Recurrent Small Cell Lung Cancer Research Articles

Abstract A022: Dissecting patterns of small cell lung cancer evolution using deep whole genome sequencing of circulating tumor DNA

Abstract Background: Small cell lung cancer (SCLC) is the most lethal form of lung cancer. A key driver of this near universal lethality is SCLC’s recalcitrance to therapy. The standard of care for SCLC is a chemotherapy doublet of etoposide and cis/carboplatin in combination with immunotherapy (EP+IO). While most tumors respond to these therapies, >80% of SCLCs progress within one year of treatment. Additionally, the aggressive clinical course of SCLC has historically precluded collection of patient-matched treatment naïve and recurrent tumor tissue traditionally required to study evolution. In lieu of tissue, several groups have used circulating tumor DNA (ctDNA) to study SCLC evolution. However, these studies used targeted sequencing panels that analyze <0.04% of the SCLC genome. Using new methods to comprehensively trace how SCLCs rapidly evolve to therapy resistance is a significant unmet need. Methods: Medical records were reviewed to identify treatment naïve SCLC patients treated at MD Anderson that had both pre- and post-EP+IO liquid biopsies collected under IRB approved protocols. ctDNA was isolated from plasma using a MiniMax High Efficiency Cell-Free DNA Isolation Kit (Apostle Bio). Germline DNA was extracted from buffy coat samples using a QIAamp DNA Blood Midi Kit (Qiagen). Deep whole genome sequencing (WGS) (>100X) of ctDNA and WGS of germline DNA (>60X) was performed using an Illumina NovaSeq X sequencer. Reads were aligned to the hg38 reference genome using BWA-mem. Somatic mutations were called using MuTect2, and clonal and subclonal copy number alterations were identified using Battenberg. DPClust was used to reconstruct cancer cell populations, leveraging mutation and copy number calls. Results: We identified several deleterious genomic alterations impacting TP53 and RB1 tumor suppressor genes, known genetic drivers of SCLC development. We also detected recurrent, whole chromosome arm loss of heterozygosity events impacting many chromosomes in treatment naïve samples, some of which are known to be present in >80% of SCLCs. Additionally, we found that both treatment naïve and recurrent SCLCs were composed of multiple subclones, each defined by dozens to thousands of unique somatic mutations. COSMIC signature analysis identified high activity of tobacco carcinogens, APOBEC, and replicative-based processes across ctDNA samples. We also identified emergence of novel subclones carrying unique copy number alterations following EP+IO recurrence. Importantly, the affected regions encode key effectors that regulate anti-tumor immune responses and cell survival following DNA damage, both of which are intimately related to the mechanism of action of EP+IO. Conclusions: Our data shows that deep WGS of ctDNA recapitulates known genetics of SCLC and allows for sensitive characterization of therapy resistant clones. Using this method, we have captured snapshots of both intrinsic and acquired resistance mechanisms to frontline EP+IO. Deep WGS of ctDNA is a promising approach to comprehensively dissect routes of SCLC evolution and therapy resistance. Citation Format: Benjamin B. Morris, Zhihui Zhang, Simon Heeke, Kyle Concannon, Bingan Zhang, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J. Jack Lee, Jianjun Zhang, Don L. Gibbons, Ara A. Vaporciyan, Carl M. Gay, Hai T. Tran, John V. Heymach, Lauren A. Byers, Peter Van Loo. Dissecting patterns of small cell lung cancer evolution using deep whole genome sequencing of circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A022.

Synergistic effect of a nonsteroidal anti-inflammatory drug in combination with topotecan on small cell lung cancer cells.

The topoisomerase I inhibitor topotecan (TPT) is used in the treatment of recurrent small cell lung cancer (SCLC). However, the drug has a limited success rate and causes distress to patients due to its side effects, such as hematologic toxicities, including anemia and thrombocytopenia. Due to these pharmacokinetic limitations and undesirable side effects of chemotherapeutic drugs, the development of combination therapies has gained popularity in SCLC. Meclofenamic acid (MA), a nonsteroidal anti-inflammatory drug, has demonstrated anticancer effects on various types of cancers through different mechanisms. This study aims to investigate the potential synergistic effects of MA and TPT on the small cell lung cancer cell line DMS114. To assess the cytotoxic and apoptotic effects of the combined treatment of MA and TPT, trypan blue exclusion assay, Annexin V, acridine orange/propidium iodide staining, western blot, and cell cycle analysis were conducted. The results demonstrated that the combination of MA and TPT elicited synergistic effects by enhancing toxicity in DMS114 cells (P < 0.01) without causing toxicity in healthy epithelial lung cells MRC5. The strongest synergistic effect was observed when the cells were treated with 60 µM MA and 10 nM TPT for 48h (CI = 0,751; DRI = 10,871). This study, for the first time, furnishes compelling evidence that MA and TPT synergistically reduce cellular proliferation and induce apoptosis in SCLC cells. Combinations of these drugs holds promise as a potential therapeutic strategy to improve efficacy and reduce the side effects associated with TPT.

P2.17-03 CAN: A Phase II Trial of Combination of Niraparib and Anlotinib in Patients with Recurrent Small Cell Lung Cancer

P2.17-03 CAN: A Phase II Trial of Combination of Niraparib and Anlotinib in Patients with Recurrent Small Cell Lung Cancer

Survival benefit with checkpoint inhibitors versus chemotherapy is modified by brain metastases in patients with recurrent small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear. In this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival. Among 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59). CPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM.

Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: Updated results from a single-arm, phase Ⅱ study.

e20629 Background: There is still no unsatisfactory treatment strategy for patients (pts) with advanced SCLC relapsed within six months after first-line treatment, although chemotherapy alone is the standard treatment. Anlotinib, an oral multitarget tyrosine kinase inhibitor, effectively inhibits angiogenesis and enhances tumor cell response to chemotherapy. In the ALTER 1202 trial, anlotinib had significantly improved progression-free survival (PFS) and overall survival (OS) of advanced SCLC pts who received at least two lines chemotherapy. Therefore, we presented the updated efficacy and safety of anlotinib plus irinotecan or docetaxel in SCLC relapsed within six months after first-line treatment. Methods: Eligible pts with advanced SCLC who have relapsed within six months after first-line platinum-based treatment received anlotinib (12mg, QD from day 1 to 14 of a 21-day cycle, the dose could be adjusted to 10mg or 8mg according to the patient's tolerance) and irinotecan (65mg/m2, day1,8, q3w, up to 4 cycles) or docetaxel (60mg/m2, q3w, up to 4 cycles) until progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included PFS, the disease control rate (DCR), OS and safety. Results: As of Jan 31, 2023, we recruited 39 pts, among which 36 pts (median age: 63.2 years, male: 86.1%, ECOG PS 1: 80.6%, brain metastasis: 58.3%, liver metastasis: 36.1%) were eligible for efficacy analysis. Median follow-up time was 17.2 months (95% Cl, 8.27 -26.13 ). Of 36 evaluable pts, 1 pts had complete response (CR) , 20 pts reached partial response (PR) and 11 pts had stable disease(SD). The ORR was 58% (21/36) and the DCR was 89% (32/36), respectively. The median PFS was 4.4 months (95%Cl: 3.73- 5.08). The median OS was 7.9 months (95%Cl: 5.28-10.52). The Progression-free survival and overall survival in patients with recurrence &gt; 3 months and ≤ 6 months (PFS 6.5 m and OS 11.9 m) after first-line therapy improved more significantly than in patients with recurrence ≤ 3 months (PFS 4.1 m and OS 5.9 m). Most common grade 1-2 treatment-related adverse events (TRAEs) included weakness(58.3%), anorexia(38.9%), anemia(25%), hypertension (15.6%), Oral mucositis (13.9%) and leucopenia (11.1%). 3 pts (8.3%) suffered from grade 3 AEs, which were thrombocytopenia, leukopenia, and anemia. Conclusions: Anlotinib combined with irinotecan or docetaxel as second-line treatment for non-sensitive recurrent SCLC (i.e., extensive-stage disease time to relapse: 0-6 months) showed superior efficacy and safety compared with standard chemotherapy. It may become a novel therapeutic strategy for the population. Clinical trial information: NCT04757779 .

Influencing factors of efficacy and long‐term use of amrubicin in patients with small cell lung cancer

Amrubicin (AMR) has become the standard of care for post-relapse small cell lung cancer (SCLC). It has also been reported to achieve long-term disease control in patients with good treatment response. However, the optimal patient population for whom AMR is effective and the factors associated with long-term disease control are yet to be identified. The aim of the study was to identify the clinical characteristics and factors associated with long-term disease control in patients with recurrent SCLC who would benefit from AMR therapy. The clinical records of 33 patients diagnosed with recurrent SCLC and treated with AMR were retrospectively reviewed. Clinical information was compared between patients who achieved disease control (effective group) and who developed disease progression (noneffective group) on the first efficacy assessment after AMR and between patients who continued AMR for more than seven cycles (maintenance group) and those who terminated treatment after 1-6 cycles (discontinuation group). The noneffective group included significantly more patients with AMR dose reductions after the second cycle (p = 0.006). AMR dose reduction was an independent risk factor for disease progression. The maintenance group had significantly lower pretreatment lactate dehydrogenase (LDH) levels than the discontinuation group (p = 0.046). A high LDH level was an independent risk factor for short AMR discontinuation. Overall survival was significantly longer in the effective group than in the noneffective group (p < 0.001). In AMR therapy for patients with relapsed SCLC, continuation of AMR without dose reduction after the second cycle may contribute to disease control and prolonged survival.

Cost-effectiveness of anlotinib vs. pembrolizumab and nivolumab as third-line treatment in recurrent small cell lung cancer in China

ABSTRACT Background The study aims to evaluate the cost-effectiveness of anlotinib versus pembrolizumab and nivolumab as the third-line treatment in recurrent small cell lung cancer (SCLC) patients from the Chinese healthcare system perspective. Research design and methods A Markov model was built to simulate the costs and health outcomes in the 4-year horizon. Efficacy and safety data of anlotinib, pembrolizumab, and nivolumab in patients with recurrent SCLC were derived from three studies. Cost and utility values were derived from local charges, the published literature, and related databases. Three scenario analyses and sensitivity analyses were performed to explore the robustness of the results. Results Compared with anlotinib, pembrolizumab and nivolumab were estimated to gain an additional 0.18 and 0.10 quality-adjusted life years (QALYs) at an incremental cost of $10,446 and $5,182, resulting in an increment cost-utility ratio (ICUR) of $58,221/QALY and $56,733/QALY. The sensitivity analyses showed that the likelihood of anlotinib being cost-effective was 87.5% to 99.9% at a willingness-to-pay (WTP) threshold of $11,144 to $33,431/QALY. The scenario analyses indicated that the results varied in different scenarios. Conclusions The findings suggest that anlotinib could be the most cost-effective option versus pembrolizumab and nivolumab in the third-line treatment of recurrent SCLC from the Chinese healthcare system perspective.

EP14.01-010 CAN: A Phase II Trial of Combination of Niraparib and Anlotinib in Patients with Recurrent Small Cell Lung Cancer

Small cell lung cancer (SCLC) accounts for 14% of all lung cancers. Despite immunotherapy approved, SCLC is still associated with a poor prognosis and many patients relapse and develop drug resistance. Subsequent therapies are limited and the overall survival for recurrent SCLC is around 26 weeks. Anlotinib is a multi-target receptor tyrosine kinase inhibitor that can significantly inhibit angiogenesis. The ALTER 1202 trial showed anlotinib monotherapy has a longer median PFS compared with placebo (4.1 vs.

Efficacy and safety of amrubicin therapy after chemoimmunotherapy in small cell lung cancer patients.

BackgroundAlthough the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined. We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs.MethodsWe retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021.ResultsThis analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 (95% CI: 2.7–4.2) and 10 (95% CI: 7.4–14.8) months, respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 (95% CI: 1.1–4.0) vs. 4.2 (95% CI: 2.3–4.8) months, P=0.1142, OS; 10.0 (95% CI: 5.2–14.8) vs. 10.4 (95% CI: 3.8–NE) months, P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events.ConclusionsAMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.

Phase I/II investigator-initiated study of olaparib and temozolomide in SCLC: Updated analysis and CNS outcomes.

8565 Background: Temozolomide has activity in small-cell lung cancer (SCLC), including patients (pts) with brain metastases (mets; Pietanza M, Clin Cancer Res 2012). Inhibition of Poly (ADP-ribose) polymerase (PARP) is another therapeutic strategy in SCLC. We hypothesized that olaparib plus temozolomide may be safe and effective for pts with relapsed SCLC and clinically active against CNS disease (Farago A, Cancer Discovery 2019). Here, we present an updated analysis of this combination in pts with relapsed SCLC, including a second cohort testing an alternative dosing strategy and an exploratory analysis of CNS-specific outcomes. Methods: In this phase I/II trial of olaparib plus temozolomide in pts with recurrent SCLC, pts were sequentially enrolled into two cohorts defined by dosing schedule. In cohort 1, olaparib was dosed on D1-7 of each 21d cycle. In cohort 2, olaparib was dosed on D1-21. Temozolomide was dosed on D1-7 in both cohorts. Each cohort had a phase I portion (conventional 3+3 dose-escalation) for determination of MTD and RP2D and a phase II portion with primary endpoint of ORR. Per protocol, eligible pts could have untreated asymptomatic brain mets &lt; 1cm and, after mandatory baseline imaging, CNS imaging was performed at investigator’s discretion. A post-hoc exploratory analysis of CNS-specific outcomes was performed using modified RECIST criteria (Long GV, Lancet Oncol 2012) in which brain mets ≥5mm were considered measurable, and intracranial response was independently assessed by an attending radiologist. Results: 66 pts with median of 2 prior lines of therapy (range, 1-7) were enrolled, 50 pts in cohort 1 and 16 pts in cohort 2. 33/66 (50%) pts had history of brain mets, 15/66 (23%) pts had untreated brain mets at enrollment. The confirmed ORR of cohort 2 was 7% (1/14 evaluable pts, 95% CI: 0.2-33.9%), and the updated confirmed ORR of the entire study population was 34% (21/62 evaluable pts, 95% CI: 22.3-47.0%). The most common adverse events were hematologic toxicities (thrombocytopenia, anemia, and neutropenia). 22/50 (44%) of cohort 1 pts and 4/16 (25%) of cohort 2 pts required dose reduction. Of 15 pts with untreated brain mets, best overall intracranial response (including both confirmed and unconfirmed responses) was CR in 6 pts, PR in 4 pts, SD in 3 pts and PD in 1 for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Of 10 pts with CR/PR as their best intracranial response, 4 responses were confirmed. With non-CNS progression as a competing risk, the probability of CNS progression among the entire study population was 17% (95% CI: 8.8-26.7%) at 6 months and 21% (95% CI: 12.1-32.0%) at 12 months. Conclusions: Olaparib and temozolomide may be an effective therapy for relapsed SCLC, especially for pts with CNS disease where we observed a high rate of intracranial disease control. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination. Clinical trial information: NCT02446704.

A pilot study of ipilimumab and nivolumab in recurrent extensive-stage small cell lung cancer after platinum-based chemotherapy.

8583 Background: Immunotherapy has shown efficacy in the treatment of recurrent, extensive-stage small cell lung cancer (ES-SCLC). In the Checkmate 032 trial, ipilimumab and nivolumab combination therapy resulted in a 21% objective response rate in relapsed SCLC. At present, there are no biomarkers used in clinical practice to predict treatment responsiveness in SCLC. Ipilimumab and nivolumab act by blocking key co-inhibitory immune pathways of CTLA-4 and PD-1/PD-L1, respectively, leading to reinvigoration of anti-tumor cytotoxic T cell responses and a decrease in immune suppressive tumor infiltrating leukocytes. The ratio of intratumor Teff (CD8+) cells to Treg (CD4+/Foxp3+) cells (Teff/Treg) could be a more reliable biomarker than effector cell infiltration alone. Methods: In this open-label, single arm trial, we enrolled patients with ES-SCLC who previously received platinum-based chemotherapy; prior anti-PD-1 /PD-L1 therapy was allowed. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, for a total of 4 doses each and received nivolumab 480 mg beginning with cycle 5, every 4 weeks until progression, unacceptable toxicity or study discontinuation. On-study biopsies were performed prior to initiation of therapy and during week 4 for the biomarker primary objective—to correlate disease response with intratumor Teff/Treg changes. Secondary objectives include determining ORR, DOR, PFS, and OS. Results: Twenty-two patients (median age 63.5 [range 54-80] years, ECOG 0/1/2 [41%/50%/9%], sex M/F [45%/55%]) were enrolled and received treatment. Fourteen (64%) had paired biopsies while on treatment. Fifteen patients were evaluable per RECIST with an ORR of 13% (2/15, 2 partial responses [13%]) and DCR was 40% (6/15, 4 stable disease [27%]). Grade 3 treatment-related adverse events (TRAEs) occurred in 9/22 [40%]. Grade 4 TRAEs occurred in 2/22 [9%] (elevated lipase and elevated bilirubin) and Grade 5 TRAEs occurred in 1/22 patients (hepatic failure). Out of the 9 patients previously treated with anti- PD-1/PD-L1 therapy, 1 had a partial response and 2 had stable disease. Multiplexed quantitative immunofluorescence analysis revealed changes of both CD8+ effector T cells and Tregs in the tumor micro-environment associated with clinical benefit to immunotherapy. Conclusions: Combination immunotherapy with ipilimumab and nivolumab shows clinical efficacy in relapsed extensive-stage SCLC, including those previously treated with anti-PD-1/PDL-1 therapy. Obtaining paired biopsies was shown to be successful in this prospective trial to study the tumor microenvironment in SCLC tumors treated with checkpoint inhibitors. Early biomarker evaluation during week 4 shows local immunomodulatory effect of treatment and supports exploration as predictive biomarker in this population. Clinical trial information: 03670056.

156TiP An open-label, single-arm, phase II study evaluating the efficacy and safety of niraparib combined with radiotherapy and teriprizumab in patients with recurrent small cell lung cancer

Our previous basic research shows that radiotherapy combined with PARP inhibitors not only has direct antitumor effect in SCLC, but also can enhance antitumor immunity. At the same time, their combination can enhance the expression of PD-L1, which is considered to have a negative role in immune response. We found that triple therapy combined with PARP inhibitor and radiation plus anti-PD-1 can significantly enhance the antitumor effect and enhance the infiltration of cytotoxic T cells and memory T cells in SCLC model with immune function.

Clinical efficacy and safety of irinotecan and docetaxel combined with cisplatin in the treatment of recurrent and drug-resistant small cell lung cancer.

Clinical efficacy and safety of irinotecan and docetaxel combined with cisplatin in the treatment of recurrent and drug-resistant small cell lung cancer.

MA16.03 CRISPR Screen Reveals XPO1 as a Therapeutic Target Strongly Sensitizing to First and Second Line Therapy in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an exceptionally aggressive disease comprising 13% of all lung cancer cases. With limited treatment options that typically result in transient responses, SCLC is responsible for approximately 250,000 deaths globally per year. The recent addition of immunotherapy to first-line platinum-based doublet chemotherapy appears to benefit only a small subset of patients, resulting in a 2-month increase in median overall survival. Major hurdles to improving SCLC treatment include development of rapid chemoresistance and ineffective second line therapies. The identification of more durably effective therapeutic strategies is a major unmet clinical need. We performed an in vitro CRISPR screen in seven SCLC cell lines, including commercially available and short term-cultured cell lines derived from patient-derived-xenografts (PDXs), representing all major SCLC subtypes. We used an in-house druggable genome library including targets for which active inhibitors, either FDA-approved or in clinical development, are available. The screen was performed with two conditions per cell line, untreated and cisplatin-treated, to identify targets whose disruption would specifically sensitize to cisplatin. Candidate targets of interest were validated genetically with independent sgRNAs in Cas9-expressing in vitro and in vivo models (pSpCTRE-PDXs) and pharmacologically, with in vitro synergy assays and PDX treatments. Signaling pathways were studied by western blot, and toxicity studies were performed in vivo, to assess the safety of the agents at pharmacologically effective doses. We performed immunohistochemistry (IHC) to assess expression of candidate targets in SCLC tissue microarrays (TMAs). Our CRISPR screen approach revealed XPO1 (Exportin 1) as a candidate that may contribute to cisplatin resistance across all SCLC subtypes. Combination of Exportin 1 inhibitors with cisplatin demonstrated synergy in vitro, and use of cisplatin with the Exportin 1 inhibitor selinexor showed combinatorial efficacy in vivo in chemonäive SCLC PDXs representing all SCLC subtypes. This efficacy was associated with increased DNA damage and apoptosis. The combination was well tolerated in mice at the drug concentrations tested. Exportin 1 inhibition also exhibited combinatorial synergy with irinotecan, a standard agent use for recurrent SCLC, and combination of selinexor with irinotecan demonstrated substantial efficacy in SCLC PDXs derived from chemorelapsed tumors including models for all SCLC subtypes, again with manageable toxicity profiles. We found SCLC to have the highest XPO1 mRNA expression among a diverse array of tumor histologies. High XPO1 expression was confirmed at the protein level in a SCLC tissue microarray, independent of SCLC subtype. Exportin 1 is highly expressed in SCLC tumors, independent of their subtype, and its inhibition enhances sensitivity to the chemotherapeutic drugs used in first line and second line treatment of SCLC tumors. Our results provide preclinical rationale for the combination of selinexor with cisplatin or with irinotecan as first or second line treatment, respectively, of SCLC.

Advances in Treatment of Recurrent Small Cell Lung Cancer (SCLC): Insights for Optimizing Patient Outcomes from an Expert Roundtable Discussion

Second-line treatment options for patients with relapsed, extensive-stage small cell lung cancer (ES-SCLC) are limited, and even with currently available treatments, prognosis remains poor. Until recently, topotecan (a topoisomerase I inhibitor) was the only drug approved by the United States (US) Food and Drug Administration (FDA) for the management of ES-SCLC following progression after first-line treatment with etoposide plus a platinum derivative (EP; carboplatin preferred). With the most recent approval of EP plus a programmed death ligand 1 (PD-L1) inhibitor, there are now more therapeutic options for managing ES-SCLC. A number of novel agents have emerging data for activity in relapsed ES-SCLC, and single-agent lurbinectedin (an alkylating drug and selective inhibitor of oncogenic transcription and DNA repair machinery in tumor cells) has conditional FDA approval for use in this patient population. Trilaciclib, a short-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor, has also been recently approved as a supportive intervention for use prior to an EP or a topotecan-containing regimen to diminish the incidence of chemotherapy-induced myelosuppression. The current review is based on a recent expert roundtable discussion and summarizes current therapeutic agents and emerging data on newer agents and biomarkers. It also provides evidence-based clinical considerations and a treatment decision tool for oncologists treating patients with relapsed ES-SCLC. This paper discusses the importance of various factors to consider when selecting a second-line treatment option, including prior first-line treatment, available second-line treatment options, tumor platinum sensitivity, and patient characteristics (such as performance status, comorbidities, and patient-expressed and perceived values).

Abstract 1412: Whole exome sequencing reveals PI3K-ATK pathway alterations are frequent in relapsed small cell-lung cancer after chemoradiation

Abstract Background: Although small-cell lung cancer (SCLC) is sensitive to chemotherapy and radiotherapy initially, nearly all patients recur often with treatment-resistant disease. Comparing genomic profiles of paired treatment-naïve and recurrent tumors to understand the clonal architecture and molecular evolution of SCLC under treatment may provide novel insights into mechanisms underlying recurrence and susceptibility to further treatment. Methods: Paired tumor samples procured at diagnosis and relapse were collected from 11 patients with limited-stage SCLC treated with concurrent chemoradiation (CCRT). All tissues underwent whole exome sequencing (WES). Genomic landscape including somatic mutations, somatic copy number alterations (SCNAs), and clonal architecture were compared between treatment-naïve and paired recurrent tumor samples. Baseline and paired recurrent plasma samples from another 9 patients with SCLC treated with CCRT were performed deep sequencing using a targeted panel containing 1021 cancer related genes. Results: In both pre- and post-treatment tumors, TP53 (73% vs 73%), FAM135B (55% vs 64%), RB1 (45% vs 55%), and CTNND2 (45% vs 55%) were the top four most frequently mutated genes. Tobacco exposure related mutational signature was predominant in all samples. Compared with primary tumors, relapsed tumors showed significantly increased number of mutations (220 in recurrent SCLC vs 210 in primary tumor, Wilcoxon paired test, p-value = 0.016). Six of the 11 patients had increased chromosomal instability (CIS) in recurrent tumors. Relapsed tumors had more genes with copy number amplification compared to pre-treatment primary tumors although the difference did not reach statistical significance (18 vs 10, p-value = 0.066). In all of the patients, an average of 94% mutations at baseline were present in relapsed tumors. The number of clones in recurrent samples was higher than that in pre-treatment samples (13 vs 12, p-value = 0.004), indicating that new clones emerged under the treatment and tumor heterogeneity increased. A total of 648 acquired mutations in 600 genes and 140 acquired SCNAs in 123 genes were identified, in which 126 mutations were clonal (CCF&amp;gt;0.6) in relapsed tumors. These genes were enriched in PI3K-ATK signaling pathway and covered 91% (10/11) patients, implying the potential mechanism of chemoradiation resistance. Based on the specific mutations and mutations with increased CCF in relapsed plasma samples from the other 9 SCLCs, acquired alterations were also enriched in PI3K-ATK signaling pathway. Conclusions: Acquired mutations and chromosomal copy number gains may play a role in relapse of limited stage SCLC post CCRT. PI3K-ATK pathway alterations are frequent in recurrent SCLCs, which may be a candidate resistant mechanism after chemoradiation. Citation Format: Ying Jin, Yamei Chen, Xiao Hu, Huarong Tang, Qian Li, Pansong Li, Xinze Lv, Xuefeng Xia, Jianjun Zhang, Ming Chen. Whole exome sequencing reveals PI3K-ATK pathway alterations are frequent in relapsed small cell-lung cancer after chemoradiation [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 1412.

Abstract CT157: An exploratory phase 2 study of chiauranib monotherapy for small cell lung cancer after two or more lines of previous therapy

Abstract Background: Chiauranib (CS2164) selectively inhibits multiple kinase targets, including Aurora B, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, c-Kit and colony stimulating factor 1 receptor. Phase 1 studies showed that chiauranib 50mg once daily was well tolerated. Here we report results from an exploratory phase 2 study of chiauranib monotherapy for small cell lung cancer (SCLC) conducted in China (NCT03216343). Methods: This single arm phase 2 study involved SCLC patients with progression after platinum-based regimen and at least one other chemotherapy therapy. Patients received chiauranib 50 mg once daily orally until disease progression or unacceptable toxicity. Tumor assessments were conducted at baseline, 4 weeks for the first time and every 8 weeks thereafter. The primary endpoint of this study was objective response rate (ORR) by investigator assessment per the Response Evaluation Criteria in Solid Tumors, version 1.1. Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety were evaluated as secondary endpoints. Results: Between November 21, 2017 and March 21, 2019, 28 patients were enrolled in six study sites in China. The median age was 55.5 (range 32-71) years and 21 (75%) patients were male. Eastern Cooperative Oncology Group performance status was 0 in 8 (28.6%) patients and 1 in 20 (71.4%) patients. 12 (42.9%) patients were treated with two prior systemic treatment regimens, 16 (57.1%) patients were treated with three or more. At the cut-off date of Nov 15, 2020, the median follow-up duration was 25.6 (Range, 19.5-not evaluable) months. Two patients were still receiving treatment. Patients received a median of 3.5 cycles treatment. Twenty-seven patients had at least one tumor assessment and one patient died before the first assessment. The ORR and DCR were 17.9% (95% confidence interval [CI]: 6.06%-36.89%) and 64.3% (95% CI: 44.07%-81.36%), respectively. The median PFS, DOR and OS were 3.6, 8.2 and 8.4 months, respectively. The ≥ 10% adverse events (AEs) were mainly grade 1-2, and grade 3-4 AEs were hypertension (25%), hyponatremia (14.3%), fatigue (7.1%), diarrhea (3.6%), hypertriglyceridemia (3.6%), cough (3.6%) and limb pain (3.6%). No treatment related death was reported in the study. Two patients discontinued treatment due to grade 3 fatigue. Conclusions: Chiauranib exhibited impressing antitumor activity in patients with recurrent or metastatic SCLC who had undergone two or more previous lines of chemotherapy, and was well tolerated. Further clinical studies are in plan to verify the findings from the current report. Citation Format: Yuankai Shi, Jian Fang, Xingya Li, Yutao Liu, Zhendong Chen, Zhiyong Ma, Tao Sun. An exploratory phase 2 study of chiauranib monotherapy for small cell lung cancer after two or more lines of previous therapy [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 CT157.

Albumin-bound paclitaxel plus PD-1/PD-L1 inhibitor versus second-line chemotherapy for patients with recurrent small cell lung cancer.

e20591 Background: The main aim of this study was to evaluate the efficiency of albumin-bound paclitaxel (nab-PTX) plus PD-1/PD-L1 inhibitor versus second-line chemotherapy in small cell lung cancer (SCLC) patients who have failure to the first-line standard treatment. Methods: We retrospectively collected patients’ data from medical records between January 2015 to July 2020 in Shandong Cancer Hospital and Institute. Consecutive 42 patients who were treated with nab-PTX plus PD-1/PD-L1 inhibitor were enrolled and compared with, 126 patients who received second-line chemotherapy (1:3 matched with patient and tumor characteristics). Progress free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Results: Patients treated with nab-PTX plus immunotherapy group and second-line chemotherapy group achieved the median PFS of 5.6 months and 3.3 months ( p = 0.043), respectively. The median OS were 7.7 months and 6.3 months ( p = 0.021), respectively. The ORR and DCR were also higher in nab-PTX plus PD-1/PD-L1 inhibitor group (ORR: 33.3% vs 20.6%, p = 0.094; DCR: 61.9% vs 41.3%, p = 0.020, respectively). The most common incidences of grade ≥3 adverse events were leukopenia and neutropenia, there were no significance difference between the two groups. Conclusions: Albumin-bound paclitaxel plus PD-1/PD-L1 inhibitor conferred higher ORR and DCR, and improved PFS and OS in SCLC patients failed with first-line treatment. Further prospective and randomized trial that directly compares the treatments is urgently warranted.

PI3K-AKT pathway alterations are revealed as a potential mechanism of chemoradiation resistance in small cell lung cancer by whole-exome sequencing.

e20573 Background: Although small-cell lung cancer (SCLC) is sensitive to chemotherapy and radiotherapy initially, nearly all patients recur often with treatment-resistant disease. Comparing genomic profiles and clonal architecture of paired treatment-naïve and recurrent tumors may provide novel insights into mechanisms underlying recurrence and susceptibility to further treatment. Methods: Paired tumor samples procured at diagnosis and relapse were collected from 11 patients (pts) with limited-stage SCLC treated with concurrent chemoradiation (CCRT). All tissues underwent whole exome sequencing (WES). Genomic landscape including somatic mutations, somatic copy number alterations (SCNAs), and clonal architecture were compared between treatment-naïve and paired recurrent tumor samples. Baseline and paired recurrent plasma samples from another 9 pts with SCLC treated with CCRT were performed deep sequencing using a targeted panel containing 1021 cancer related genes. Results: We observed TP53 and RB1 alterations including mutations and SCNAs in the majority of treatment-naïve ( TP53 in 10 of 11, RB1 in 7 of 11 pts) and relapse samples ( TP53 in 8 of 11, RB1 in 8 of 11 pts). Tobacco exposure related mutational signature was most or second predominant in 11 pre-treatment and 9 recurrent samples, respectively. Compared with primary tumors, relapsed tumors showed significantly increased number of mutations (220 vs 210, p = 0.016). A high proportion of shared mutations between baseline and PD samples ranging from 39% to 94% was observed. More than half (n = 6) of the 11 pts had increased chromosomal instability in recurrent tumors. A total of 687 relapse-specific also called acquired mutations in 633 genes were identified, in which 158 mutations with cancer cell fraction (CCF) &gt; 0.6. These genes were enriched in PI3K-ATK signaling pathway and covered 73% (8/11) pts. Of the 9 paired plasma samples performed by targeted sequencing, genes with specific mutations and mutations with increased CCF in relapsed plasma samples were also enriched in PI3K-ATK pathway. In vitro proliferation assay indicated that PI3K inhibitor gave rise to a marked decrease in proliferation after combined with cisplatin, implying the potential mechanism of chemoradiation resistance. The number of clones in recurrent samples was higher than that in pre-treatment samples (13 vs 12, p = 0.004), indicating that new clones emerged under the treatment and tumor heterogeneity increased. Patients characterized by weakening of the major treatment-naïve clone tended to exhibit relatively longer PFS than those with sustaining major clone in both b baseline and relapsed tumors (p = 0.034). Conclusions: PI3K-ATK pathway alterations are frequent in recurrent SCLCs, which may be a candidate resistant mechanism after chemoradiation. PFS is probably associated with clonal evolutionary pattern.

58P Outcome and toxicity of reirradiation for locally recurrent small cell lung cancer: An international multicenter study

Background: Recurrent small cell lung cancer (SCLC) is associated with a dismal prognosis and treatment options are still limited. In this study, we evaluated the outcome of thoracic reirradiation for locally recurrent small cell lung cancer in order to identify prognostic factors and assess treatment-related toxicity.