Chemotherapy In First-line Treatment Research Articles

Molecular response with blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia

AbstractMinimal residual disease (MRD), where leukemic cell levels are lower than the morphologic detection threshold, is the most important prognostic factor for acute lymphoblastic leukemia (ALL) relapse during first-line chemotherapy treatment and is standard of care in treatment monitoring and decision making. Limited data are available on the prognostic value of MRD response after relapse. We evaluated the relationship between MRD response and outcomes in blinatumomab-treated adults with relapsed/refractory (R/R) B-cell precursor ALL. Of 90 patients with complete remission (CR) or CR with partial hematologic recovery (CRh), 64 (71.1%) achieved a complete MRD response (no detectable individual rearrangements of immunoglobulin/T-cell receptor genes by polymerase chain reaction [PCR] at a minimum sensitivity level of 10−4). Eleven patients had MRD <10−4. Therefore, overall, 75 (83.3%) experienced an MRD response (no detectable MRD or detectable MRD) measured by PCR within the first 2 treatment cycles. Overall survival (OS) and relapse-free survival (RFS) were significantly longer in patients who achieved CR/CRh and MRD response (median, 20.6 and 9.0 months, respectively) compared with CR/CRh patients without MRD response (median, 12.5 and 2.3 months, respectively). In conclusion, longer durations of OS and RFS associated with MRD response support the value of achieving MRD response and its use as a prognostic factor for blinatumomab treatment in R/R ALL. This trial was registered at www.clinicaltrials.gov as #NCT01466179.

Role of Sonic hedgehog signaling in cell cycle, oxidative stress, and autophagy of temozolomide resistant glioblastoma.

The first-line chemotherapy treatment for Glioblastoma (GBM) - the most aggressive and frequent brain tumor - is temozolomide (TMZ). The Sonic hedgehog (SHH) pathway is involved with GBM tumorigenesis and TMZ chemoresistance. The role of SHH pathway inhibition in the potentiation of TMZ's effects using T98G, U251, and GBM11 cell lines is investigated herein. The combination of GANT-61 and TMZ over 72 hr suggested a synergistic effect. All TMZ-resistant cell lines displayed a significant decrease in cell viability, increased DNA fragmentation and loss of membrane integrity. For T98G cells, G2 /M arrest was observed, while U251 cells presented a significant increase in reactive oxygen species production and catalase activity. All the cell lines presented acidic vesicles formation correlated to Beclin-1 overexpression. The combined treatment also enhanced GLI1 expression, indicating the presence of select resistant cells. The selective inhibition of the SHH pathway potentiated the cytotoxic effect of TMZ, thus becoming a promising in vitro strategy for GBM treatment.

P2.01-26 EMPOWER-Lung 3: Phase 3 Study of Combinations of Cemiplimab and Chemotherapy in First-Line Treatment of Advanced NSCLC

P2.01-26 EMPOWER-Lung 3: Phase 3 Study of Combinations of Cemiplimab and Chemotherapy in First-Line Treatment of Advanced NSCLC

Les patients ALK et ROS1: quelle séquence ?

Crizotinib is a tyrosine kinase inhibitor of ALK (iALK) more effective and better tolerated that chemotherapy in first-line treatment of advanced non-small cell lung cancer with ALK fusion (ALK+ NSCLC). Crizotinib resistance will eventually occur in all patients. This is about on target resistance mutations in one third of the cases, bypass pathway emergence in one third and central nervous system progression in one third. Next generation iALK (ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) are effective at time of crizotinib failure. The “classic” iALK sequencing with crizotinib followed by next generation iALK is associated with survival from diagnosis of metastatic disease exceeding 4 years. The second-generation iALK alectinib demonstrated its superiority in terms of progression-free survival (34,8 mo. vs 11 mo. in ALEX trial), tolerability and cerebral disease control. This result paves the way for a new standard of care with alectinib front-line followed by lorlatinib. Crizotinib is the standard of care in ROS1+ NSCLC. Treatment at time of crizotinib failure is not well settle.

P2.01-01 Cemiplimab, a Human PD-1 Monoclonal Antibody, Versus Chemotherapy in First-Line Treatment of Advanced NSCLC with PD-L1 ≥50%

P2.01-01 Cemiplimab, a Human PD-1 Monoclonal Antibody, Versus Chemotherapy in First-Line Treatment of Advanced NSCLC with PD-L1 ≥50%

Retrospective analysis of patients with locally advanced or metastatic gastric cancer in Argentina.

To assess patient and disease characteristics, treatment patterns and associated costs in patients with locally advanced or metastatic gastric cancer in Argentina, in the public and private sectors. A historic cohort of patients who had received first-line chemotherapy treatment (platinum analog and/or a fluoropyrimidine) and were followed-up for at least three months after the last administration of a first-line cytotoxic agent were eligible. Case-report forms were prepared based on medical records from four Argentinian hospitals. Estimates of treatment costs were also calculated using the unit costs of the participating hospitals. Of 101 patients, more than three quarters (79.2%) were male, 41.6% were diagnosed with metastatic stage IV disease (mean age, 57.7years), and 27.7 % had a smoking history. Before locally advanced or metastatic gastric cancer diagnosis, 42.4% of the patients had received total gastrectomy. Ninety-seven percent of the patients received a doublet or triplet therapy, of which epirubicin in combination with oxaliplatin and capecitabine was the most common treatment (38%), followed by capecitabine plus oxaliplatin (29%). Around 36% of the patients responded to first-line treatment (complete and partial response). Out of the 76.2% of the patients who followed a second-line treatment, 37.7% were still administered a platinum analog and/or fluoropyrimidine. During the reported follow-up period, 50% of the patients progressed, and 32.8% had stable disease. The best supportive care consisted mostly of outpatient visits after last-line therapy (16.8%), palliative radiotherapy (16.8%), and surgery (30.7%). We observed significant differences between public and private hospital costs. Understanding treatment patterns in patients with locally advanced or metastatic gastric cancer may help address unmet medical needs for better patient management and improvement of their clinical outcome in Argentina.

&lt;p&gt;Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives&lt;/p&gt;

Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.

Radiological Response Patterns in Malignant Pleural Mesothelioma (MPM): Subgroup Analyses of the Phase 2 Stellar Trial of TTFields Plus Chemotherapy for First-Line Treatment

Radiological Response Patterns in Malignant Pleural Mesothelioma (MPM): Subgroup Analyses of the Phase 2 Stellar Trial of TTFields Plus Chemotherapy for First-Line Treatment

Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer.

Previous studies have demonstrated a significant difference in clinical characteristics between patients with non-small cell lung cancer (NSCLC) harboring exon 19 deletion (19-del) and an exon point mutation (21-L858R) in EGFR. The present retrospective study aimed to investigate the differential prognosis in patients with NSCLC harboring exon 19-del and 21-L858R mutations. The clinical and follow-up data of 137 patients treated at the Zhongnan Hospital of Wuhan University (Wuhan, Hubei, China) between August 2012 and August 2016, who were diagnosed with stage IIIB-IV NSCLC harboring either exon 19-del or 21-L858R mutations, were analyzed. The patients were divided into the first-line tyrosine kinase inhibitor (TKI), first-line chemotherapy and second-line TKI treatment groups. The median progression-free survival (PFS) time of patients harboring the exon 19-del mutation was significantly improved compared with that in patients harboring the 21-L858R mutation (11.3 vs. 8.8 months, respectively; P=0.017) following first-line TKI treatments. However, no significant difference in the median PFS time was observed between the exon 19-del and 21-L858R groups following the first-line chemotherapy or second-line TKI treatment. In patients with the exon 19-del, first-line TKI treatment achieved an increased objective response rate (ORR; 51.9 vs. 18.5%; P=0.004) and disease control rate (96.2 vs. 77.8%; P=0.030), and a longer PFS time (11.3 vs. 8.0 months; P=0.034) compared with that in the patients following first-line chemotherapy. First- and second-line TKI treatment achieved a similar PFS time (11.3 vs. 11.0 months, respectively; P=0.140). However, in patients with the 21-L858R mutation, the first-line TKI therapy and first-line chemotherapy groups exhibited a similar PFS time (8.8 vs. 3.5 months, respectively; P=0.063), while the second-line TKI treatment group exhibited a significantly longer PFS time compared with the first-line TKI treatment group (13.6 vs. 8.8 months, respectively; P=0.030). There was a differential sensitivity to treatment between patients harboring the exon 19-del and 21-L858R mutations. Therefore, chemotherapy may increase the sensitivity to TKIs in patients harboring the 21-L858R mutation.

Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy.

The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that-in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours-oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC.

Abstract 4771: The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose

Abstract Background: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU). The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently being evaluated in a randomized phase III clinical trial for recurrent high grade glioma (glioblastoma (GBM) and anaplastic astrocytoma) (NCT02414165, Toca 5). Temozolomide (TMZ), in combination with radiation therapy, is the standard of care used for first-line chemotherapy treatment of patients with GBM, the most common and aggressive form of primary brain cancer. Previously, we have shown that: (1) Toca 511/5-FC treatment provides durable response in a syngeneic murine glioma model and supports anti-tumor immune memory; (2) The combination of TMZ and Toca 511/5-FC had synergistic efficacy in a TMZ-sensitive human glioma nude mouse model; (3) TMZ did not inhibit the efficacy of Toca 511/5-FC in a TMZ resistant murine glioma syngeneic model; (4) Toca 511/5-FC caused significant radiosensitization in a radioresistant murine glioma model. Results: To assess the interaction of TMZ with escalating doses of Toca 511 (as defined by percent of tumor transduction by RRV), an orthotopic TMZ-resistant murine glioma model, Tu-2449, was utilized. These results show that moderate levels of tumor transduction of Toca 511 (30% - 50%) with 5-FC treatment prolongs survival in the presence of TMZ compared with lower transduction rates (10%). Additionally, mice treated with Toca 511/5-FC and TMZ are being tested for the establishment of anti-tumor immune memory. Conclusion: These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006). Citation Format: Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, Cornelia Bentley. The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4771.

Pertuzumab in combination with trastuzumab and chemotherapy for Chinese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: a subpopulation analysis of the JACOB trial

BackgroundThe JACOB trial (NCT01774786) was a double-blinded, placebo-controlled, randomized, multicenter, international, phase III trial evaluating the efficacy and safety of adding pertuzumab to trastuzumab and chemotherapy in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer/gastroesophageal junction cancer (GEJC). The aim of this analysis was to investigate efficacy and safety outcomes in the Chinese subpopulation from the JACOB trial.MethodsThis post hoc subpopulation analysis included all patients recruited in mainland China (n = 163; 20.9%) between June 2013 and January 2016. The patients were randomly assigned in a 1:1 ratio to receive pertuzumab plus trastuzumab and chemotherapy (pertuzumab group; n = 82) or placebo plus trastuzumab and chemotherapy (control group; n = 81). Intravenous pertuzumab (840 mg) and trastuzumab (8 mg/kg loading and 6 mg/kg maintenance doses) were given every 3 weeks until disease progression or unacceptable toxicity. Chemotherapy was given as per standard regimens/doses of capecitabine or 5-fluorouracil plus cisplatin. The primary endpoint was overall survival (OS); secondary efficacy endpoints included progression-free survival (PFS), and overall objective response rate (ORR).ResultsThe median OS was 18.7 months in the pertuzumab group and 16.1 months in the control group (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.49 to 1.14). The median PFS was 10.5 and 8.6 months in the pertuzumab and control groups, respectively (HR 0.85; 95% CI 0.60 to 1.21), and the median ORRs were 68.9% and 55.7%, respectively. The treatment effect in this Chinese subpopulation showed consistency with that in the global ITT population with numerically lower HR for OS and PFS compared with the control group. The safety profiles of the pertuzumab and control groups in this Chinese subpopulation analysis were generally comparable. The most common grade 3–5 adverse events were neutropenia, anemia, and leukopenia. However, due to the nature of being a post hoc subgroup analysis, the results presented here are descriptive only and need to be interpreted with caution.ConclusionsOS and PFS were numerically improved by adding pertuzumab to trastuzumab and chemotherapy as first-line treatment in Chinese HER2-positive gastric cancer/GEJC patients, and this regimen demonstrated an acceptable safety profile.Trial registration ClinicalTrials.gov. NCT01774786. Registered on 24 January 2013, https://clinicaltrials.gov/ct2/show/NCT01774786

Retrospective analysis of patients with advanced or metastatic gastric cancer in Colombia

Aims: To assess patient and disease characteristics, treatment patterns, and associated costs in patients with advanced or metastatic gastric cancer (A/MGC) in Colombia, in both the public and private hospitals.Materials and methods: A total of 145 patients who had received first-line chemotherapy treatment (platinum analog and/or a fluoropyrimidine) and were followed for at least 3 months after the last administration of a first-line cytotoxic agent were eligible for inclusion. Case-report forms were elaborated based on the patients’ medical records from three Colombian hospitals. Estimates of treatment costs were calculated using unit costs from the participating hospitals.Results: Of the 145 patients, more than half (64.83%) were male, 79.56% were diagnosed with metastatic stage IV disease (mean age = 58.14 years). Prior to MGC diagnosis, 31.71% of the patients being operated on received a total gastrectomy; 66.9% of the patients received a doublet therapy, of which 5-fluorouracil (5-FU) in combination with cisplatin was the standard treatment (14%), followed by combination with leucovorin (12%). Only around 10% of the patients responded to first-line treatment. Out of 41.38% of the patients who received a second-line treatment, 71.67% were still administered a platinum analog and/or fluoropyrimidine. During the follow-up period, 52% of the patients progressed and 20% achieved stable disease. Best supportive care mostly consisted of outpatient visits after last line-therapy (72.41%), palliative radiotherapy (18.6%), and surgery (37.2%).Limitations and conclusions: Gastric cancer is one of the main causes of cancer-related death in Colombia, as most of the patients are diagnosed at an advanced stage, when prognosis is poor. Treatment patterns are highly heterogeneous. Second-line treatments were mostly initiated with paclitaxel, capecitabine, irinotecan, or cisplatin.

Immunotherapy plus chemotherapy versus chemotherapy alone in metastatic non–small-cell lung cancer: A systematic review with meta-analysis.

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p &lt; 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p &lt; 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p &lt; 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

e20558 Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemoimmunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through January 31, 2019. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Nine phase 2 &amp; 3 RCTs (Keynote – 021,189, 407, IMpower – 130, 131, 132, 150, checkmate-227, and Govindan et al) including 5042 patients with advanced NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.65 (95% CI: 0.57-0.73; P = 0.00001), the pooled HR for OS was 0.72 (95% CI: 0.61-0.86; P = 0.0003), and the pooled RR for ORR was 1.45 (95 CI: 1.23-1.72; P = 0.0001). The pooled RRs for all-grade AEs and high-grade AEs were 1.03 (95% CI: 0.99-1.07; P = 0.13) and 1.21 (95% CI: 1.1-1.34; P = 0.0001), respectively. Conclusions: The combined chemoimmunotherapy can significantly improve PFS, OS, and ORR compared to standard chemotherapy for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.

MiR-20a-5p regulates gemcitabine chemosensitivity by targeting RRM2 in pancreatic cancer cells and serves as a predictor for gemcitabine-based chemotherapy.

Ribonucleotide reductase subunit M2 (RRM2) acts as an important gemcitabine resistance-related gene in pancreatic cancer (PC). Here, we aimed to investigate the potential microRNA that regulates gemcitabine chemosensitivity by targeting RRM2 and explores the clinical significance of candidate miRNA in PC. MTT assay and Western blot analysis revealed that long-time gemcitabine treatment in PC cells induced drug resistance and RRM2 increase, and silence of RRM2 blocked gemcitabine resistance. Among the predicted eight RRM2-related microRNAs, the expression of miR-20a-5p showed the most significant discrepancy between gemcitabine-resistant cells and parental cells. Furthermore, the Dual-Luciferase reporter gene assay indicated that miR-20a-5p directly targeted RRM2 3′UTR, thus inhibited expression of RRM2 and overcame gemcitabine resistance of PC cells. Retrospective study suggested that plasma miR-20a-5p level was correlated with gemcitabine resistance in PC patient. ROC curve showed that miR-20a-5p abundant level might predict gemcitabine resistance with an AUC of 89% (P<0.0001). Additionally, the PFS of patients with high and low expression levels miR-20a-5p was 2.8 and 4.5 months (P<0.001), respectively. Taken together, our results suggests that miR-20a-5p regulated gemcitabine chemosensitivity by targeting RRM2 in PC cells and could serve as a predictor for predicting the efficacy of gemcitabine-based chemotherapy in first-line treatment of PC patients.

Tumor Treating Fields plus chemotherapy for first-line treatment of malignant pleural mesothelioma: Final Results of the STELLAR Trial

Tumor Treating Fields plus chemotherapy for first-line treatment of malignant pleural mesothelioma: Final Results of the STELLAR Trial

Cisplatin-Based Chemotherapy of Human Cancers.

Cisplatin (cis-diammine-dichloro-platinum II) was initially discovered to prevent the growth of Escherichia coli and was further recognized for its anti-neoplastic and cytotoxic effects on cancer cells. Administered intravenously to humans, cisplatin is used as first-line chemotherapy treatment for patients diagnosed with various types of malignancies, such as leukemia, lymphomas, breast, testicular, ovarian, head and neck, and cervical cancers, and sarcomas. Once cisplatin enters the cell it exerts its cytotoxic effect by losing one chloride ligand, binding to DNA to form intra-strand DNA adducts, and inhibiting DNA synthesis and cell growth. The DNA lesions formed from cisplatin-induced DNA damage activate DNA repair response via NER (nuclear excision repair system) by halting cisplatin-induced cell death by activation of ATM (ataxia telangiectasia mutated) pathway. Although treatment has been shown to be effective, many patients experience relapse due to drug resistance. As a result, other platinum compounds such as oxaliplatin and carboplatin have since been used and have shown some levels of effectiveness. In this review, the clinical applications of cisplatin are discussed with a special emphasis on its use in cancer chemotherapy.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced squamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

121 Background: Squamous Non-small cell lung cancer (NSCLC) accounts for ~30% of lung cancers, and long-term survival remains poor for advanced disease. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 3 RCTs (Keynote – 407, IMpower – 131, and Govindan et al) including 1991 patients with advanced squamous NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, or atezolizumab, while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.71 (95% CI: 0.56-0.9; P = 0.005), the pooled HR for OS was 0.84 (95% CI: 0.68-1.04; P = 0.11), and the pooled RR for ORR was 1.19 (95 CI: 0.9-1.56; P = 0.22). The pooled RRs for all-grade AEs and high-grade AEs were 1.17 (95% CI: 0.99-1.39; P = 0.07) and 1.36 (95% CI: 1.19-1.56; P = 0.0001), respectively. Conclusions: The combined chemo-immunotherapy improves PFS without significant improvement in OS &amp; ORR compared to standard chemotherapy for the first-line treatment of advanced squamous NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

117 Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥ grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Seven phase 2 &amp; 3 RCTs (Keynote-021,189, 407, IMpower-131, 150, checkmate-227, and Govindan et al) including 3785 patients with advanced NSCLC were included in the analysis. IMpower 150 trial allowed EGFR or ALK mutated patients. The study arm used standard treatment regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab, while control arm used only standard treatment regimens. The pooled HR for PFS was 0.65 (95% CI: 0.56-0.77; P=0.00001), the pooled HR for OS was 0.73 (95% CI: 0.59-0.90; P=0.003), and the pooled RR for ORR was 1.45 (95 CI: 1.17-1.8; P=0.0007). The pooled RRs for all-grade AEs and high-grade AEs were 1.1 (95% CI: 1-1.21; P=0.05) and 1.28 (95% CI: 1.13-1.46; P=0.0001), respectively. Conclusions: Adding immunotherapy to standard regimen significantly improves PFS, OS, and ORR for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.