxel resulted in a statistically significant and clinically meaningful improvement in PFS in both the dMMR and pMMR study populations. We look forward to presenting these exciting findings at an upcoming scientific congress.”

Ramez Eskander, MD, of the University of California San Diego Moores Cancer Center and the Principal Investigator of the NRG-GY018 trial

This project was supported by the NRG Oncology Operations grant U10CA180868 and the NRG Oncology SDMC grant U10CA180822 from the National Cancer Institute (NCI), part of the National Institutes of Health and conducted by the NCI National Clinical Trials Network. Funding and support were also received from Merck & Co., Inc. through a Cooperative Research and Developmental Agreement with NCI. NRG-GY018 was conducted with funding supplemental to the CRADA from Merck in an Agreement between Merck and The GOG Foundation d/b/a NRG Oncology Philadelphia East.

Lifestyle Factors Associated With Carcinoma Incidence and Mortality

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TAKE-HOME MESSAGE

  • Incidence of and death related to carcinoma was estimated in a prospective study examining 89,571 women and 46,339 men who were classified as either low-risk or high-risk based on their lifestyle patterns. The population-attributable risk (PAR)—the proportion of cases that would not occur if individuals adopted the low-risk lifestyle—was calculated by dividing the difference in incidence and mortality rates by the rates of the high-risk group. The PARs for incidence and mortality of total carcinoma (excluding skin, brain, lymphatic, hematologic, and nonfatal prostate cancers) were 25% and 48% in women, and 33% and 44% in men, respectively. The PARs for incidence of individual cancers in women and men were 82% and 78% for lung, 29% and 20% for colon and rectum, 30% and 29% for pancreas, and 36% and 44% for bladder. For breast cancer incidence and mortality, the PARs were 4% and 12%. The PAR for incidence of fatal prostate cancer was 21%. When the low-risk group was compared with the US population, substantially higher PARs were obtained.
  • Lifestyle is an important factor in estimating cancer risk.

We’re spending all this money on advanced cancer as opposed to spending money on preventing cancer. My personal feeling is that we haven’t spent enough on that. Why should we try to cure a disease that we can prevent? Here are some pretty strong data.

Abstract

IMPORTANCE

Lifestyle factors are important for cancer development. However, a recent study has been interpreted to suggest that random mutations during stem cell divisions are the major contributor to human cancer.

OBJECTIVE

To estimate the proportion of cases and deaths of carcinoma (all cancers except skin, brain, lymphatic, hematologic, and nonfatal prostate malignancies) among whites in the United States that can be potentially prevented by lifestyle modification.

DESIGN, SETTING, AND PARTICIPANTS

This prospective cohort study analyzes cancer and lifestyle data from the Nurses’ Health Study, the Health Professionals Follow-up Study, and US national cancer statistics to evaluate associations between lifestyle and cancer incidence and mortality.

EXPOSURES

A healthy lifestyle pattern was defined as never or past smoking (pack-years <5), no or moderate alcohol drinking (≤1 drink/d for women, ≤2 drinks/d for men), BMI of at least 18.5 but lower than 27.5, and weekly aerobic physical activity of at least 75 vigorous-intensity or 150 moderate-intensity minutes. Participants meeting all 4 of these criteria made up the low-risk group; all others, the high-risk group.

MAIN OUTCOMES AND MEASURES

We calculated the population-attributable risk (PAR) by comparing incidence and mortality of total and major individual carcinomas between the low- and high-risk groups. We further assessed the PAR at the national scale by comparing the low-risk group with the US population.

RESULTS

A total of 89 571 women and 46 339 men from 2 cohorts were included in the study: 16 531 women and 11 731 men had a healthy lifestyle pattern (low-risk group), and the remaining 73 040 women and 34 608 men made up the high-risk group. Within the 2 cohorts, the PARs for incidence and mortality of total carcinoma were 25% and 48% in women, and 33% and 44% in men, respectively. For individual cancers, the respective PARs in women and men were 82% and 78% for lung, 29% and 20% for colon and rectum, 30% and 29% for pancreas, and 36% and 44% for bladder. Similar estimates were obtained for mortality. The PARs were 4% and 12% for breast cancer incidence and mortality, and 21% for fatal prostate cancer. Substantially higher PARs were obtained when the low-risk group was compared with the US population. For example, the PARs in women and men were 41% and 63% for incidence of total carcinoma, and 60% and 59% for colorectal cancer, respectively.

CONCLUSIONS AND RELEVANCE

A substantial cancer burden may be prevented through lifestyle modification. Primary prevention should remain a priority for cancer control.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.

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Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma.

METHODS: In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib.
FINDINGS: Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0.019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]).
INTERPRETATION: The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease.