Research Spotlight

Nadler, E., M. Pavilack, J. L. Espirito, J. Clark and A. Fernandes (2020). “Observational Study of Treatment Patterns in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer After First-Line EGFR-Tyrosine Kinase Inhibitors.” Adv Ther 37(2): 946-954.

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INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are observed in approximately 15% of patients with non-small cell lung cancer (NSCLC) in the USA. Little is known about treatment patterns in EGFR mutation-positive NSCLC following progression on or after first-line (1L) treatment with first- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib, a third-generation EGFR-TKI, is a treatment option for patients with EGFR T790M-positive NSCLC following progression on 1L EGFR-TKIs. This study analyzed real-world treatment sequencing of EGFR-TKIs, EGFR T790M testing rates, and disposition of patients with EGFR mutations after 1L EGFR-TKI post-FDA approval of osimertinib in patients with EGFR mutation-positive NSCLC. METHODS: Adult patients with stage IV NSCLC and documented EGFR mutation-positive status were identified between December 1, 2015 and May 31, 2017 from the US Oncology Network iKnowMed electronic health record (EHR). Data were abstracted from the EHR database and supplemented by chart review. RESULTS: Of 308 patients, 302 (98%) received an EGFR-TKI overall, and 246 patients (80%) received a 1L EGFR-TKI. The most common 1L EGFR-TKI was erlotinib (66%); the remaining 1L regimens were predominantly combination chemotherapies with or without an EGFR-TKI. Only 80 patients (26%) received any 2L therapy. The most common EGFR-TKIs used as 2L monotherapy in patients who received 1L EGFR-TKI were afatinib and osimertinib (n = 7 for both). Among all patients treated with 1L EGFR-TKI (n = 246), 47 (19%) were tested for EGFR T790M [16 patients (34%) were positive], 48 (20%) remained on 1L EGFR-TKI, 29 (12%) received subsequent therapy, 38 (15%) had died on or after their 1L EGFR-TKI therapy, and 131 (53%) stopped their EGFR-TKI with no recorded evidence of having received subsequent therapy at follow-up end. CONCLUSION: Following 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.

Morris, C. S., M. O. Baerlocher, S. R. Dariushnia, E. D. McLoney, N. Abi-Jaoudeh, K. Nelson, M. Cura, A. K. Abdel Aal, J. W. Mitchell, S. Madassery, S. Partovi, T. D. McClure, A. L. Tam and S. Patel (2020). “Society of Interventional Radiology Position Statement on the Role of Percutaneous Ablation in Renal Cell Carcinoma: Endorsed by the Canadian Association for Interventional Radiology and the Society of Interventional Oncology.” J Vasc Interv Radiol 31(2): 189-194.e183.

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In accordance with multidisciplinary and society guidelines, Society of Interventional Radiology (SIR) considers thermal PA to be an acceptable treatment option for stage T1a renal cell carcinoma (RCC) neoplasms (≤4 cm in diameter) in carefully selected patients and can be offered over active surveillance. Perccutaneous ablation (PA) may also have a potential beneficial role to play in the treatment of T1b tumors as well as oligometastatic RCC. However, future research in this area is warranted before strong recommendations can be made. SIR also recommends further investigation directly comparing ablation modalities, as well as comparing PA to surgical therapies with RCTs or other prospective study designs with adherence to standardized reporting of trials. RECOMMENDATIONS: 1. In patients with small renal tumors (stage T1a), percutaneous thermal ablation is a safe and effective treatment with fewer complications than nephrectomy and acceptable long-term oncological and survival outcomes. (Level of Evidence: C; Strength of Recommendation: Moderate). 2. In selected patients with suspected T1a RCC, percutaneous thermal ablation should be offered over active surveillance. (Level of Evidence: C; Strength of Recommendation: Moderate). 3. Percutaneous biopsy of small renal masses is recommended before or during PA, whenever possible. (Level of Evidence C; Strength of Recommendation: Moderate). 4. In high-risk patients with T1b RCC who are not surgical candidates, percutaneous thermal ablation may be an appropriate treatment option; however, further research in this area is required. (Level of Evidence D; Strength of Recommendation: Weak). 5. PA of oligometastatic RCC may be appropriate in patients with surgically resectable primary RCC who are not candidates for metastasectomy. (Level of Evidence D; Strength of Recommendation: Weak). 6. Radiofrequency ablation, cryoablation, and MW ablation are all appropriate modalities for thermal ablation, and method of ablation should be left to the discretion of the operating physician. (Level of Evidence: D; Strength of Recommendation: Weak). (Excerpt from text, p. 192-193; no abstract available.)

McMurray, J. J. V., A. M. Jackson, C. S. P. Lam, M. M. Redfield, I. S. Anand, J. Ge, M. P. Lefkowitz, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, A. R. Rizkala, S. V. Sabarwal, A. M. Shah, S. J. Shah, V. C. Shi, D. J. van Veldhuisen, F. Zannad, M. R. Zile, M. Cikes, E. Goncalvesova, T. Katova, A. Kosztin, M. Lelonek, N. Sweitzer, O. Vardeny, B. Claggett, P. S. Jhund and S. D. Solomon (2020). “Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.” Circulation 141(5): 338-351.

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BACKGROUND: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. METHODS: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. RESULTS: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. CONCLUSIONS: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Maurer, M. S. and M. Packer (2020). “Impaired systemic venous capacitance: the neglected mechanism in patients with heart failure and a preserved ejection fraction?” Eur J Heart Fail Jan 16. [Epub ahead of print].

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The cardinal feature of HFpEF is an increase in LV filling pressure in the face of a LV ejection fraction that is not meaningfully reduced. In patients with a hypertrophic or infiltrative cardiomyopathy, the increase in LV filling pressures is primarily driven by an upward and leftward shift of the LV end‐diastolic pressure–volume relation. In contrast, in inflammatory‐metabolic HFpEF, LV end‐diastolic volumes (when indexed for age and sex) are not reduced; there is little evidence for a consistent shift in the end‐diastolic pressure–volume relation; and LV filling pressures are increased because the left ventricle is overfilled. The mechanisms leading to the increase in LV filling pressures and central blood volume in HFpEF have not been fully elucidated. Sodium retention and plasma volume expansion often play a role and can be ameliorated with diuretics. However, abnormalities of systemic venous capacitance likely play a critical (and unappreciated) role in driving an increase in central blood volume in HFpEF, explaining why diuretics are typically insufficient to ameliorate the increase in LV filling pressures. Mineralocorticoid receptor antagonists and neprilysin inhibitors may exert favourable effects on systemic venous capacitance, thus contributing to their action to lower LV filling pressures and wall stress in HFpEF. Additionally, treatments that block sympathetically‐mediated vasoconstriction of the splanchnic venous bed may also alleviate pulmonary congestion in patients with decompensated heart failure, a finding that also might be applicable to patients with HFpEF. Admittedly, the assessment of the effects of drugs on systemic venous capacitance is challenging, since it is extremely difficult to reliably evaluate the function of the splanchnic venous system in the clinical setting. Despite its potential importance, little work has been dedicated to understanding the role of changes in the functions of the systemic venous system in HFpEF. In the 1970s, the systemic venous system was the focus of considerable work in understanding the pathogenesis of HFrEF. It is time that we understood that, as in the case of HFrEF, HFpEF is a disorder of the entire circulation, inclusive of the peripheral circulation, and not simply a disorder of LV structure and function. (Excerpt from text, p. 3; no abstract available.)

Lebwohl, M. G., C. L. Leonardi, N. N. Mehta, A. B. Gottlieb, A. M. Mendelsohn, J. Parno, S. J. Rozzo and A. Menter (2020). “Tildrakizumab efficacy and safety are not altered by metabolic syndrome status in patients with psoriasis: Post hoc analysis of 2 phase 3 randomized controlled studies (reSURFACE 1 and reSURFACE 2).” J Am Acad Dermatol 82(2): 519-522.

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This post hoc analysis evaluated tildrakizumab efficacy, durability of response, and safety in patients with moderate to severe chronic psoriasis with vs without metabolic syndrome (MetS) using pooled data from 2 phase 3, double-blind, randomized, placebo-controlled studies, reSURFACE 1 and reSURFACE 2. Patients with vs without MetS had higher prevalence of pre-existing cardiovascular disease and diabetes and higher median baseline weight and body mass index. Six patients (4.1%) with MetS (n = 5 tildrakizumab 100 mg; n = 1 tildrakizumab 200 mg) and 25 patients (4.5%) without MetS (n = 12 tildrakizumab 100 mg; n = 13 tildrakizumab 200 mg) did not complete the study. Percentages of patients with ≥75% improvement on the Psoriasis Area and Severity Index (PASI 75 responders) at weeks 12 and 52 were comparable between patients with and without MetS for both tildrakizumab doses. Percentages of PASI 90 and PASI 100 responders through week 52 were similar regardless of MetS status for both tildrakizumab doses. Tildrakizumab efficacy through week 52 was maintained comparably in patients with and without MetS. Reductions in mean PASI from baseline were similar regardless of MetS status for both tildrakizumab doses. Percentages of patients with ≥1 serious adverse event (AE) and those with ≥1 serious infection were similar in patients with and without MetS. The most common serious AEs for patients with vs without MetS were gastrointestinal and cardiac disorders after tildrakizumab 100 mg and injury/procedural complications and nervous system disorders after tildrakizumab 200 mg. Fatal AEs occurred in 2 patients with MetS (both tildrakizumab 100 mg) and 2 patients without MetS (1 per tildrakizumab dose). Infection was the most commonly reported treatment-emergent AE. Incidence was similar in patients with and without MetS receiving tildrakizumab 100 mg and numerically higher in patients with and without MetS receiving tildrakizumab 200 mg. The incidence of cardiovascular events did not vary by MetS status, and there were no reports of diabetes worsening after treatment. Weight increases through week 28 were limited (∼1 kg on average) in patients with and without MetS across both tildrakizumab doses. Exposure-adjusted rates of tier 1 treatment-emergent AEs were comparable across doses regardless of MetS status. These post hoc analyses were not powered for statistical analyses based on MetS status, and populations were not matched for smoking history and other potential cofactors. Although abdominal obesity is more highly correlated with MetS risk factors relative to body mass index, 2 the latter was used because abdominal obesity data were not collected. Sample sizes for patients with MetS were relatively small. Further evaluation of the effect of weight only on treatment efficacy and safety was not feasible because only 25 patients with a body mass index of <30 kg/m 2 met ≥3 criteria for MetS. Despite limitations, these results suggest efficacy, safety, and drug survival of tildrakizumab are comparable in patients with psoriasis regardless of MetS status. (Excerpts from text, p. 519-521; no abstract available; full text contains links to supplemental data.)