Charles L. Cowey M.D.

Cowey, C.L., Liu, F.X., Kim, R., Boyd, M., Fulcher, N., Krulewicz, S., Kasturi, V. and Bhanegaonkar, A. (2021). “Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel.” Future Oncol 17(18): 2339-2350.

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Aim: To assess clinical outcomes in patients with locally advanced (la) or metastatic (m) Merkel cell carcinoma (MCC) initiating first-line (1L) avelumab in a USA community oncology setting. Materials & methods: Adults with laMCC or mMCC initiating 1L avelumab were identified from The US Oncology Network electronic health record database and chart review. Results: Median overall survival and progression-free survival were not reached in laMCC (n = 9) vs 20.2 and 10.0 months in mMCC (n = 19); response rates were similar (66.7% vs 63.2%). Conclusion: This is the first study to show clinical benefit in patients with laMCC receiving 1L avelumab in a US real-world setting. Response rates in patients with mMCC were consistent with pivotal trials. Lay abstract Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Because MCC progresses quickly, many patients have a poor prognosis. Avelumab is a type of drug that helps the patient’s immune system to fight cancer. Avelumab was the first such drug approved by the US FDA for treating metastatic MCC based on the results of the JAVELIN Merkel 200 clinical trial. In SPEAR-Merkel, we studied how MCC patients with locally advanced as well as metastatic disease responded when they were treated with first-line avelumab in a real-world setting. These patients were from oncology practices in communities throughout the USA. Overall response rates in SPEAR-Merkel were comparable between patients with locally advanced and metastatic MCC.

Pham, V., Nguyen, L., Hedin, R.J., Shaver, C., Hammonds, K.A.P. and Culp, W.C., Jr. (2021). “Coronavirus Disease 2019: Anesthesia Machine Circuit Pressure During Use as an Improvised Intensive Care Unit Ventilator.” Anesth Analg 132(5): 1191-1198.

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BACKGROUND: Use of anesthesia machines as improvised intensive care unit (ICU) ventilators may occur in locations where waste anesthesia gas suction (WAGS) is unavailable. Anecdotal reports suggest as much as 18 cm H2O positive end-expiratory pressure (PEEP) being inadvertently applied under these circumstances, accompanied by inaccurate pressure readings by the anesthesia machine. We hypothesized that resistance within closed anesthesia gas scavenging systems (AGSS) disconnected from WAGS may inadvertently increase circuit pressures. METHODS: An anesthesia machine was connected to an anesthesia breathing circuit, a reference manometer, and a standard bag reservoir to simulate a lung. Ventilation was initiated as follows: volume control, tidal volume (TV) 500 mL, respiratory rate 12, ratio of inspiration to expiration times (I:E) 1:1.9, fraction of inspired oxygen (Fio2) 1.0, fresh gas flow (FGF) rate 2.0 liters per minute (LPM), and PEEP 0 cm H2O. After engaging the ventilator, PEEP and peak inspiratory pressure (PIP) were measured by the reference manometer and the anesthesia machine display simultaneously. The process was repeated using prescribed PEEP levels of 5, 10, 15, and 20 cm H2O. Measurements were repeated with the WAGS disconnected and then were performed again at FGF of 4, 6, 8, 10, and 15 LPM. This process was completed on 3 anesthesia machines: Dräger Perseus A500, Dräger Apollo, and the GE Avance CS2. Simple linear regression was used to assess differences. RESULTS: Utilizing nonparametric Bland-Altman analysis, the reference and machine manometer measurements of PIP demonstrated median differences of -0.40 cm H2O (95% limits of agreement [LOA], -1.00 to 0.55) for the Dräger Apollo, -0.40 cm H2O (95% LOA, -1.10 to 0.41) for the Dräger Perseus, and 1.70 cm H2O (95% LOA, 0.80-3.00) for the GE Avance CS2. At FGF 2 LPM and PEEP 0 cm H2O with the WAGS disconnected, the Dräger Apollo had a difference in PEEP of 0.02 cm H2O (95% confidence interval [CI], -0.04 to 0.08; P = .53); the Dräger Perseus A500, <0.0001 cm H2O (95% CI, -0.11 to 0.11; P = 1.00); and the GE Avance CS2, 8.62 cm H2O (95% CI, 8.55-8.69; P < .0001). After removing the hose connected to the AGSS and the visual indicator bag on the GE Avance CS2, the PEEP difference was 0.12 cm H2O (95% CI, 0.059-0.181; P = .0002). CONCLUSIONS: Displayed airway pressure measurements are clinically accurate in the setting of disconnected WAGS. The Dräger Perseus A500 and Apollo with open scavenging systems do not deliver inadvertent continuous positive airway pressure (CPAP) with WAGS disconnected, but the GE Avance CS2 with a closed AGSS does. This increase in airway pressure can be mitigated by the manufacturer's recommended alterations. Anesthesiologists should be aware of the potential clinically important increases in pressure that may be inadvertently delivered on some anesthesia machines, should the WAGS not be properly connected.

LoRusso, P.M., Sekulic, A., Sosman, J.A., Liang, W.S., Carpten, J., Craig, D.W., Solit, D.B., Bryce, A.H., Kiefer, J.A., Aldrich, J., Nasser, S., Halperin, R., Byron, S.A., Pilat, M.J., Boerner, S.A., Durecki, D., Hendricks, W.P.D., Enriquez, D., Izatt, T., Keats, J., Legendre, C., Markovic, S.N., Weise, A., Naveed, F., Schmidt, J., Basu, G.D., Sekar, S., Adkins, J., Tassone, E., Sivaprakasam, K., Zismann, V., Calvert, V.S., Petricoin, E.F., Fecher, L.A., Lao, C., Eder, J.P., Vogelzang, N.J., Perlmutter, J., Gorman, M., Manica, B., Fox, L., Schork, N., Zelterman, D., DeVeaux, M., Joseph, R.W., Cowey, C.L. and Trent, J.M. (2021). “Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.” PLoS One 16(4): e0248097.

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Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.

Cowey, C.L., Scherrer, E., Boyd, M., Aguilar, K.M., Beeks, A. and Krepler, C. (2021). “Pembrolizumab Utilization and Clinical Outcomes Among Patients With Advanced Melanoma in the US Community Oncology Setting: An Updated Analysis.” J Immunother Mar 17. [Epub ahead of print].

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Favorable outcomes have been observed with pembrolizumab among patients with advanced melanoma in clinical trials; however, limited evidence exists on the long-term efficacy in the real-world setting. This was an updated, retrospective observational study of adult patients with advanced (unresectable or metastatic) melanoma who initiated pembrolizumab (in any line of therapy) between January 1, 2014, and December 31, 2016, in The US Oncology Network and were followed through December 31, 2019 [median follow-up: 18.2 mo (range: 0.1-63.1 mo)]. Study data were sourced from electronic health records. Patient demographic, clinical, and treatment characteristics were assessed descriptively. Kaplan-Meier methods were used to evaluate overall survival (OS), time to treatment discontinuation, time to next treatment, physician-assessed time to tumor progression, and physician-assessed progression-free survival (rwPFS). Independent risk factors for OS and rwPFS were identified with multivariable Cox regression models. Of the 303 study-eligible patients, 119, 131, and 53 received pembrolizumab in the first-line, second-line, and third-line or beyond setting, respectively. Median OS across the study population was 29.3 months [95% confidence interval (CI): 20.3-49.7] and was the longest among those who received first-line pembrolizumab [42.8 mo (95% CI: 24.8-not reached)]. Median rwPFS across the study population was 5.1 months (95% CI: 4.0-7.6) and 8.1 months (95% CI: 4.6-14.4) among those who received first-line pembrolizumab. In the multivariable analyses for OS, increased age, worsening performance status, elevated lactate dehydrogenase, brain metastases, and pembrolizumab use in later lines were significantly associated a worse prognosis.

Cowey, C.L., Liu, F.X., Kim, R., Boyd, M., Fulcher, N., Krulewicz, S., Kasturi, V. and Bhanegaonkar, A. (2021). “Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel.” Future Oncol Mar 12. [Epub ahead of print].

Full text of this article.

Aim: To assess clinical outcomes in patients with locally advanced (la) or metastatic (m) Merkel cell carcinoma (MCC) initiating first-line (1L) avelumab in a USA community oncology setting. Materials & methods: Adults with laMCC or mMCC initiating 1L avelumab were identified from The US Oncology Network electronic health record database and chart review. Results: Median overall survival and progression-free survival were not reached in laMCC (n = 9) vs 20.2 and 10.0 months in mMCC (n = 19); response rates were similar (66.7% vs 63.2%). Conclusion: This is the first study to show clinical benefit in patients with laMCC receiving 1L avelumab in a US real-world setting. Response rates in patients with mMCC were consistent with pivotal trials.