Sunday, June 12, 2016

ASCO 2016: Final Odds and Ends.....A study looking at Digoxin plus trametinib, what oncs DON'T know about clinical trials, and NSAID's many not aide response to anti-PD1 after all!

There's this.  Hmmm.....

Digoxin plus trametinib therapy of BRAF wild type metastatic melanoma patients.  ASCO 2016. # 9527.  J Clin Oncol 34, 2016.  Frankel, Eskiocak, Froehlich, et al.

Background: A 200,000 small molecule library was screened for cytotoxicity with an in vitro 2D and 3D culture of primary human melanoma cells and other normal human cells. Several cardiac glycosides exhibited potent toxicity against melanomas. When combined with the MEK inhibitor trametinib, synergistic effects on the survival of patient-derived melanoma xenograft models were observed. Based on these observations, we conducted a phase 1B study of digoxin plus trametinib in BRAF wild-type metastatic melanoma patients. Methods: Seventeen BRAF wild-type metastatic melanoma patients who were immunotherapy refractory (n = 6) or ineligible for immunotherapy (11) were enrolled. Patients greater than 18 year old with good performance status and organ function received 8 week cycles of daily digoxin 0.25 mg oral daily adjusted for serum level of 1-2ng/mL and trametinib 2mg oral daily adjusted for side effects. Toxicities were measured by histories, exams and labs using NCI CTCAE v4.1, and responses assessed with exams and CT scans employing RECIST v1.1. Results: Seventeen patients are evaluable for toxicities. 16/17 had grade 1-2 rash, diarrhea, and/or fatigue. Four of the first seven patients discontinued therapy secondary to these side effects. After institution of early patient education and symptomatic interventions, no further patients stopped therapy early. Of sixteen assessable patients for responses, there were 4 partial remissions--PR lasting 2, 2, 4 and 8 months and six stable disease--SD lasting 2, 2, 2+, 8+ and 7 months. The disease control rate - DCR composed of PRs + SDs was 10/16 or 63% with median duration of 4+ months. The DCR in NRAS mutant melanoma patients was 4/5 or 80% compared with 5/10 or 50% in NRAS wild-type patients. Conclusions:These results compare favorably with the published activity of trametinib alone in BRAF wild-type melanoma patients where the PR and DCR rates were 10% and 36%, respectively. Trametinib alone yielded a DCR of 2/7 or 29% in NRAS mutant melanoma patients. Further patient accrual is warranted in an expansion cohort of digoxin + trametinib in BRAF wild-type and NRAS mutant melanoma patients. 

What the tub?????!!!!!!!!!!!!!!  This one makes me wonder whether to cry....or pray!  What do these people DO in medical school??!!!!!

Evaluating clinical trials: What exactly do medical oncologists know and use? A re-evaluation.  ASCO 2016.  # e18184.  J Clin Oncol 34, 2016.  Hoffman.

Background: The correct evaluation and use of clinical trial data is essential for giving our patients the best treatment. Methods: Twenty-five medical oncologists participated in a study evaluating their knowledge of recently published clinical trials (2013-15), including their knowledge of trial design, ability to evaluate the data and what was missing for better patient care. Results: This is a follow-up study to one done in 2010 (JCO, 28:15 supp (May 20 Supplement), 2010: 6152). Sixteen oncologists were in both studies. Part 1 of the study listed 12 studies involving breast cancer, non-small cell lung cancer, renal cell carcinoma, multiple myeloma or malignant melanoma. While 80% of participants knew which disease was being studied but only 60% (15/25) knew which agents were being studied. While 80% of physicians were able to tell which trials were Phase II or Phase III, only 60% (15/25) were able to explain the difference. In part 2, the name of the trial, the drug(s) used, the stage of the disease and the line(s) of therapy were provided. The oncologists were asked to identify the primary end point of the study: response rate, progression free survival or overall survival. Only 76% (19/25) were able to correctly identify the end points of at least eight studies. Over 50% of respondents (13/25) felt that progression free survival was equivalent to overall survival while 88% (22/25) of oncologists gave the study agents a better response rate (average over 60%) and efficacy rate (over 50%) than the published data. The studies were then shown. In Part 3, particpants needed to define common statistical terms including p-value, power, hazard ratio, confidence levels and how they are used in clinical decisions. Only 32% (8/25) oncologists correctly understood all these terms. Lastly, all particpants wished that authors would discuss the financial cost of the published therapy, treatment strategies, clearer toxicity information and survival data, when available, with quality of life and functional status evaluation. Conclusions: Oncologists continue to need help in evaluating clinical trial data for optimal patient care. Study summaries need to be clearer in how their findings will help our patients live better lives.

Well...maybe not so fast! 
Cyclooxygenase inhibition and response to anti-PD1/L1 in advanced melanoma.  ASCO 2016. # e21023.  J Clin Oncol 34, 2016.  Johnpulle, Pollack, Riememschneider, et al.

Background: The advent of agents blocking programmed death 1/ligand (PD-1/PD-L1) has transformed the treatment of melanoma and other malignancies. A recent study suggested that suppression of the cyclooxygenase (COX) pathway, remodels the tumor microenvironment and can act synergistically with PD-1 blockade. We hypothesized that patients (pts) with advanced melanoma treated with anti-PD-1/PD-L1, who were concomitantly receiving a non-steroidal anti-inflammatory agent (NSAID) or aspirin (ASA) may have improved clinical outcomes compared to pts not using these agents. Methods: We performed a retrospective, single-institution review of 167 pts with metastatic melanoma, who were treated with anti-PD-1/PD-L1. We characterized prognostic features (prior therapies, disease stage, lactate dehydrogenase (LDH)), NSAID/ASA use and dose, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). Results: 167 pts with advanced melanoma received either nivolumab, pembrolizumab, or atezolizumab monotherapy. Seventy-two (43%) of these pts concomitantly received NSAIDs/ASA. Baseline characteristics were similar between the two groups. An NSAID or ASA alone was used by 34 (47%) and 28 (39%) pts, respectively, while 10 (14%) pts received both agents. Of the 44 pts on NSAIDs, 36 received them as needed (prn). Of the 38 pts who were on ASA, all but 2 received less than or = to, 81mg daily. ORR in the NSAID/ASA group was 43% (31/72) vs. 34% (32/95) in pts not on either of these agents. When comparing pts on NSAID/ASA with those not on these agents, the median PFS and OS were 6.7 vs. 5.3 months and 25.7 vs. 14 months, respectively. No difference in grade 3+ irAEs was observed between groups. No pts on NSAIDs developed immune-related nephritis. Conclusions: In this small cohort of pts with melanoma treated with anti-PD1/L1 and receiving NSAIDs/ASA, there was no statistically significant improvement in outcomes compared to those not taking these medications. However, the predominance of low-dose/prn dosing in this study and the numerical trends towards improved ORR, PFS and OS suggest that this should be studied in a larger and prospective fashion using various doses.

Still hopeful that higher NSAID dosing could make things better...but not a done deal. 

Before I lay me down to sleep, this I pray melanoma souls to keep.  That docs in school will learn indeed, how to add, subtract, and think and read.  Amen - c

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