Background

EAST-LC (JapicCTI-101155) was a randomized phase III trial conducted in East Asia that demonstrated the non-inferiority of oral S-1 to docetaxel (DTX) in previously treated patients (pts) with advanced non-small cell lung cancer (NSCLC) [H. Nokihara and S. Lu, Annals of Oncology (2017)]. Here, we report the results of elderly pts (EP) subgroup.

Methods

The key inclusion criteria were as follows: age ≥18 years; an ECOG performance status (PS) of 0 to 2; and ≤ 2 previous chemotherapy regimens, including a platinum-based one [if pts had received gefitinib or erlotinib, then three regimens were allowed]. Eligible pts were randomized 1:1 to receive S-1 (80-120 mg/day; days 1-28 in a 6-week cycle) or DTX (60 mg/m² in Japan, 75 mg/m² at the other sites; day 1 in a 3-week cycle). EP were defined as aged ≥ 70 years and evaluated the efficacy, safety and quality of life (QOL), using the EORTC QLQ-C30. The primary endpoint of the trial was overall survival (OS).

Results

A total of 190 EP were subjects to this analysis (90 in the S-1 arm and 100 in the DTX arm). There were no significant differences between both arms in terms of baseline characteristics, except for ECOG PS (P = 0.0132). Disease progression was the most common reason for treatment discontinuation in both arms (63.6% and 51.5% in S-1 and DTX arms, respectively), followed by adverse events (AEs) (13.6% and 24.2%). The median OS were 14.7 months versus 12.1 months; HR 0.76 (95% CI: 0.54–1.07) for S-1 versus DTX, respectively. The most common treatment-related AEs were decreased appetite (61.4%), diarrhea (47.7%) and pigmentation (39.8%) in the S-1 arm, and neutropenia (66.7%), alopecia (49.5%) and leukocytopenia (47.5%) in the DTX arm, respectively. The adjusted mean score difference (S-1 – DTX) of EORTC QLQ-C30 global health status until 48 weeks was 7.41 (95% CI: 0.37–14.46).

Conclusions

S-1 was showed the comparable efficacy, safety and QOL to DTX in previously treated EP with advanced NSCLC, and the results were consistent to those of the overall EAST-LC population. These results could support the usage of S-1 as a viable treatment option for EP.

Clinical trial identification

JapicCTI-101155.

Legal entity responsible for the study

Taiho Pharmaceutical.

Funding

Taiho Pharmaceutical.

Disclosure

J.C-H. Yang: Honoraria (institution), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Roche/Genentech; Honoraria (institution), Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy: MSD Oncology; Honoraria (institution), Advisory/Consultancy: Merck Serono; Honoraria (institution), Advisory/Consultancy: Celgene; Honoraria (institution), Advisory/Consultancy: Bayer; Honoraria (institution), Advisory/Consultancy: Pfizer; Honoraria (institution), Advisory/Consultancy: Ono Pharmaceutical; Honoraria (institution), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (institution), Advisory/Consultancy: Yuhan; Honoraria (institution), Advisory/Consultancy: Hansoh; Honoraria (institution), Advisory/Consultancy: Blueprint Medicines; Honoraria (institution), Advisory/Consultancy: Daiichi Sankyo; Honoraria (institution), Advisory/Consultancy: Amgen; Honoraria (institution), Advisory/Consultancy: Takeda Oncology; Honoraria (institution), Advisory/Consultancy: Incyte. T.S.K. Mok: Honoraria (self): Taiho; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Officer/Board of Directors: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Clovis Oncology; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): SFJ Pharmaceuticals; Shareholder/Stockholder/Stock options, Officer/Board of Directors: Sanomics; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Takeda; Advisory/Consultancy, Officer/Board of Directors: Chi-Med; Honoraria (self), Advisory/Consultancy: ACEA Biosciences; Honoraria (self), Advisory/Consultancy: Janssen; Honoraria (self), Advisory/Consultancy: Merck Serono; Research grant/Funding (institution): XCovery; Honoraria (self), Advisory/Consultancy: Ignyta; Honoraria (self), Advisory/Consultancy: ertex Pharmaceuticals. S. Lu: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Hutchison; Research grant/Funding (self): BMS; Research grant/Funding (self): Heng Rui ; Research grant/Funding (self): Beigene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self): Hansoh; Honoraria (self): Hengrui Therapeutics; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: MediPharma; Advisory/Consultancy: Simcere; Advisory/Consultancy: ZaiLab; Advisory/Consultancy: GenomiCare; Advisory/Consultancy: Yuhan Corporation; Advisory/Consultancy: PrIME Oncology. K. Nakagawa: Honoraria (self), Research grant/Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant/Funding (institution): Astellas Pharma Inc.; Honoraria (self), Research grant/Funding (institution): MSD K.K.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Novartis Pharma K.K.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer Japan Inc.; Honoraria (self), Advisory/Consultancy: Kyorin Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Bayer Yakuhin, Ltd.; Honoraria (self): Nichi-Iko Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly Japan K.K.; Research grant/Funding (institution): Kyowa Hakko Kirin Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo Co., Ltd.; Honoraria (self): Nippon Kayaku Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd.; Honoraria (self), Research grant/Funding (institution): AbbVie Inc. N. Yamamoto: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Ono Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Daiichi Sankyo Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda Pharmaceutical Co. Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Boehringer-Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Pfizer Inc.; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self): Nippon Kayaku; Honoraria (self), Advisory/Consultancy: Merck Biopharma Co., Ltd; Research grant/Funding (self), Research grant/Funding (institution): Astellas Pharma Inc; Research grant/Funding (self), Research grant/Funding (institution): Tsumura & Co.; Research grant/Funding (self), Research grant/Funding (institution): AbbVie GK.; Research grant/Funding (institution): Amgen Inc; Research grant/Funding (institution): Kyorin Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Eisai Co., Ltd. L. Zhang: Research grant/Funding (institution): Roche; Research grant/Funding (institution): BMS; Honoraria (self): MSD; Research grant/Funding (institution): Henrui Pharm. R.A. Soo: Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self), Research grant/Funding (self): Boehringer Ingelheim; Honoraria (self): Amgen; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Taiho; Honoraria (self): Takeda; Honoraria (self): Yuhan. S. Morita: Honoraria (self): AstraZeneca K.K.; Honoraria (self): Bristol-Myers Squibb Company; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self): Eli Lilly Japan K.K; Honoraria (self): MSD K.K.; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self): Ono Pharmaceutical Co. Ltd.; Honoraria (self): Pfizer Japan Inc.; Honoraria (self): Taiho Pharmaceutical Co. Ltd. T. Tamura: Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self): Chugai; Honoraria (self): Eli Lilly; Honoraria (self): Nippon Kayaku; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Ono; Honoraria (self): MSD; Honoraria (self): Cmic Shift-Zero. All other authors have declared no conflicts of interest.

Background

Due to the increasing number of trials with immune checkpoint inhibitors (ICI) in first line therapy of non–small cell lung cancer (NSCLC), we performed a systematic review and meta-analyses about the differences between anti PD-1 and PD-L1 in naïve-treatment NSCLC patients through adjusted indirect analysis to minimize the potential bias regarding overall survival (OS), progression free survival (PFS), overall response rate (ORR) and grade 3-5 adverse event (AE).

Methods

We included studies published until May 30 2020. Applicable terms, such as “lung cancer AND first line AND immunotherapy OR PD-1 OR PL-D1,” were used. Primary outcomes were OS, PFS, ORR and grade 3-5 AE. We used the random-effects model to generate pooled estimates for proportions. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies with the random effect model. As there are no studies with direct analyzes between PD-1 and PD-L1 treatments, we carry out indirect data analyzes using the Excel spreadsheet. All analyses were performed by REVMAN version 5.0.

Results

Thirteen studies met our eligibility criteria, including 7673 patients (4077 cases in experimental and 3596 cases in control group). Six trials investigated ICI in monotherapy (four of them with anti-PD-1 and three with anti-PD-L1) and seven trials investigated ICI-chemotherapy combination; three used Pembrolizumabe and four used Atezolizumabe. Related to prognosis, in the ICI-chemotherapy combination group, anti-PD-1 were associated with better OS (P=0.02) and PFS (P=0.03) compared to anti-PD-L1. In monotherapy, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 for OS and PFS. Regarding ORR and toxicity, in the ICI-chemotherapy combination group, anti-PD-1 was associated with a trand better ORR (p=0.12) and less frequent grade 3-5 AE compared to the use of anti-PD-L1. In monotherapy, no statistical difference between the use of anti-PD-1 and anti-PD-L1 was observed.

Conclusions

Our study suggests that the combination of anti-PD-1 and chemotherapy is superior to anti-PD-L1 + chemotherapy in 1^st line NSCLC therapy; in monotherapy both strategies appear to be similar.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Palonosetron (PALO) is a second generation 5HT-3 receptor antagonist recommended as a preferred drug for high-emetogenic chemotherapies. PALO 0.25 mg has been reported to be as effective as 0.75 mg with less adverse events, such as constipation, when used alone or in combination with dexamethasone (DEX). The efficacy and safety of PALO 0.25 mg compared to 0.75 mg in combination with aprepitant (APR) plus DEX in patients (pts) with esophageal cancer remain unclear.

Methods

We retrospectively evaluated the efficacy and safety of PALO 0.25 mg versus 0.75 mg in combination with APR plus DEX in pts with localized or metastatic esophageal cancer who received cisplatin (CDDP)-containing chemotherapy between Nov. 2015 and Mar. 2017 at our institution. Complete response was defined as no emetic episodes and no rescue medication use.

Results

This study enrolled 58 and 55 pts who received PALO 0.25 mg and 0.75 mg. The baseline characteristics were similar between both groups. Sixteen (28%) and 24 (44%) pts received triplet regimen (docetaxel, CDDP and 5-fluorouracil), respectively. The complete response rates were 72% for 0.25 mg and 62% for 0.75 mg, with no significant difference (odds ratio [OR] = 0.62, p = 0.23). Percentages of no nausea was also similar with 40% and 33%, respectively (OR = 0.74, p = 0.44). Grade 2-3 constipation and any grade of aspartate aminotransferase increase were more frequently observed in 0.75 mg group (38% vs. 58%, p < 0.05; 7% vs. 22%, p < 0.05). In univariate and multivariate analyses, no association between baseline characteristics, including dose of PALO, and complete response rate was observed. Meanwhile, PALO 0.75 mg, older age, localized disease, and tobacco consumption were significantly associated with grade 2 or more constipation (OR = 0.28, p < 0.01; OR = 0.28, p < 0.01; OR = 3.09, p < 0.05; OR = 0.27, p < 0.05).

Conclusions

PALO 0.25 mg in combination with APR plus DEX may contributed to the decrease in constipation in pts with esophageal cancer who received CDDP-containing chemotherapy without compromising the anti-emetic effect compared to 0.75 mg.

Legal entity responsible for the study

National Cancer Center.

Funding

Has not received any funding.

Disclosure

Y. Nakamura: Research grant/Funding (institution): Taiho Pharmaceutical. H. Taniguchi: Honoraria (self): Bayer; Honoraria (self): Sanofi; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self): Chugai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Lilly Japan; Honoraria (self): Merck Serono; Honoraria (self): Yakult Honsha; Honoraria (self): MBL; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (self): Mitsubishi Tanabe Pharma; Honoraria (self): Nippon Kayaku; Research grant/Funding (institution): Sumitomo-Dainippon Pharma; Research grant/Funding (institution): Array BioPharma; Research grant/Funding (institution): MSD Oncology; Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): Sysmex. T. Kojima: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Advisory/Consultancy, Research grant/Funding (institution): MSD; Research grant/Funding (institution): Astellas Amgen BioPharma; Research grant/Funding (institution): Chugaiseiyaku; Research grant/Funding (institution): Parexel; Research grant/Funding (institution): Shionogi; Advisory/Consultancy: Bristol-Myers Squibb Company; Advisory/Consultancy: Merck Biopharma; Honoraria (self): Oncolys BioPharma. T. Yoshino: Research grant/Funding (institution): Novartis Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Sumitomo Dainippon Pharma; Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Parexel International; Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): GlaxoSmithKline. All other authors have declared no conflicts of interest.

Background

According to the SEER cancer statistics from 2013 to 2017, 43.4% of all newly breast cancers are diagnosed in women aged 65 years and older. Despite a relatively high prevalence of older adults with newly diagnosed breast cancer, elderly patients are often under-represented in the pivotal neoadjuvant trials. Recommendations for treatment with neoadjuvant chemotherapy (NAC) are based on subgroup analyses and extrapolation of study results from younger patients.

Methods

This retrospective observational study collected data from the Joint Breast Cancer Registry (JBCR) on older adults aged ≥ 65 years treated with NAC for breast cancer at the National Cancer Centre Singapore from October 2014 to October 2019. Patients in the JBCR had detailed clinical and pathological information including hormone receptor (HR), HER2 status, type of NAC. Outcomes and adverse events were retrieved from electronic medical records. Pathological complete response(pCR) was defined by the absence of residual disease in the breast and lymph nodes following NAC.

Results

Of 353 patients who underwent NAC, 66(18%) patients were older adults aged ≥ 65 years. Patients characteristics are decribed in the table. The median age was 69 (65-83) years. 31(46%) patients had HER2+ disease. 13(19%) were triple negative breast cancer (TNBC). 18(27%) patients were unable to complete NAC, of which 10(15%) were due to side effects while 5 (7.5%) had progressive disease during treatment and the remainder 3(5%) refused the planned treatment. Half of the cohort with HER2+ disease had anthracycline/taxane based chemotherapy along with HER2 directed therapy of either trastuzumab or the combination trastuzumab and pertuzumab. 13 (19%) patients had pCR, 11 were HER2+ while 1 was HR+/HER 2- and the other was TNBC. Table: 13P

Patient characteristics

Conclusions

We report a cohort of older adults who had undergone NAC at our centre. Consistent with existing studies, 72 % of the patients completed NAC. In keeping with data on younger patients, older adults with HER2+ breast cancer had higher pCR. However, unlike younger women with TNBC, older adults in this study had lower rates of pCR which was also noted in a recent pooled analysis. This could reflect a heterogeneity of TNBC in older women which warrants further investigations in the future

Legal entity responsible for the study

CIRB Singhealth 2019/093/A.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Sarcopenia is a degenerative loss of skeletal muscle mass that can be found in the development of cancer cachexia. Based on recent studies, the prevalence of sarcopenia is relatively high in mRCC (metastatic renal cell carcinoma) patients, with the rate of 29-68%. Sarcopenia has been associated with increased adverse outcomes and could be an important predictor of outcomes in some types of cancer. However, the prognostic value of sarcopenia in renal cancer patients is still unclear. Thus, in this systematic review, we aim to evaluate the prognostic value of sarcopenia in mRCC patients.

Methods

Data is collected from PMC, PubMed, Scopus, and Science Direct, using combinations of keywords related to Sarcopenia and mRCC. We included studies that investigate sarcopenia in relation to survival and primary chemotoxicity in mRCC patients. Quality of each included study is assessed using the Newcastle-Ottawa Scale (NOS).

Results

A total of 10 studies consisting of 849 mRCC patients were included. According to the NOS, there were 5 studies with good quality, 4 studies with moderate quality, and 1 study with poor quality. The association of sarcopenia and OS (Overall Survival) was found in 4 studies. However, other 5 studies showed that sarcopenia was not associated with OS. Similar results for PFS (Progression Free Survival) were found. Two studies found that sarcopenia was associated with PFS, while other 2 studies found that there was no association between sarcopenia and PFS. There were 3 studies that found a higher DLT (Dose-Limiting Toxicity) rate in sarcopenic patients vs. non sarcopenic patients treated with sunitinib and sorafenib. However, other 2 studies found that there were no significant differences in chemotherapy toxicity between sarcopenic and non-sarcopenic patients treated with tyrosine kinase inhibitor and everolimus.

Conclusions

In this systematic review, we observed that sarcopenia was associated with increased DLT and poor survival in some studies, but the results were inconsistent and conflicting. There were 5 studies with good quality, 4 studies with moderate quality, and 1 study with poor quality. Further investigation is needed with better methods and outcome that focuses on chemotherapy toxicity and quality of life.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Indigenous women with breast cancer (BrCa) have markedly higher mortality then non-Indigenous women. Here, we examine the impact of site of metastasis on overall survival (OS) in women with breast cancer by indigenous status.

Methods

We retrospectively examined data from WA cancer registry from 2001 to 2016 with metastatic BrCa by indigenous status. Cases with confirmed location of metastatic disease were analysed and divided into groups of bone, liver, brain, lung, gastrointestinal (GI)/genitourinary (GU), contralateral breast (CBr) and skin metastasis. We performed a univariate and linear regression analysis to determine the impact of metastasis site on OS. Kaplan-Meier, Chi-square, Mann-Whitney analysis were done.

Results

A total of 152 patients were studied, 39% (n=60) were indigenous vs 61% (n=92) non-indigenous. Inferior median OS for indigenous group 34 vs 51 months in non-indigenous group, p=0.015. Indigenous group had higher rates of metastasis to bone 61% vs 40% (p=0.014), lung 41% v 25% (p=0.031), liver 41% v 23% (p=0.021) when compared to non-indigenous patients. The GI/GU metastasis was higher in non-indigenous group 32% v 15% (p=0.015) in indigenous group. There were no significant differences in rate of relapse at the local, CBr, brain, spleen, non-axillary LN nor skin (p>0.05). The bone metastasis was most common in luminals, liver and lung metastasis were frequent in luminal B and Her2+ subtypes. Brain metastasis was most frequent in HER2+. Indigenous cohort had more HER2+, luminal B and TN’s than non-indigenous but this was non-significant, p < 0.467. The multiple linear regression in both groups to predict OS for site-specific metastasis was non-significant with p-value 0.067 and R² of 0.097, explaining slight variability of OS by sites of metastasis. After adjustment, only brain metastasis had significant regression weights, but further analysis shown non-significant effect on OS with p=0.072 and an R² of 0.021.The group with brain metastasis had OS of 38 vs 52 months with no brain metastasis, p=0.072.

Conclusions

The indigenous group had inferior survival and higher rates of relapse to bones and viscera. A larger prospective study is needed to establish links of site of metastasis and OS.

Legal entity responsible for the study

Dr Azim Khan.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR-mutant (L858R and ex19del) driven non-small-cell lung cancer (NSCLC). T790M is the most prevalent acquired EGFR resistance mutation to treatment with 1^st and 2^nd generation TKIs. 3^rd generation TKIs, such as osimertinib, were developed to treat patients with tumors driven by this mutation. The C797S mutation is the most significant on-target resistance mechanism to osimertinib, leading to EGFR T790M/C797S double-resistant mutants. There are currently no approved targeted therapies for NSCLC patients with T790M/C797S mutations. BLU-945 is designed to target and selectively inhibit the EGFR T790M/C797S and T790M resistant mutations.

Methods

BLU-945 activity on EGFR mutants and EGFR wild-type (WT) was tested in biochemical assays and cellular phosphorylation specific EGFR AlphaLisa assays. The in vivo anti-tumor activity of BLU-945 was evaluated in an NCI-H1975 cell line-derived tumor xenograft (CDX) model, as well as in osimertinib-resistant CDX- and patient-derived xenograft (PDX) models of NSCLC.

Results

BLU-945 inhibits EGFR^{ex19del/T790M/C797S}, EGFR^{L858R/T790M/C797S}, EGFR^{ex19del/T790M}, and EGFR^L858R/T790M mutants with sub-nanomolar IC₅₀ values in an enzyme assay with a >1000-fold window over EGFR^WT enzyme activity. BLU-945 achieves potent EGFR pathway inhibition in NCI-H1975 EGFR^L858R/T790M, Ba/F3 EGFR^{L858R/T790M/C797S}, and Ba/F3 EGFR^{ex19del/T790M/C797S} cell lines and a large window relative to EGFR^WT inhibition. Oral administration of BLU-945 to tumor-bearing mice demonstrated potent EGFR pathway inhibition and anti-tumor activity at well-tolerated doses in the subcutaneous NCI-H1975 CDX model, and osimertinib-resistant CDX and PDX models, as well as in the intracranial luc-H1975 model of NSCLC.

Conclusions

BLU-945 is a potent, selective, and orally available EGFR inhibitor that shows robust anti-tumor activity in osimertinib-resistant EGFR xenograft models. Because of its pharmacological activity and selectivity for mutant EGFR, BLU-945 has the potential to demonstrate activity in osimertinib-resistant EGFR-mutant NSCLC.

Editorial acknowledgement

Medical writing support was provided by Cristina Tomas, PhD, and editorial support by Sinead Stewart, both of Paragon, Knutsford, UK, supported by Blueprint Medicines Corporation.

Legal entity responsible for the study

Blueprint Medicines Corporation.

Funding

Blueprint Medicines Corporation.

Disclosure

S.S. Schalm, T. Dineen, J. Hsieh, R. Woessner, Z. Zhang, M. Eno, D. Wilson, J. Campbell, C. de Savi, F. Stevison, C. Utt, M. Dorsch, K. Hoeflich: Shareholder/Stockholder/Stock options, Full/Part-time employment: Blueprint Medicines Corporation. K. Wilson, B. Williams, T. Guzi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Formerly of Blueprint Medicines Corporation. B.C. Cho: Advisory/Consultancy, Research grant/Funding (self): Novartis; Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): MOGAM Institute; Research grant/Funding (self): Dong-A ST; Research grant/Funding (self): Champions Oncology; Advisory/Consultancy, Research grant/Funding (self): Janssen; Advisory/Consultancy, Research grant/Funding (self): Yuhan; Advisory/Consultancy, Research grant/Funding (self): Ono; Research grant/Funding (self): Dizal Pharma; Advisory/Consultancy, Research grant/Funding (self): MSD; Research grant/Funding (self): AbbVie; Research grant/Funding (self): Medpacto; Research grant/Funding (self): GIInnovation; Advisory/Consultancy, Research grant/Funding (self): Eli Lilly; Advisory/Consultancy, Research grant/Funding (self): Blueprint Medicines Corporation; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Roche; Advisory/Consultancy: BMS; Advisory/Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Background

Radiotherapy is a primary or an adjuvant treatment for most brain tumor patients for better tumors control and prolong survival [1]. However, cranial irradiation may cause damages to hippocampus (plural: hippocampi), which may induce dementia after they recovered from the disease [2]. To minimise radiation dose to hippocampus becomes a new trend in radiation therapy [3], [4]. This study is to investigate whether traditional coplanar VMAT (CO-VMAT) or proposed non-coplanar VMAT (NC-VMAT) is dosimetrically superior for brain tumor radiotherapy treatment in view of hippocampus sparing.

Methods

Both CO-VMAT plan and NC-VMAT plan were generated for 16 brain tumor patients (Glioblastoma: 11, Meningioma: 5) using Varian Eclipse planning system version 15.6. The prescription was to give 54 Gy to PTV in 30 fractions. Dose constraints applied for plan optimization were benchmarked against Radiation Therapy Oncology Group (RTOG). In the CO-VMAT plans, there were 1 full arc (179°-181°) and 2 half arcs. The couch angle for all arcs were 0°. For cases with PTV located at the left side of the brain, the gantry angle for the 2 half arcs were set from 0°to 179° and 179° to 0°. While for cases with PTV on the right side of the brain, the gantry angle of the 2 half arcs were set from 0° to 181°and 181°to 0°. In the NC-VMAT plans, all setting were the same as CO-VMAT plans, except that the couch angle for the 2 half arcs was at 315° for PTV located at the left side of the brain, and 45° for PTV located on the right side of the brain.

Results

Homogeneity index, conformation number, dose to other organs at risk and ipsilateral hippocampus were similar in CO-VMAT and NC-VMAT plans. The maximum dose (D-Max_CH) received by contralateral hippocampus in NC-VMAT is 4Gy lower (p=0.049) than that of the CO-VMAT. The dose received by 40 % of the contralateral hippocampus (D40%_CH) in NC-VMAT is 1.46Gy (p=0.003) lower than that of the CO-VMAT. The mean D-Max_CH and mean D40%_CH were reduced by 23% and 23.5% respectively in NC-VMAT plans when compared with CO-VMAT.

Conclusions

The NC-VMAT is able to minimize radiation dose to contralateral hippocampus while maintaining good plan quality. The NC-VMAT approach may help to consolidate the development of a new standard of care for brain tumor patients.

Legal entity responsible for the study

Tung Wah College.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.