Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.
Abstract Background: In the CANTOS study, canakinumab (selective interleukin 1β inhibitor) treatment was associated with reduced incidence and mortality from non-small cell lung cancer (NSCLC) in stable post-myocardial infarction patients with elevated high-sensitivity C-reactive protein (hsCRP) levels. The CANOPY-A study was designed to investigate the therapeutic role of canakinumab in NSCLC. Methods: The CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult patients with completely resected NSCLC. Patients with American Joint Committee on Cancer/Union for International Cancer Control version 8 stage IIA-IIIA and IIIB (T >5 cm, N2), any histology, completely resected (R0) NSCLC and completion of adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiotherapy (if applicable) are eligible. Patients must not have had prior neoadjuvant chemotherapy or radiotherapy. Patients (~1500) are randomized 1:1 to receive canakinumab (200 mg) or placebo subcutaneously every 3 weeks for 18 cycles or until disease recurrence as determined by investigator, unacceptable toxicity, or treatment discontinuation at the discretion of the investigator. The primary objective is disease-free survival (DFS) per local investigator assessment. Secondary objectives are overall survival (OS), lung cancer-specific survival, safety, pharmacokinetics, immunogenicity, and patient-reported outcomes. Adult patients with stage IIA-IIIA and IIIB (T>5 cm, N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker substudy to understand how resection may impact biomarkers involved in the interleukin 1β inflammatory pathway and mutations present in blood. In the substudy, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed before and after surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamic biomarkers). For patients who will enroll in the main study, possible associations between pre- and postsurgery biomarker levels with canakinumab efficacy will be assessed (endpoint: DFS and OS by hs-CRP and other pharmacodynamic biomarkers). The CANOPY-A study is currently enrolling. As of October 19, 2020, there are 356 study locations. Citation Format: Alexander Spira, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz Kowalski, Shun Lu, Luis Paz-Ares, David R. Spigel, Michael Thomas, Sabine Turri, Vanessa Rodrik-Outmezguine, Wen Zhou, Terri Kreisl, James Chih-Hsin Yang, Edward B. Garon. Canakinumab as adjuvant therapy in patients with completely resected non-small cell lung cancer: CANOPY-A trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT255.
Abstract Background: In the CANTOS study, treatment with canakinumab (selective IL-1β inhibitor) was associated with reduced incidence and mortality of NSCLC in patients with stable post-myocardial infarction who had elevated high-sensitivity C-reactive protein (hs-CRP) levels. The results provided a rationale to investigate the therapeutic role of canakinumab in NSCLC. Methods: The phase III, multicenter, randomized, double-blind, placebo-controlled CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult patients with completely resected NSCLC. Patients with AJCC/UICC v.8 stages II-IIIA and IIIB (T>5 cm, N2), any histology, completely resected (R0) NSCLC who have completed adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiation therapy (if applicable) are eligible. Patients must not have had prior neoadjuvant chemotherapy or neoadjuvant radiotherapy. Patients (~1500) are randomized 1:1 to receive canakinumab (200 mg Q3W, SC) or placebo (Q3W, SC) for 18 cycles or until NSCLC disease recurrence as determined by investigator, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, start of a new antineoplastic therapy, death, or loss to follow-up. Randomization is stratified by AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T>5 cm, N2 disease), tumor histology (squamous vs non-squamous), and region (western Europe and North America vs eastern Asia vs rest of the world). Primary objective is disease-free survival (DFS) per local investigator assessment. Secondary objectives are overall survival (OS), lung cancer specific survival, safety, pharmacokinetics, immunogenicity, and patient reported outcomes. Adult patients with stage IIA-IIIA, IIIB (N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker sub-study to understand how resection surgery may impact biomarkers involved in the IL-1β inflammatory pathway as well as mutations present in blood. For all patients participating into the sub-study, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed at pre- and post-surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamics [PD] biomarkers). For patients who will also enroll into the main study, possible associations between pre- and post-surgery biomarker levels with canakinumab efficacy will be determined (endpoint: DFS and OS by hs-CRP and other PD biomarkers). The CANOPY-A study is currently enrolling. As of Jan 13, 2020, there are 307 study locations. Citation Format: Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz Kowalski, Shun Lu, Luis Paz-Ares, David R. Spigel, Alexander Spira, Michael Thomas, Mimi Leung, Jason Baum, Zewen Zhu, Bijoyesh Mookerjee, James Chih-Hsin Yang. CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT287.
Background: Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach. Methods: We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied. Results: There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful. Conclusion: The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.
Abstract Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Materials and Methods:This is an open-label, national multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC.The primary endpoint was the objective response rate (ORR) for evaluable patients (pts). The study was designed according to the Simon's two stage optimal design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A prospective, molecular correlative study has been being carried out on germinal DNA of study population to assess the role of BRCA mutations and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016, 83 evaluable pts (37 in the first stage, 46 in the second one) were enrolled. They received a median number of 6 cycles of treatment (range 1-24). The ORR (CR+PR) was 37.35% (90% CI: 28.47-46.93) and the clinical benefit rate (CR+PR+SD ≥ 24wks) was 48.78% (90% CI: 39.24%-58.39%). The most common grade 3-4 adverse events (> 10% of patients) were neutropenia and liver toxicity. With a median follow-up of 28.8 months, the median progression-free survival (PFS) and overall survival (OS) were 5.1 months (95% CI: 4.2-7.0) and 14.7 months (95% CI: 10.2-20.0), respectively. BRCA1/2 deleterious mutations were observed in 15 (22%) out of 68 genotyped pts. Women with BRCA1/2 mutations were associated with worse ORR, PFS and OS than those with BRCA1/2 wild-type. A panel of SNPs in genes of study drug metabolism pathways was evaluated. Among these, CYP3A4 392A >G and FGD4 2044236G>A SNPs were associated with greater liver toxicity by logistic regression analysis. Furthermore, CDA*2 79A>C, RRM1 2455 A>G, and CYP2C8 416G>A SNPs were associated with poorer overall survival by Cox proportional hazards model. Conclusions:The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify pts with high probability of response with negligible toxicity. Citation Format: Musolino A, Cavanna L, Boggiani D, Zamagni C, Frassoldati A, Caldara A, Rocca A, Gori S, Piacentini F, Berardi R, Brandes AA, Foglietta J, Villa F, Pellegrino B, Todeschini R, Tognetto M, Naldi N, Bortesi B, Boni L, Montemurro F, Ardizzoni A. Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-05.
Background Atezolizumab treatment improves survival, with manageable safety, in patients with previously treated advanced/metastatic non-small cell lung cancer. The global phase III/IV study TAIL ( NCT03285763 ) was conducted to evaluate the safety and efficacy of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer, including those not eligible for pivotal trials. Methods Patients with stage IIIB/IV non-small cell lung cancer whose disease progressed after 1–2 lines of chemotherapy were eligible for this open-label, single-arm, multicenter study, including those with severe renal impairment, an Eastern Cooperative Oncology Group performance status of 2, prior anti-programmed death 1 (PD-1) therapy, and autoimmune disease. Atezolizumab was administered intravenously (1200 mg every 3 weeks). Coprimary endpoints were treatment-related serious adverse events and immune-related adverse events. Results 619 patients enrolled and 615 received atezolizumab. At data cutoff, the median follow-up was 12.6 months (95% CI 11.9 to 13.1). Treatment-related serious adverse events occurred in 7.8% and immune-related adverse events in 8.3% of all patients and as follows, respectively, in these subgroups: renal impairment (n=78), 11.5% and 12.8%; Eastern Cooperative Oncology Group performance status of 2 (n=61), 14.8% and 8.2%; prior anti–PD-1 therapy (n=39), 5.1% and 7.7%; and autoimmune disease (n=30), 6.7% and 10.0%. No new safety signals were reported. In the overall population, the median overall survival was 11.1 months (95% CI 8.9 to 12.9), the median progression-free survival was 2.7 months (95% CI 2.1 to 2.8) and the objective response rate was 11%. Conclusions This study confirmed the benefit–risk profile of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer. These safety and efficacy outcomes may inform treatment decisions for patients generally excluded from checkpoint inhibitor trials.
Myopericytoma is a rare tumor generally arising from skin and soft tissues of extremities, trunk, head, and neck regions, rarely from visceral sites. An intrathoracic visceral localization may carry a broad differential diagnosis including primary lung, pleura and chest wall lesions, or metastatic lesions. To date, any radiological features have been recognized and diagnosis of myopericytoma with intrathoracic localization remains still challenging. Here, we describe the case of a subpleural lesion incidentally diagnosed in an older adult affected by gastric cancer. Radiological features did not allow a differential diagnosis between a benign lesion, a primary tumor, or a metastasis. After resection, the histological examination showed histopathological features congruent with the diagnosis of myopericytoma. This unusual presentation reflects the need to share clinical, radiological, and histopathological data about this uncommon but frequently misdiagnosed disease.
