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Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial

Takahashi, Nobuyuki; Hao, Zhonglin; Villaruz, Liza C; Zhang, Jun; Ruiz, Jimmy; Petty, W Jeffrey; Mamdani, Hirva; Riess, Jonathan W; Nieva, Jorge; Pachecho, Jose M; Fuld, Alexander D; Shum, Elaine; Chauhan, Aman; Nichols, Samantha; Shimellis, Hirity; McGlone, Jessie; Sciuto, Linda; Pinkiert, Danielle; Graham, Chante; Shelat, Meenakshi; Kattappuram, Robbie; Abel, Melissa; Schroeder, Brett; Upadhyay, Deep; Krishnamurthy, Manan; Sharma, Ajit Kumar; Kumar, Rajesh; Malin, Justin; Schultz, Christopher W; Goyal, Shubhank; Redon, Christophe E; Pommier, Yves; Aladjem, Mirit I; Gore, Steven D; Steinberg, Seth M; Vilimas, Rasa; Desai, Parth; Thomas, Anish
IMPORTANCE/UNASSIGNED:Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. OBJECTIVE/UNASSIGNED:To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. INTERVENTIONS/UNASSIGNED:Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. RESULTS/UNASSIGNED:Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. TRIAL REGISTRATION/ Identifier: NCT03896503.
PMID: 37824137
ISSN: 2374-2445
CID: 5628102

Selective Personalized Radioimmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial

Ohri, Nitin; Jolly, Shruti; Cooper, Benjamin T; Kabarriti, Rafi; Bodner, William R; Klein, Jonathan; Guha, Chandan; Viswanathan, Shankar; Shum, Elaine; Sabari, Joshua K; Cheng, Haiying; Gucalp, Rasim A; Castellucci, Enrico; Qin, Angel; Gadgeel, Shirish M; Halmos, Balazs
PURPOSE/OBJECTIVE:Standard therapy for locally advanced non-small-cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. For biomarker-selected patients with LA-NSCLC, we hypothesized that sequential pembrolizumab and risk-adapted radiotherapy, without chemotherapy, would be well-tolerated and effective. METHODS:Patients with stage III NSCLC or unresectable stage II NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible for this trial. Patients with a PD-L1 tumor proportion score (TPS) of ≥50% received three cycles of induction pembrolizumab (200 mg, once every 21 days), followed by a 20-fraction course of risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic volume exceeding 20 cc, 48 Gy delivered to smaller lesions), followed by consolidation pembrolizumab to complete a 1-year treatment course. The primary study end point was 1-year progression-free survival (PFS). Secondary end points included response rates after induction pembrolizumab, overall survival (OS), and adverse events. RESULTS:Twenty-five patients with a PD-L1 TPS of ≥50% were enrolled. The median age was 71, most patients (88%) had stage IIIA or IIIB disease, and the median PD-L1 TPS was 75%. Two patients developed disease progression during induction pembrolizumab, and two patients discontinued pembrolizumab after one infusion because of immune-related adverse events. Using RECIST criteria, 12 patients (48%) exhibited a partial or complete response after induction pembrolizumab. Twenty-four patients (96%) received definitive thoracic radiotherapy. The 1-year PFS rate is 76%, satisfying our efficacy objective. One- and 2-year OS rates are 92% and 76%, respectively. The most common grade 3 adverse events were colitis (n = 2, 8%) and esophagitis (n = 2, 8%), and no higher-grade treatment-related adverse events have occurred. CONCLUSION/CONCLUSIONS:Pembrolizumab and risk-adapted radiotherapy, without chemotherapy, are a promising treatment approach for patients with LA-NSCLC with a PD-L1 TPS of ≥50%.
PMID: 37988638
ISSN: 1527-7755
CID: 5608482

Neoadjuvant Targeted Therapy in Resectable Non-Small Cell Lung Cancer: Current and Future Perspectives

Lee, Jay M; McNamee, Ciaran J; Toloza, Eric; Negrao, Marcelo V; Lin, Jules; Shum, Elaine; Cummings, Amy L; Kris, Mark G; Sepesi, Boris; Bara, Ilze; Kurtsikidze, Nino; Schulze, Katja; Ngiam, Celina; Chaft, Jamie E
The standard of care (SoC) for medically operable patients with early-stage (stage I-IIIB) non-small cell lung cancer (NSCLC) is surgery combined with (neo)adjuvant systemic therapy for patients with II-IIIB disease and some stage IB or, rarely, chemoradiation (stage III disease with mediastinal lymph node metastases). Despite these treatments, metastatic recurrence is common and associated with poor survival, highlighting the need for systemic therapies that are more effective than the current SoC. Following the success of targeted therapy (TT) in patients with advanced NSCLC (aNSCLC) harboring oncogenic drivers, these agents are being investigated for the perioperative (neoadjuvant and adjuvant) treatment of patients with early-stage NSCLC (eNSCLC). Adjuvant osimertinib is the only TT approved for use in the early-stage setting and there are no approved neoadjuvant TTs. We discuss the importance of comprehensive biomarker testing at diagnosis to identify individuals who may benefit from neoadjuvant targeted treatments and review emerging data from neoadjuvant TT trials. We also address the potential challenges for establishing neoadjuvant TTs as SoC in the early-stage setting, including the identification and validation of early response markers to guide care and accelerate drug development, and discuss safety considerations in the perioperative setting. Initial data indicate that neoadjuvant TTs are effective and well tolerated in patients with EGFR- or ALK-positive eNSCLC. Data from ongoing trials will determine whether neoadjuvant targeted agents will become a new SoC for individuals with oncogene-addicted resectable NSCLC.
PMID: 37451404
ISSN: 1556-1380
CID: 5537892

Extended Survival in Patients With Non-Small-Cell Lung Cancer-Associated Brain Metastases in the Modern Era

Berger, Assaf; Mullen, Reed; Bernstein, Kenneth; Alzate, Juan Diego; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Chachoua, Abraham; Shum, Elaine; Velcheti, Vamsidhar; Sabari, Joshua; Golfinos, John G; Kondziolka, Douglas
BACKGROUND:Brain metastases (BM) have long been considered a terminal diagnosis with management mainly aimed at palliation and little hope for extended survival. Use of brain stereotactic radiosurgery (SRS) and/or resection, in addition to novel systemic therapies, has enabled improvements in overall and progression-free (PFS) survival. OBJECTIVE:To explore the possibility of extended survival in patients with non-small-cell lung cancer (NSCLC) BM in the current era. METHODS:During the years 2008 to 2020, 606 patients with NSCLC underwent their first Gamma Knife SRS for BM at our institution with point-of-care data collection. We reviewed clinical, molecular, imaging, and treatment parameters to explore the relationship of such factors with survival. RESULTS:The median overall survival was 17 months (95% CI, 13-40). Predictors of increased survival in a multivariable analysis included age <65 years (P < .001), KPS ≥80 (P < .001), absence of extracranial metastases (P < .001), fewer BM at first SRS (≤3, P = .003), and targeted therapy (P = .005), whereas chemotherapy alone was associated with shorter survival (P = .04). In a subgroup of patients managed before 2016 (n = 264), 38 (14%) were long-term survivors (≥5 years), of which 16% required no active cancer treatment (systemic or brain) for ≥3 years by the end of their follow-up. CONCLUSION/CONCLUSIONS:Long-term survival in patients with brain metastases from NSCLC is feasible in the current era of SRS when combined with the use of effective targeted therapeutics. Of those living ≥5 years, the chance for living with stable disease without the need for active treatment for ≥3 years was 16%.
PMID: 36722962
ISSN: 1524-4040
CID: 5420082

Low dose computed tomography (LDCT) screening in Asian female never-smokers is as efficacious in detecting lung cancer as in Asian male-ever-smokers: a systematic review and meta-analysis

Triphuridet, Natthaya; Zhang, Shannon S; Nagasaka, Misako; Gao, Yanfei; Zhao, Joseph J; Syn, Nicholas L; Hanaoka, Takaomi; Ou, Sai-Hong Ignatius; Shum, Elaine
INTRODUCTION/BACKGROUND:Lung cancer in never-smokers is the major cancer cause of death globally. We compared the efficacy of low-dose computed tomography (LDCT) lung cancer screening among never-smokers versus ever-smokers using systematic review and meta-analysis. METHODS:LDCT lung cancer screening studies simultaneously included both ever-smoker and never-smoker participants published by April 30, 2021 were searched via Pubmed/Scopus. Primary outcome measure was relative risk (RR) of lung cancer diagnosed among never-smokers versus ever-smokers. RESULTS:Fourteen studies (13 from Asia) were included (141,396 ever-smokers, 109,251 never-smokers, 1961 lung cancer cases diagnosed). RR of lung cancer diagnosed between ever-smokers versus never-smokers overall was 1.21 (95%CI: 0.89 - 1.65), 1.37 (95%CI: 1.08 - 1.75) among males, and 0.88 (95%CI: 0.59 - 1.31) among females. RR was 1.78 (95%CI: 1.41 - 2.24) and 1.22 (95%CI: 0.89 - 1.68) for Asian female never-smokers versus male never-smokers and versus male ever-smokers respectively, and 0.99 (95%CI: 0.65 - 1.50) versus high-risk ever-smokers (≥30 pack-years). Proportional meta-analysis showed significantly more lung cancers diagnosed at first scan (95.4% {95%CI: 84.9 - 100.0} versus 70.9% {95%CI: 54.6 - 84.9}, P = 0.010) and at stage 1 (88.5% {95%CI: 79.3 - 95.4} versus 79.7% {95%CI: 71.1 - 87.4}, P = 0.071) among never-smokers versus ever-smokers, respectively. RR of lung-cancer death and 5-years all-cause mortality in never-smokers versus ever-smokers was 0.27 (95%CI: 0.1 - 0.55, p<0.001), and 0.13 (95%CI: 0.05 - 0.33) respectively. CONCLUSIONS:The RR of lung cancer detected by LDCT screening among female never-smokers and male ever-smokers in Asia was statistically similar. Mortality from the lung cancer diagnosed was significantly reduced among never-smokers versus ever-smokers.
PMID: 36775191
ISSN: 1556-1380
CID: 5421172

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer

Deng, Jiehui; Peng, David H; Fenyo, David; Yuan, Hao; Lopez, Alfonso; Levin, Daniel S; Meynardie, Mary; Quinteros, Mari; Ranieri, Michela; Sahu, Soumyadip; Lau, Sally C M; Shum, Elaine; Velcheti, Vamsidhar; Punekar, Salman R; Rekhtman, Natasha; Dowling, Catríona M; Weerasekara, Vajira; Xue, Yun; Ji, Hongbin; Siu, Yik; Jones, Drew; Hata, Aaron N; Shimamura, Takeshi; Poirier, John T; Rudin, Charles M; Hattori, Takamitsu; Koide, Shohei; Papagiannakopoulos, Thales; Neel, Benjamin G; Bardeesy, Nabeel; Wong, Kwok-Kin
UNLABELLED:. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE/CONCLUSIONS:tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.
PMID: 37131623
ISSN: 2692-8205
CID: 5507602

The Selective Personalized Radio-Immunotherapy for Locally Advanced NSCLC Trial (SPRINT) [Meeting Abstract]

Ohri, N; Jolly, S; Cooper, B T; Kabarriti, R; III, W R B; Klein, J; Viswanathan, S; Kaufman, R; Shum, E; Sabari, J K; Cheng, H; Gucalp, R; Castellucci, E; Qin, A; Gadgeel, S M; Halmos, B
Purpose/Objective(s): Standard therapy for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy (chemoRT), which is usually followed by adjuvant durvalumab. We performed a prospective trial testing sequential pembrolizumab and risk-adapted radiotherapy without chemotherapy for biomarker-selected LA-NSCLC patients. Materials/Methods: Patients with AJCC version 8 stage III NSCLC or unresectable stage II NSCLC and ECOG performance status 0-1 were eligible for this trial. Subjects with PD-L1 tumor proportion score (TPS) >= 50% received three cycles of induction pembrolizumab (200 mg, every 21 days), underwent restaging FDG-PET/CT, received risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic tumor volume exceeding 20 cc and 48 Gy delivered to smaller lesions, all in 20 daily fractions), and then received up to 13 cycles of additional pembrolizumab. Subjects with PD-L1 TPS < 50% received concurrent chemoRT, and adjuvant durvalumab was recommended for patients without disease progression. The primary study endpoint was one-year progression-free survival (PFS) for subjects treated with pembrolizumab and radiotherapy (pembroRT), which we hypothesized would exceed 65%. Other study endpoints included 1-year overall survival (OS) and rates of clinician-scored (CTCAE v. 4.03) and patient-reported (PRO-CTCAE) adverse events observed over one year.
Result(s): Twenty-five subjects with PD-L1 TPS >= 50% and 12 subjects with PD-L1 TPS < 50% from three institutions were enrolled between August 2018 and November 2021. Median age was 70. Twenty-four subjects had stage II-IIIA disease, and 13 had stage IIIB-IIIC disease. Except for PD-L1 TPS, subject characteristics did not differ significantly across treatment groups. Ten out of the 12 subjects with ChemoRT received adjuvant durvalumab, and one received adjuvant osimertinib for EGFR mutation. The median follow-up duration is 15 months. Compared to patients treated with chemoRT, treatment with pembroRT has yielded numerically higher 1-year PFS (72% v. 46%, log rank p=0.232) and OS (91% v. 73%, log rank p=0.213) rates. Similar rates of grade 3 physician-scored adverse events have been observed with pembroRT (24%) and chemoRT (25%). Less severe patient-reported adverse events occurred with pembroRT compared to chemoRT (See Table).
Conclusion(s): Treatment with pembrolizumab and risk-adapted radiotherapy without chemotherapy is a promising approach for LA-NSCLC patients with PD-L1 TPS >= 50%. In addition to yielding high disease control rates, this strategy appears to reduce patient-reported adverse events compared to standard chemoRT and adjuvant therapy.
ISSN: 1879-355x
CID: 5366302

Nemvaleukin alfa, a novel engineered IL-2 fusion protein, drives antitumor immunity and inhibits tumor growth in small cell lung cancer

Pan, Yuanwang; Hao, Yuan; Han, Han; Chen, Ting; Ding, Hailin; Labbe, Kristen E; Shum, Elaine; Guidry, Kayla; Hu, Hai; Sherman, Fiona; Geng, Ke; Stephens, Janaye; Chafitz, Alison; Tang, Sittinon; Huang, Hsin-Yi; Peng, Chengwei; Almonte, Christina; Lopes, Jared E; Losey, Heather C; Winquist, Raymond J; Velcheti, Vamsidhar; Zhang, Hua; Wong, Kwok-Kin
BACKGROUND:T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity. METHODS:SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures. RESULTS:T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis. CONCLUSIONS:mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.
PMID: 36472839
ISSN: 2051-1426
CID: 5378672

Characteristics of Women with Lung Adenocarcinoma in the World Trade Center Environmental Health Center

Shum, Elaine; Durmus, Nedim; Pehlivan, Sultan; Lu, Yuting; Zhang, Yian; Arslan, Alan A; Shao, Yongzhao; Reibman, Joan
The destruction of the World Trade Center towers on 11 September 2001 exposed local residents, workers, and individuals in the area (Survivors) to dust and fumes that included known and suspected carcinogens. Given the potential for inhalation of toxic substances and the long latency after exposure, the incidence of lung cancer is expected to increase in WTC-exposed individuals. We describe the characteristics of women WTC Survivors with lung adenocarcinoma who were enrolled in the WTC Environmental Health Center (WTC EHC) between May 2002 and July 2021. A total of 173 women in WTC EHC had a diagnosis of any type of lung cancer, representing 10% of all cancers in women. Most of the lung cancers (87%) were non-small cell carcinomas, with adenocarcinoma (77%) being the most common subtype. Nearly half (46%) of these patients were exposed to dust clouds on 11 September 2001. Race and ethnicity varied by smoking status, as follows: 44% of Asian women compared with 29% of non-Hispanic White women were never-smokers (p &lt; 0.001). There was no significant difference between the pathologic characteristics of adenocarcinomas between never and ever smokers. We also summarize EGFR, ALK, KRAS, ROS-1 and BRAF mutation status stratified by smoking, race and ethnicity. The identification of a relatively high proportion of women never-smokers with lung cancer warrants further investigation into the role of WTC dust exposure.
PMID: 35805276
ISSN: 1660-4601
CID: 5278432

Functional analysis of MET exon 14 skipping alteration in cancer invasion and metastatic dissemination

Wang, Feng; Liu, Yang; Qiu, Wanglong; Shum, Elaine; Feng, Monica; Zhao, Dejian; Zheng, Deyou; Borczuk, Alain; Cheng, Haiying; Halmos, Balazs
MET exon 14 skipping alteration (MET∆14Ex) is an actionable oncogenic driver that occurs in 2-4% of non-small cell lung cancer (NSCLC) cases. The precise role of MET∆14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic MET∆14Ex cell models established with CRISPR editing, we demonstrate that MET∆14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, significantly boosting cell scatter, migration, and invasion capacity in vitro as well as metastasis in vivo. RNA sequencing analysis revealed that MET∆14Ex preferentially activates biological processes associated with cell movement, providing novel insights into its unique molecular mechanism of action. Activation of PI3K/Akt/Rac1 signaling and upregulation of multiple matrix metallopeptidases (MMPs) by MET∆14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed MET∆14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for MET∆14Ex-altered NSCLC patients. These mechanistic insights into MET∆14Ex-mediated invasion and metastasis provide a deeper understanding of the role of MET∆14Ex in NSCLC.
PMID: 35078819
ISSN: 1538-7445
CID: 5154452