Platinum-based Doublet Therapy Research Articles

Impact of DNA damage repair alterations on real-world response to therapy in metastatic colorectal cancer.

e15557 Background: Alterations in the DNA damage repair (DDR) pathway genes contribute to tumor development. These alterations can be exploited by cytotoxic chemotherapy regimens that induce DNA damage. Platinum chemotherapy agents have been shown to be particularly effective in breast and ovarian cancer patients with alterations in the DDR pathway. However, the clinical impact of DDR alterations in metastatic colorectal cancer (mCRC) is still poorly understood. In this study, we utilize a large national database to evaluate clinical outcomes in patients with mCRC and alterations in DDR pathway genes. Methods: We reviewed 5602 patients that received standard fluorouracil based first-line chemotherapy regimens for mCRC using the nationwide Flatiron Health EHR-derived de-identified database. Chemotherapy regimens were categorized as a platinum-based doublet (FOLFOX, CAPOX), irinotecan-based doublets (FOLFIRI), or triplet (FOLFOXIRI). Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates. OS was compared between groups in the context of univariable and multivariable Cox proportional hazards models controlling for age, gender, DDR status, stage at diagnosis, ECOG, RAS/RAF status, MMR status, albumin and CEA at diagnosis. OS was defined as the time in months between date of first line therapy initiation to death. Results: DDR gene alterations were indentified in 35.7% (2001) patients.The most frequent mutations were in ATM (13.3%) and BRCA2 (8.3%). There was no significant difference in OS based on DDR mutation status. Within DDR altered patients, there was no difference in OS between those who received a platinum-based doublet, irinotecan-based doublet or triplet first-line therapy. Time to next treatment or death (TTNTD) was significantly improved with an irinotecan-containing doublet regimen and triplet regimen compared to a platinum-based doublet in a multivariable model (HR 0.79, p = 0.001 and HR 0.68, p = 0.002, respectively). There was no difference in OS in DDR-mutated patients that received an irinotecan-based regimen in the first line followed by an oxaliplatin-based regimen in the second line or the reverse sequence. When evaluating the impact of commonly co-mutated genes on survival we observed a worse OS in patients with a KRAS mutation in addition to a DDR mutation (HR 1.19, p = 0.045). An APC mutation was associated with an improved OS in the entire cohort, regardless of DDR status (HR 0.76, p < 0.001). Conclusions: In this real-world population, approximately one third of patients with mCRC harbored an alteration in a DDR pathway gene. In these patients, TTNTD was greater with irinotecan-containing first line therapies (doublet or triplet). However, OS was similar regardless of which first-line chemotherapy was used.

Overall survival from a phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non–small cell lung cancer previously treated with immunotherapy: Lung-MAP nonmatched substudy S1800A.

9004 Background: Resistance to immune checkpoint inhibitor (ICI) therapy develops in most patients (pts) with advanced non-small cell lung cancer (NSCLC). Tumors that develop resistance to ICI constitute a major unmet need. Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types through immune modulation. We evaluated pembrolizumab and ramucirumab (P+R) in advanced, ICI-exposed NSCLC, under the aegis of Lung-MAP, a master protocol for pts with stage IV, previously treated NSCLC. Pt characteristics and treatment toxicities were presented at ASCO 2021. Methods: S1800A was a randomized phase II trial for pts ineligible for a biomarker-matched substudy with acquired resistance to ICI defined as previous ICI therapy for at least 84 days with progressive disease (PD) on or after therapy. Eligibility stipulated PD on prior platinum-based doublet therapy (sequential or in combination with ICI) and ECOG PS of 0-1. Pts were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm and were randomized to P+R or SOC (investigator’s choice of docetaxel+R; docetaxel, pemetrexed, gemcitabine). With a goal of 144 total/130 eligible pts, the primary objective was to compare overall survival (OS) between the arms using a 1-sided 10% level log-rank test upon 90 deaths. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts were enrolled with 137 eligible (69 P+R; 68 SOC [45 +R, 23 w/o R]). Main causes for ineligibility were lack of PD on ICI or chemotherapy (6 SOC, 6 P+R), > 1 line of ICI (2 P+R), ICI discontinued due to toxicity (2 SOC), or lack of measurable disease (2 SOC, 1 P+R). OS was significantly improved with P+R (HR: 0.61 [0.38-0.97], 1-sided p-value = 0.019; median [95% CI] OS of 15.0 (13.2-17) months (mo) for P+R and 11.6 (8.5-13.8) mo in SOC arm). Progression-free survival (PFS) was not different between the arms (HR: 0.86 [0.57-1.31], 1-sided p-value=0.25; median PFS (95% CI) of 4.5 (4.0-6.9) mo for P+R and 5.2 (4.0-6.6) mo in SOC arm). ORR was not different between the arms (p=0.28). OS benefit for P+R was seen in most subgroups. Analysis of survival based on genomic alterations, tumor mutational burden and PD-L1 will be presented. Conclusions: Pembrolizumab + ramucirumab in pts with advanced NSCLC previously treated with chemotherapy and immunotherapy led to improved OS compared to SOC. Discordance of ORR and PFS from OS has been reported in prior ICI trials (Rittmeyer et al. Lancet 2017). This is the first trial in the 2nd line setting without a chemotherapy backbone to demonstrate a potential survival benefit compared to SOC regimens including docetaxel and ramucirumab using the Lung-MAP platform. Clinical trial information: NCT03971474.

Role of Thoracic Radiotherapy in Extensive Stage Small Cell Lung Cancer (ES-SCLC) in the Immunotherapy Era: A National Hospital-Based Registry Analysis

Immunotherapy has shaped the treatment for a number of metastatic cancer types. Based on IMPower 133 and CASPIAN results, chemoimmunotherapy has become standard of care for de-novo ES-SCLC, with increase in median survival of approximately 2-3 months compared to prior standard of care platinum-based doublet therapy with etoposide. However, neither of these trials allowed consolidative thoracic radiotherapy (TRT). Prior to chemo-immunotherapy trials, addition of consolidative TRT to standard chemotherapy improved 2 years survival in patients with any response to chemotherapy. At present, there is no prospective data of role of TRT in ES-SCLC with chemoimmunotherapy. We undertook this study to examine any benefit of TRT in patients with ES-SCLC who received chemoimmunotherapy.We queried the National Cancer Database (NCDB) for patients with ES-SCLC between the ages of 18-90 years treated between 2012-2017 treated with combination of chemotherapy and immunotherapy at the time of diagnosis, and with and without TRT. We excluded patients with unknown treatment status or follow-up time. Overall survival was estimated using Kaplan-Meier method and compared between treatment groups utilizing log-rank testing. An optimal-full propensity-score match was performed utilizing clinical and demographic covariates to reduce the impact of potential confounders of overall survival on the probability of receipt of TRT. Cox proportional hazards regression was used to identify predictors of overall survival.A total of 244 patients were identified meeting selection criteria, treated between 2012 and 2016. There were 63 patients that received TRT and 181 patients that did not. The median age was 65 (40-90) years. The median follow-up was 9.68 (range 0.7-48.3) months. After propensity score matching by age, gender, race, comorbidity score, and type of chemotherapy, there was a trend towards improved median survival from 9 to 11 months and 2 year OS at 18.1% with the addition of TRT vs 12.0% with chemoimmunotherapy alone (P = 0.067). On multivariable analysis only female gender was significantly associated with improved OS after adjustment for age, race, comorbidity score, gender, and receipt of TRT (HR = 0.67 (95% CI 0.51 - 0.89), P = 0.01).In patients with ES-SCLC, the addition of TRT to chemoimmunotherapy is associated with a trend towards improved median and 2 year OS on the order of magnitude of the addition of immunotherapy to chemotherapy as reported in recent trials, though this was not statistically significant in the context of a limited sample size from a non-randomized cohort. Data from prospective, randomized trials are needed to help identify which patients may benefit from TRT in the immunotherapy era.

812P Demographics and survival outcomes in patients with advanced or recurrent endometrial cancer (EC) following platinum-based doublet (PBD) in the English real-world (RW) setting

Patients with advanced/recurrent EC following disease progression on or after a PBD therapy have a poor prognosis. This descriptive, noninterventional, retrospective cohort study reports on English patient characteristics and survival outcomes, specifically in a population with advanced/recurrent EC that has progressed on or after a first-line (1L) PBD therapy.

Phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non-small cell lung cancer previously treated with a checkpoint inhibitor: Toxicity update (Lung-MAP non-matched sub-study S1800A).

9075 Background: The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of immunotherapy agents in both treatment-naïve and previously treated cancer patients (pts) and irrespective of histology. Pts with tumors that develop resistance is a significant area of unmet need. Vascular endothelial growth factor (VEGF) has been shown to modulate the tumor immune microenvironment and combination immune checkpoint and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types. Lung-MAP is a master protocol for pts with stage IV, previously treated NSCLC. Pts who were not eligible for a biomarker-matched substudy enrolled in S1800A. The adverse event profile will be presented. Methods: S1800A is a phase II randomized trial for pts who previously received PD-1 or PD-L1 inhibitor therapy for at least 84 days and platinum-based doublet therapy with ECOG 0-1 stratified by PD-L1 expression, histology and intent to receive ramucirumab in the standard of care (SOC) arm. Pts were randomized 1:1 to pembrolizumab and ramucirumab P+R or SOC (docetaxel +R [SOC w R]; docetaxel, pemetrexed or gemcitabine [SOC wo R]). The primary endpoint was overall survival. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and evaluation of toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts enrolled and 140 determined eligible [69 (49%) P+R; 46 (33%) SOC w R; 25 (18%) SOC wo R]. Treatments for those who received SOC wo R included 3 on docetaxel (19%); 12 on gemcitabine (75%); and on 1 on pemetrexed (6%). 131 were eligible for adverse event (AE) assessment. The most common AE were fatigue (38%), proteinuria (28%), hypertension (23%), diarrhea (22%) and hypothyroidism (22%) on P+R; fatigue (61%), anemia (48%), diarrhea (41%) and neutropenia (39%) on SOC w R and anemia (56%), leukopenia (56%), fatigue (44%) and neutropenia (44%) on SOC wo R. Grade ≥ 3 treatment-related AEs occurred in 32% of pts on P+R, 54% of pts on SOC w R and 56% of pts on SOC wo R. Cardiac and thromboembolic events occurred in 12% of pts on P+R, 11% of pts on SOC w R and 0% of pts on SOC wo R. Grade 5 AE occurred in 2 pts on P+R (respiratory failure and cardiac arrest), 3 pts on SOC w R (2 respiratory failure and sepsis) and 1 pt on SOC wo R (sepsis). Four patients were diagnosed with COVID-19 (1 on P+R and 3 on SOC) and 3 died (1 on P+R and 2 on SOC). Conclusions: Grade 3 toxicities were lower in P+R compared to SOC arms with or without R. Cardiac and thromboembolic events were similar in arms that included R. P+R was generally well-tolerated. Efficacy outcomes will be presented when data matures. Clinical trial information: NCT03971474.

In small cell lung cancer patients treated with RRx-001, a downregulator of CD47, decreased expression of PD-L1 on circulating tumor cells significantly correlates with clinical benefit

BackgroundSmall cell lung cancer (SCLC) is the most aggressive lung tumor, characterized by a rapid doubling time and the development of widespread metastases, for which immune checkpoint inhibitors have been approved to overcome T cell anergy. In light of its dismal prognosis, and lack of curative options, new therapies for extensive-disease SCLC are desperately needed.MethodsRRx-001 is a small molecule Myc inhibitor and down-regulates CD47 expression on tumor cells. We evaluated the programmed death-ligand 1 (PD-L1) status of circulating tumor cells (CTCs) pre and post RRx-001 treatment in a phase 2 clinical trial, called QUADRUPLE THREAT, where patients with previously treated SCLC received RRx-001 in combination with a platinum doublet. The trial was registered with ClinicalTrials.gov, number NCT02489903. Fourteen patients with SCLC were analyzed to investigate the association between clinical outcome and PD-L1 expression on CTCs pre and post RRx-001. The correlation between the binary clinical outcome (clinical benefit vs. progressive disease) and the change of PD-L1 expression on CTCs after RRx-001 was analyzed using a logistic regression adjusting for baseline PD-L1 expression.ResultsThe logistic model McFadden goodness of fit score was 0.477. The logistic model analyzing the association between decreased PD-L1 expression on CTCs after RRx-001 and response to reintroduced platinum doublet had an approximate 92.8% accuracy in its prediction of clinical benefit. The estimated receiver operating characteristic (ROC) displayed a ROC area under the curve (AUC) of 0.93 (95% confidence interval, 0.78–0.99).ConclusionsThese results suggest that PD-L1 expression on CTCs decreased after RRx-001 was significantly correlated with response to reintroduced platinum-based doublet therapy. Monitoring PD-L1 expression on CTCs during RRx-001 treatment may serve as a biomarker to predict response to RRx-001-based cancer therapy.

Water only fasting and its effect on chemotherapy administration in gynecologic malignancies

ObjectiveAs a protective response, during starvation organisms withdraw energy from growth and reproduction to focus on cellular maintenance. Cancer cells cannot undergo this differential response which has been theorized as an adjunct to improve both the effect of chemotherapy treatment and reduce treatment side effects. We sought to investigate the feasibility and effect of short-term fasting in patients receiving chemotherapy for gynecologic malignancy. MethodsA randomized control trial was conducted of women with gynecologic malignancies receiving at least 6 planned chemotherapy cycles. Fasting patients maintaining a water-only fast for 24 h before and 24 h following each chemotherapy cycle were compared to nonfasting patients. Treatment related side effects and quality of life (QOL) was assessed using NCCN-FACT FOSI-18 questionnaire. ResultsAnalysis included data from 120 cycles of chemotherapy. The majority of patients had stage 3 and 4 malignancy requiring multi-agent chemotherapy. Eleven patients had ovarian, 8 had uterine, and 1 had cervical cancer. Ninety percent received taxane and platinum-based doublet therapy. Weight loss and unanticipated hospitalizations were similar between treatment groups. Fewer dose reductions or delays were seen in the fasting group. There was no significant difference in mean QOL scores, but fasting group QOL scores improved over the course of treatment to a level that reached the minimal clinically important difference. ConclusionA 48-h fast is well tolerated without increasing weight loss, hospital admissions, or chemotherapy dose reduction/delays. Fasting resulted in fewer treatment modifications and improved quality of life scores over the course of treatment.

EGFR tyrosine kinase inhibitor therapy for lung cancer treatments and their clinical outcomes: A cohort study in Taiwan.

Malignant cancer is the top cause of mortality in Taiwan. In particular, the mortality rate of with lung cancer reached 39.2/100,000 in 2017. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are being increasingly used to treat lung cancer.; however, due to small sample sizes and a limited number of adequately controlled studies, it is difficult to compare survival rates of traditional chemotherapy with EGFR-TKI therapy when used as a first- or second-line treatment for patients with lung cancer, and therefore data on its efficacy are inconclusive. Therefore, Taiwan's entire 2010–2015 National Health Insurance Database (NHID) was used to perform a retrospective study. The top two anti-neoplastic first-line therapies used for lung cancer were traditional platinum-based doublet chemotherapy and EGFR-TKI therapy. Patients with stage III and IV lung cancer undergoing first-line EGFR-TKI therapy exhibited improved overall survival rates. However, patients with stage I and II lung cancer demonstrated limited benefits. Patients with stage IIIB and IV EGFR mutation (−) patients did not benefit from treatment with EGFR-TKI therapy. The EGFR-TKI gefitinib may be more effective in patients with lung cancer than erlotinib, irrespective of whether patients had been previously treated or not. Patients treated with Gefitinib also exhibited improved survival rates compared with other frequently used chemotherapeutic drugs.

ORION: A Phase 2, randomized, multicenter, double-blind study to assess efficacy and safety of durvalumab+olaparib vs durvalumab alone as maintenance therapy in Stage IV non-small cell lung cancer (NSCLC).

TPS9126 Background: Systemic chemotherapy for first-line (1L) metastatic NSCLC shows mixed outcomes. Results from studies using immunotherapy alone or combined with chemotherapy as 1L treatment in patients (pts) with metastatic NSCLC represent a substantial advance, but further improvement is needed. Increased DNA damage triggered by polyadenosine 5’diphosphoribose polymerase inhibition may confer antitumor activity, modify tumor immunogenicity, and further sensitize tumors to immune checkpoint inhibition, thus promoting a more durable antitumor response. This Phase 2, randomized, multicenter, double-blind study (NCT03775486) is designed to assess the efficacy and safety of durvalumab + olaparib vs durvalumab alone as maintenance therapy in pts whose Stage IV NSCLC has not progressed following 1L platinum-based chemotherapy + durvalumab. Methods: Adult pts with Stage IV NSCLC with tumors lacking activating EGFR mutations and ALK fusions are eligible. In the initial therapy phase, all pts will receive durvalumab (1500 mg IV) concurrent with platinum-based doublet therapy. Durvalumab + chemotherapy will be administered for 4 cycles for both squamous NSCLC (nanoparticle albumin-bound [nab]-paclitaxel + carboplatin or gemcitabine + carboplatin/cisplatin) and nonsquamous NSCLC (nab-paclitaxel + carboplatin or pemetrexed + carboplatin/cisplatin). Pts whose disease does not progress (complete or partial response [CR/PR] or stable disease [SD]; investigator-assessed RECIST 1.1) will be randomized (1:1) to durvalumab (1500 mg IV, every 4 weeks) + either olaparib (300 mg, oral, BID) or its matching placebo until disease progression. Randomization will be stratified based on objective response to durvalumab + chemotherapy (CR/PR or SD) during the initial therapy phase and histology (squamous or nonsquamous). The primary endpoint is PFS (investigator-assessed, RECIST 1.1). Secondary endpoints are OS, PFS in pts with homologous recombination repair related gene mutation, ORR, duration of response, HRQoL, pharmacokinetics and immunogenicity of durvalumab, and safety. Pt enrollment is ongoing. Clinical trial information: NCT03775486.

The Role of PARP Inhibitors in Ovarian Cancer: An Emerging Picture

Dr Oaknin welcomed the delegates to the symposium and presented the objectives and agenda for the meeting as well as a case study presentation. Dr Birrer presented on the current landscape of platinum-sensitive recurrent ovarian cancer (PSR OC), including USA and European treatment guidelines. He highlighted data from three landmark Phase III studies that demonstrated the efficacy of platinum-based doublet therapy for patients with PSR OC. The role of cytoreductive surgery is still being debated but bevacizumab and a newer anti-angiogenic agent, cediranib, may both extend progression-free survival (PFS) in these patients. He predicted that new combinations of therapies will be tested. Prof Ledermann followed with a presentation on the role of poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib, niraparib, and rucaparib, in the treatment of PSR OC. The largest increase in PFS is seen in patients with platinum-sensitive BRCA-mutant tumours but there is also significant benefit over placebo in groups of patients with platinum-sensitive BRCA wild-type tumours. Prof McNeish discussed the challenge of identifying the 30% of women with high-grade serous OC who would respond to treatment with a PARP inhibitor even though their tumour does not carry a BRCA mutation. Loss of heterozygosity (LOH) is a key indicator of homologous recombination deficiency (HRD) but current tests miss some women who would benefit from treatment. Dr Lorusso concluded the meeting by exploring future directions for research into PARP inhibitors, such as whether they should be used in the front-line setting and as single agents rather than in combination with chemotherapy. New combinations with anti-angiogenic and immune-oncology agents show promise, as does the potential for retreatment with a different PARP inhibitor.

MS21.02 Chemotherapy through the 21st Century

MS21.02 Chemotherapy through the 21st Century

Clinical and molecular characteristics of pulmonary sarcomatoid carcinoma.

Background/AimsPulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) that contains components of spindle or giant cells. Owing to its low prevalence, there are insufficient data regarding its clinical features, therapeutic strategies and prognosis.MethodsThe medical records of 26 patients diagnosed with PSC from January 2009 to June 2015 were reviewed and analyzed for clinicopathological characteristics, treatment modality, and outcomes.ResultsThe median age was 69.5 years. Twenty-three patients (88%) were male. Twenty-four patients (92%) were smokers. The median time from symptom onset to diagnosis was one month. Eighteen patients (69%) were diagnosed at an advanced stage. Pleomorphic carcinoma was the most common subtype, and epidermal growth factor receptor (EGFR) mutation was positive in two of 11 patients. Among 13 patients tested for programmed death ligand 1 (PD-L1) immunohistochemistry assay, eight showed high expression of PD-L1. The median overall survival (OS) of all patients was 9.5 months. In total, 12 patients were treated with chemotherapy: nine with platinum-based doublet therapy, two with tyrosine kinase inhibitor, and one with docetaxel. Seven patients showed partial response or stable disease. The median OS and progression-free survival of patients who received chemotherapy were 8.7 and 2.8 months, respectively.ConclusionsPSC was more common in males, smokers, and the elderly, with worse prognosis than ordinary NSCLC; chemotherapy response was favorable, and EGFR mutation status and PD-L1 expression may offer more therapeutic options.

Effectiveness outcomes and health related quality of life impact of disease progression in patients with advanced nonsquamous NSCLC treated in real-world community oncology settings: results from a prospective medical record registry study

BackgroundTreatment options for advanced nonsquamous non-small cell lung cancer (NSCLC) in the first line include platinum-based doublet therapy with or without bevacizumab. This study examined efficacy outcomes and patient reported outcomes (PROs) in a community oncology patient sample.MethodsAdvanced nonsquamous NSCLC patients from 34 U.S. community oncology practices treated in first line with bevacizumab regimens (A platinum doublet; gemcitabine doublet; pemetrexed with platinum) or non-bevacizumab regimens (B platinum doublet; gemcitabine doublet; C pemetrexed with platinum) were recruited for this prospective study. Patient characteristics and clinical outcomes were accessed from routine care records. Three validated and widely used PRO measures of health related quality of life (HRQOL) and symptom burden were collected prospectively at each visit and up to one-year follow-up. Effectiveness outcomes were progression free survival (PFS) and overall survival (OS) assessed by Kaplan-Meier and Cox regression methods. PROs were analyzed with linear mixed model regression to examine changes over time, and the effect of disease progression.ResultsOf 147 patients in the study, 145 provided PRO data. Patients in treatment groups were: A (n = 66, 44.9%); B (n = 25, 17.0%); C (n = 56, 38.1%). A was associated with significantly longer OS than B (HR = 0.341, p = 0.0012), and significantly longer than C (HR = 0.602, p = 0.0354). PFS results were similar. Irrespective of regimen group and on 12/32 measures, patients showed significant and clinically meaningful worsening of symptoms and HRQOL at disease progression. After disease progression, the pattern of symptom and HRQOL change showed continued worsening.ConclusionsBevacizumab-containing regimens were associated with longer PFS and OS compared with non-bevacizumab regimens. PRO measures show disease progression is associated with worsening HRQOL. Delaying disease progression can sustain better HRQL and reduce symptom burden.

Abstract 2638: Clinical characteristics and PD-L1 expression of pulmonary sarcomatoid carcinoma

Abstract Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) containing a component of spindle cell or giant cell. Because the prevalence of PSC is very rare, there is insufficient data about clinical feature, therapeutic strategy and prognosis. Method: We reviewed the medical records of 26 patients diagnosed with PSC from January 2009 to June 2015, and analyzed the clincopathological characteristics, treatment modality and their outcome, and risk factors of overall survival (OS). Programmed death ligand 1 (PD-L1) expression was tested in 13 patients by using archival tissues (PD-L1 IHC 22C3 pharmDx assay). Results: The median age of PSC patients was 69.5 years. 23 patients were male. 25 patients were current or former heavy smokers. Pleomorphic carcinoma was the most common subtype, and epidermal growth receptor mutation (EGFR) was positive in 2 of 11 patients who were tested. Among 13 patients tested for programmed death ligand 1 (PD-L1), eight showed PD-L1 high expression (tumor proportion score, TPS ≥ 50%). Four patients showed low expression (1% ≤ TPS ≤ 49%), and one patient showed no expression (TPS < 1%). The median OS of all patients was 286 days. Age and the time from symptom onset to diagnosis were significantly associated with OS. PD-L1 expression showed the trend of positive prognostic value on OS in univariate analysis but was insignificant in multivariate analysis. 12 patients were treated with chemotherapy: 9 with platinum-based doublet therapy, 2 with tyrosine kinase inhibitor and 1 with docetaxel. 7 patients showed partial response or stable disease. The median OS and progression free survival of patients receiving chemotherapy were 260 days and 85 days, respectively. Conclusions: It has poor prognosis compared with ordinary NSCLC. However, PSC patients showed comparatively fair response to chemotherapy and generally showed higher PD-L1 expression. Active treatment with cytotoxic chemotherapy, EGFR TKIs or immune checkpoint inhibitors are necessary to achieve a better results of PSC management. Citation Format: Sung Yong Lee, Jae Kyeom Shim, Jee Youn Oh, Kyung Hoon Min, Gyu Young Hur, Jae Jeong Shim, Kyung Ho Kang, Bong Kyung Shin, Young Seok Lee. Clinical characteristics and PD-L1 expression of pulmonary sarcomatoid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2638. doi:10.1158/1538-7445.AM2017-2638

Immune checkpoint inhibitors in non-small cell lung cancer: is simultaneous blockade better?

Immunotherapy has proven to be a major breakthrough in the treatment of a variety of cancers, having been called the major oncologic achievement in 2015 by the American Society of Clinic Oncology. Two immune checkpoint inhibitors, antibodies to the programmed cell death protein-1 receptor (PD-1), received FDA approval in 2015 for the treatment of advanced non-small cell lung cancer, and others similar agents are actively being studied. Advancements in the treatment of lung cancer have been desperately needed as treatment strategies utilizing platinum-based doublet therapy result in modest improvements in overall survival with a median of 8–10 months and 2-year survival rates of 10–15% in patients with metastatic disease (1).

Abstract A1-55: Combination of a three-microRNA signature and TP53 genotype predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma

Abstract Platinum-based doublet, i.e., a combination of a platinum agent and another agent, is a standard regimen to treat non-small cell lung cancer, since molecular target therapy using tyrosine kinase inhibitors is effective only in a subset of patients with tumors with druggable oncogene mutations. Therefore, to identify biomarkers that can discriminate responders who received platinum-based chemotherapy before treatment is important to improve the efficacy of chemotherapy for non-small cell lung cancer. We found that a SNP in TP53 tumor suppressor gene, TP53-Arg72Pro is associated with response to the platinum-based doublet therapy (Shiraishi et al, JCO, 2010). We recently assessed intra-tumor micro (mi)RNA expression as a biomarker for predicting responses to platinum-based chemotherapy in patients with recurrent lung adenocarcinoma. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and non-responders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Finally, combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power (Saito et al., Clin. Cancer Res. 2014). Citation Format: Kouya Shiraishi, Motonobu Saito, Takashi Kohno. Combination of a three-microRNA signature and TP53 genotype predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-55.

A phase 3 randomized trial of veliparib (ABT-888) plus carboplatin and paclitaxel versus investigator’s choice of standard chemotherapy in previously untreated patients with metastatic/advanced non-squamous (NSq) non-small cell lung cancer (NSCLC).

TPS8106 Background: Standard chemotherapy for patients (pts) with metastatic NSq NSCLC consists of 4−6 cycles of platinum-based doublet therapy +/– subsequent maintenance monotherapy. Clinical outc...

Delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer

ObjectivesThe objective of this study was to characterize chemotherapy treatment patterns in elderly patients with epithelial ovarian cancer (EOC) and their impact on overall survival (OS). MethodsWe identified patients age ≥65years with stage II–IV EOC who underwent cytoreduction from 2003 to 2011. Relevant clinical variables were extracted and correlated with OS. Statistical analyses were performed using logistic regression, Kaplan–Meier methods, and multivariable Cox proportional hazard models. ResultsOne hundred and eighty-four patients were included in the analysis. The average age was 73years with American Society of Anesthesiology Physical Status Class 2 or 3. Approximately 78% underwent primary debulking surgery (PDS). OS for the entire cohort was 3.3years. One hundred and fifty-seven patients received adjuvant chemotherapy, of which 70% received initial platinum-based doublet therapy; 67.5% of patients were able to complete the intended six cycles of chemotherapy; of these, 34% experienced a dose reduction and 45% experienced one or more dose delays. Any dose delay was associated with a decrease in overall survival (p=0.02) and remained significant even after controlling for age, stage, and residual disease and number of chemotherapy cycles received (p=0.029). ConclusionsElderly EOC patients frequently required chemotherapy dose reductions and delays in chemotherapy administration. Multivariate analysis confirmed that dose delays are an independent factor associated with decreased OS.

Individualizing adjuvant therapy for early stage non-small cell lung cancer: we see the destination, but we don't yet know the route.

Though the survival benefit of adjuvant therapy for at least stage II-IIIA non-small cell lung cancer (NSCLC) has been demonstrated in multiple prospective randomized phase III trials, we should recognize that our approach to post-operative management of early stage NSCLC is relatively primitive. In hopes of curing more patients, we recommend a challenging, toxic therapy to all fit patients, despite understanding that many should already be cured with no further therapy. Moreover, we can readily appreciate that platinum-based doublet therapy is far more effective for some patients than for others and that, as we have now entered an era of molecularly-guided oncology treatment, specific targeted therapies may be far superior to conventional chemotherapy for prospectively identified populations.

New & Emerging Drugs for Squamous Cell Lung Cancer

Lung Cancer is the leading cause of cancer-related death worldwide. Squamous cell lung cancer (SQCLC) is the second most common histology (20-30% of cases) among non-small cell lung cancers (NSCLC), yet the treatment options remain limited [1]. The current standard for first line treatment of advanced or metastatic SQCLC consists of mainly platinum based chemotherapy. Recently, necitumumab in combination with platinum based doublet therapy was approved as front-line therapy. Second line options until recently included docetaxel, gemcitabine, nab-paclitaxel and erlotinib. Now newer agents including afatinib, ramucirumab/docetaxel, nivolumab and pembrolizumab are also available with superior clinical benefits