27-gene Immuno-Oncology (IO) Score is Associated With Efficacy of Checkpoint Immunotherapy in Advanced NSCLC: A Retrospective BC Cancer Study

BackgroundImmune checkpoint inhibitors (ICI) are standard of care in advanced non-small cell lung cancer (NSCLC). However, not all patients benefit, even among PD-L1 tumor proportional score (TPS) ≥50%, indicating an unmet need for additional biomarkers such as those assessing the tumor immune microenvironment (TIME). DetermaIO is a 27-gene assay that classifies TIME and has previously demonstrated association with ICI response.MethodsFFPE samples were selected from BC Cancer and West Clinic Cancer Center patients with performance status (PS) ≤2 who received at least 2 cycles of ICI monotherapy in the first (1L) or second line (2L). IO scores were generated and analyzed for association with PFS and OS.ResultsIn the entire cohort (N=147), IO score was significantly associated with OS (HR=0.68, 95%CI 0.47-0.99, P = .042) and PFS (HR=0.62, 95%CI 0.43-0.88, P = .0069). In 1L treated patients (PD-L1≥50%, N=78), IO score was significantly associated with PFS (HR=0.55, 95%CI 0.32-0.94, P = .028). In exploratory analyses, IO score was associated with benefit in 1L PS2 patients for OS (HR = 0.26, 95%CI 0.091-0.74, P = .012) and PFS (HR = 0.27, 95%CI 0.098-0.72, P = .0095) which was confirmed in PFS subgroup analysis in the independent West Cancer Center study (N=13 HR=0.14, 95%CI 0.027-0.76, P = .023).ConclusionThese data confirm the association of DetermaIO with ICI clinical benefit in NSCLC, and expand on previous studies by demonstrating that first line treated PD-L1≥50% patients can further be stratified by IO score to identify efficacy. Exploratory analysis suggested that the IO score identifies benefit in patients with poor PS.     

Prognostic and Predictive Role of Body Mass Index (BMI) in Metastatic Colorectal Cancer (mCRC): A Pooled Analisys of Tribe and Tribe-2 Studies by GONO

BackgroundObesity is associated with an increased risk of development and recurrence of colorectal cancer. The role of obesity in metastatic colorectal cancer patients (pts) is still unclear, especially in those treated with triplet plus bevacizumab (bev). The aim of our study was to evaluate the prognostic and predictive role of BMI in metastatic colorectal cancer pts treated with FOLFOXIRI plus bev or FOLFIRI/FOLFOX plus bev in the TRIBE and TRIBE-2 trial.materials and MethodsA total of 1160 pts enrolled in TRIBE and TRIBE-2 trials were included. Baseline height and weight were used to assign pts to one of the following BMI categories: underweight (group A = BMI <18.5 kg/m²; 52 pts), normal (group B = BMI 18.5-29.9 kg/m²; 952 pts) and obese (group C > 30 kg/m²; 156 pts).ResultsIn our population, no differences in terms of PFS (P = .43) or OS (P = .99) resulted between 3 groups. No interaction effect between treatment arm and BMI was evident in terms of PFS (Group A HR: 0.65 [95%CI: 0.36-1.16]; Group B HR: 0.77 [95%CI: 0.67-0.88]; Group C HR: 0.67 [95%CI: 0.48-0.93]; P for interaction = .75) or OS (Group A HR: 0.57 [95%CI: 0.29-1.12]; Group B HR: 0.85 [95%CI: 0.73-0.99];Group C HR: 0.69 [95%CI: 0.48-1.01] P for interaction = .36). No statistically significant difference in terms of dose reductions due to toxicities were found according to BMI in the overall population (P = .48) and in pts treated with FOLFOXIRI plus bev (P = .57).ConclusionBMI was neither prognostic or predictive for PFS and OS in our population. Our analyses showed that the advantage of FOLFOXIRI plus bev versus FOLFIRI/FOLFOX plus bev was independent from BMI.     

Ixabepilone plus capecitabine in metastatic breast cancer patients with reduced performance status previously treated with anthracyclines and taxanes: a pooled analysis by performance status of efficacy and safety data from 2 phase III studies

Patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes often have decreased performance status secondary to extensive tumor involvement. Here, we report the pooled analysis of efficacy and safety data from two similarly designed phase III studies to provide a more precise estimate of benefit of ixabepilone plus capecitabine in MBC patients with Karnofsky’s performance status (KPS) 70–80. Across the studies, anthracycline/taxane-pretreated MBC patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individual patient data for KPS 70–80 subset (n = 606) or KPS 90–100 subset (n = 1349) from the two studies were pooled by treatment. Analysis included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety. In patients with reduced performance status (KPS 70–80), ixabepilone plus capecitabine was associated with improvements in OS (median: 12.3 vs. 9.5 months; HR, 0.75; P = 0.0015), PFS (median: 4.6 vs. 3.1 months; HR, 0.76; P = 0.0021) and ORR (35 vs. 19%) over capecitabine alone. Corresponding results in patients with high performance status (KPS 90–100) were median OS of 16.7 versus 16.2 months (HR, 0.98; P = 0.8111), median PFS of 6.0 versus 4.4 months (HR, 0.58; P = 0.0009), and ORR of 45 versus 28%. The safety profile of combination therapy was similar between the subgroups. Ixabepilone plus capecitabine appeared to show superior efficacy compared to capecitabine alone in MBC patients previously treated with anthracyclines and taxanes, regardless of performance status, with a possible OS benefit favoring KPS 70–80 patients (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433).     

Pre-treatment serum lactate dehydrogenase level is an important prognostic factor in high-grade extremity osteosarcoma

Background  Treatment of high-grade osteosarcoma remains a challenge. The prognostic significance of the pre-treatment serum lactate dehydrogenase (LDH) level is currently controversial. Patients and methods  We reviewed records from all patients diagnosed with conventional high-grade osteosarcoma at our institution over a 25-year period and analysed the prognostic significance of LDH in high-grade localised extremity osteosarcomas treated with chemotherapy. Results  Between June 1977 and March 2003, 66 patients for whom follow-up was available were diagnosed with localised high-grade extremity osteosarcoma and treated with chemotherapy. The median age was 15 years, with only 3% older than 40 years, and the median follow-up was 100 months. The median progression-free survival (PFS) was 67 months and the median overall survival (OS) was 113 months. The absence of a response to chemotherapy was correlated with a trend toward lower PFS and OS. High serum pre-treatment LDH level was associated in multivariate analyses with a poorer prognosis for both PFS (HR=8.623, 95%CI: 1.71–43.37; p=0.009) and for OS (HR=9.38; 95%CI: 1.73–50.74; p=0.009). Conclusion  In this series, the pre-treatment serum LDH level had an independent prognostic value for both PFS and OS in patients with high-grade localised extremity osteosarcoma. This measurement should be included in a large prospective prognostic series.     

Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

In LUX‐Lung 3, afatinib significantly improved progression‐free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation‐positive lung adenocarcinoma patients and overall survival (OS) in Del19 patients. Preplanned analyses in Japanese patients from LUX‐Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut‐off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut‐off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment‐related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation‐positive lung adenocarcinoma patients and OS in Del19 but not L858R patients ( www.clinicaltrials.gov ; NCT00949650).     

Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial

The Insulin‐like growth factor (IGF)/IGF‐receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF‐1R SNPs in mCRC patients enrolled in the FIRE‐3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1‐IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct‐sequencing in the FIRE‐3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan–Meier method and log‐rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/‐ carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03‐1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/‐ variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64‐0.92], p = 0.004) and in multivariable. In the RAS wild‐type subgroup IGF1 rs2946834 T/‐ carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51–0.81], p < 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50–0.81], p < 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild‐type mCRC patient.     

Exceeding 30 ELNs is strongly recommended for pT3-4N0 patients with gastric cancer: A multicenter study of survival,recurrence, and prediction model

The argument concerning the exact minimum number of examined lymph nodes (ELNs) has continued for a long time among various regions, and no consensus has been reached for stratified pathological T stages for data to date. Data from 4607 pN0 patients with gastric cancer were analyzed. Kaplan-Meier analysis showed the similar overall survival (OS) outcomes among the 3 groups (ELNs ≤ 15, 16 ≤ ELNs ≤ 29 and ELNs ≥ 30, P = .171). However, the ELNs ≥ 30 group had a better disease-free survival (DFS) outcome compared with the others (all P < .05). An increased ELN group (ELNs ≥ 30) showed an improved OS only for pT3 patients (hazard ratio [HR] = 0.397, 95% confidence interval (CI): 0.182-0.866, P = .020), while an improved DFS for pT3 patients (HR = 0.362, 95%CI: 0.152-0.860, P = .021) and pT4 patients (HR = 0.484, 95%CI: 0.277-0.844, P = .011) in the multivariate analysis. A well discriminated and calibrated nomogram was constructed to predict the probability of the OS and DFS, with the C-index for OS and DFS prediction of 0.782 (95%CI: 0.735 to 0.829) and 0.738 (95%CI: 0.685 to 0.791), respectively. This study provides new and useful insights into the impact of ELN count on reducing stage migration and postoperative recurrence of pN0 patients with gastric cancer in 2000-2017. In conclusion, a larger number of ELNs is suggested for surgeons to prolong the prognosis of pN0 gastric cancer, especially for pT3 patients.     

Long Term Survival With Regorafenib: REALITY (Real Life in Italy) Trial - A GISCAD Study

BackgroundRegorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available.Patients and MethodsREALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression).ResultsHundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086).ConclusionThese 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.     

Outcomes of HTLV-1 Carriers with Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Matched Cohort Study

BackgroundThe human T-cell lymphotropic virus type 1 (HTLV-1) is associated with aggressive diseases, such as adult T-cell leukemia/lymphoma (ATLL). However, less is known on the impact of HTLV-1 infection in non-ATLL hematologic malignancies. We aimed to investigate if HTLV-1 carriers with diffuse large B-cell lymphoma (DLBCL) have worse survival outcomes than non-HTLV-1 carriers.Materials and MethodsWe performed a single-center retrospective cohort study by matching HTLV-1 carriers to non-carriers based on age, sex, Ann Arbor stage, and year of diagnosis. Our outcomes of interest were overall survival (OS) and progression-free survival (PFS). The Kaplan-Meier method was used to estimate OS and PFS between carriers and non-carriers. We fitted multivariate Cox regression models to assess the mortality and recurrence/disease progression risk of HTLV-1 infection.ResultsA total of 188 patients, 66 with HTLV-1 infection and 122 without HTLV-1, were included in the study. HTLV-1 carriers had higher extranodal involvement than non-carriers (47% vs. 27%, P = .010). With a median follow-up of 78 months (95% CI: 41-90 months), HTLV-1 carriers had a similar 5 year OS (41% vs. 42%, P = .940) and PFS (34% vs. 32%, P = .691) compared to non-carriers. In the multivariate Cox analysis, HTLV-1 infection was not associated with worse OS (aHR: 0.98, 95% CI: 0.64-1.50) or PFS (aHR: 0.90, 95% CI: 0.60-1.34).ConclusionHTLV-1 carriers with DLBCL did not have worse survival outcomes compared to non-carriers. Our results suggest that clinicians should follow standard guidelines for DLBCL management on HTLV-1 seropositive patients.     

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer

BackgroundOlaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes.Patients and methodsNinety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression.ResultsIn this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension.ConclusionsCombination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status.Trial RegistrationClinicaltrials.gov Identifier NCT0111648     

Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

BackgroundPaclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy.MethodsA total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed.ResultsThe median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5–9.6 months) and 26.9 months (95% CI: 23.6–30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1–6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13–10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity.ConclusionGenetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted.     

Serum matrilysin correlates with poor survival independently of <Emphasis Type="Italic">KRAS</Emphasis> and <Emphasis Type="Italic">BRAF</Emphasis> status in refractory advanced colorectal cancer patients treated with irinotecan plus cetuximab

The purpose of the study was to prospectively explore the role of serum MMP-7 as a predictive and prognostic marker of anti-epidermal growth factor receptor (EGFR) therapy and irinotecan efficacy in third-line advanced colorectal cancer therapy. One hundred patients were recruited prospectively from six Spanish hospitals. Patients were treated with biweekly irinotecan 180 mg/m² and cetuximab 400 mg/m² (loading dose) and weekly cetuximab 250 mg/m² until progressive disease or unacceptable toxicity. Baseline MMP-7 was determined using a quantitative solid-phase sandwich ELISA. KRAS and BRAF mutational status were also assessed. The clinical endpoints examined were overall survival (OS), progression-free survival (PFS), and response rate. No association between serum MMP-7 and neither KRAS nor BRAF mutational status was found. The multivariate analysis revealed that MMP-7 predicts PFS both in wild-type (WT) KRAS patients (HR 1.03, 95% CI 1.00–1.06; p = 0.046) and in mutant KRAS patients (HR 1.18, 95% CI 1.01–1.35; p = 0.036). The presence of mutant BRAF was associated with shorter PFS (HR 8.49, 95% CI 2.88–25.0; p < 0.001) and worse OS (HR 3.55, 95% CI 1.39–9.09; p = 0.008) in the subset of WT KRAS patients. Serum MMP-7 is associated with PFS in colorectal patients treated with anti-EGFR therapy as third-line treatment independently of KRAS status.     

BRCA1/2 Mutation Types Do Not Affect Prognosis in Ovarian Cancer Patients

Background: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. Methods: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1–27.5) and the median OS was 92.9 months (95% CI 69.8–116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. Conclusions: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.     

Post-induction Strategies in Metastatic Colorectal Cancer Patients Treated With First-Line Anti-EGFR-Based Treatment: A Systematic Review and Meta-Analysis

Few data from randomized clinical trials (RCTs) investigating the efficacy of post-induction strategies after the first-line treatment with anti-Epidermal Growth Factor Receptor (EGFR) in patients with metastatic colorectal cancer (mCRC) are available. A systematic review and metanalysis might therefore be useful to highlight and even strengthen these data. A literature search in Pubmed, Embase, American Society of Clinical Oncology (ASCO) Annual Meetings, ASCO Gastrointestinal Symposia, and European Society for Medical Oncology (ESMO) Congresses was performed. The search included RCTs of patients with mCRC treated with an initial period of cytotoxic chemotherapy (CT) in association with anti-EGFR (ie, panitumumab or cetuximab) as first-line regimen, and then switched to one of the following strategies: observation; maintenance with anti-EGFR, fluoropyrimidine (FP), or both; or continuing the induction regimen until disease progression or unacceptable toxicity. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the Mantel–Haenszel method fixed-effect model or the DerSimonian-Laird method random-effect model according to heterogeneity (I²). Analysis was performed on June 9, 2021. 7 studies (all phase II trials), including 1038 patients, were considered eligible for the meta-analysis. In all studies, CT (induction or maintenance with FP) + anti-EGFR until disease progression or unacceptable toxicity prolonged OS (HR = 0.72 [95%CI 0.61-0.86]; P < .01) and PFS (HR = 0.76, 95%CI 0.68-0.85; P < .01) compared to other agents (FP ± bevacizumab) or observation. Subgroup analyses for OS and PFS were performed according to type of maintenance therapy (containing or not containing single-agent anti-EGFR). Within patients evaluable for OS, CT + anti-EGFR combinations continued until disease progression were able to decrease the risk of death by 32% (HR 0.68; 95% CI 0.56-0.84; P < .01) and the risk of progression by 25% (HR 0.75; 95% CI 0.65-0.85; P < .01) over no maintenance or maintenance with anti-EGFR alone. Conversely, combination of CT + anti-EGFR were no better over anti-EGFR with FP in term of OS (HR = 0.81 [95%CI 0.60-1.09]; P = .17) and PFS (HR = 0.81 [95% 0.64, 1.01]; P = .06). Maintenance treatment with anti-EGFR + FP might be regarded as the better option following anti-EGFR based induction treatment in RAS wild-type mCRC, in terms of efficacy. This effect might be particularly amplified in left-sided BRAF wild-type mCRC patients. A higher level of evidence coming from phase III trials is auspicable.     

Effectiveness of neoadjuvant chemotherapy on the survival outcomes of patients with resectable non-small-cell lung cancer: A meta-analysis of randomized controlled trials

PurposeTo determine the effectiveness of neoadjuvant chemotherapy (NACT) versus primary surgery on survival outcomes for resectable non-small-cell lung cancer (NSCLC) using an approach based on a meta-analysis.MethodsThe PubMed, EmBase, Cochrane library, and CNKI databases were systematically browsed to identify randomized controlled trials (RCTs) which met a set of predetermined inclusion criteria throughout January 2020. Hazard ratios (HRs) were applied for the pooled overall survival (OS) and progression-free survival (PFS) values, and the pooled survival rates at 1-year and 3-year were used as the relative risk (RR). All the pooled effect estimates with 95% confidence intervals (CIs) were calculated using the random-effects model.ResultsNineteen RCTs contained a total of 4372 NSCLC at I-III stages was selected for final meta-analysis. We noted NACT was significantly associated with an improvement in OS (HR: 0.87; 95%CI: 0.81–0.94; P < 0.001) and PFS (HR: 0.86; 95%CI: 0.78–0.96; P = 0.005). Moreover, the survival rate at 1-year (RR: 1.07; 95%CI: 1.02–1.12; P = 0.007) and 3-year (RR: 1.16; 95%CI: 1.06–1.27; P = 0.001) in the NACT group was significantly higher than the survival rate for the primary surgery group. Finally, the treatment effects of NACT versus primary surgery on survival outcomes might be different when stratified by the mean age of patients and the tumor stages.ConclusionsNACT could improve survival outcomes for patients with resectable NSCLC, suggesting its suitable future applicability for clinical practice. However, large-scale RCT should be conducted to assess the chemotherapy regimen on the prognosis of resectable NSCLC.     

Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non-HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild-type HRD, n = 478) vs. non-HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non-HRD subgroup. Within the HRD subgroup, the BRCA-mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03–5.08) and PFS12 (OR: 1.95, 95% CI: 1.26–3.01) when compared to BRCA wild-type patients. Furthermore, within BRCA wild-type carcinomas, mutations in other HRD-related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27–2.43) and PFS12 (OR: 1.85, 95% CI: 1.31–2.62), as compared to non-HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non-HRD carcinomas. In addition to BRCA mutations, other non-BRCA HRD-related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy.     

Randomized study of FOLFIRI plus either panitumumab or bevacizumab for wild‐type KRAS colorectal cancer‐WJOG 6210G

This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second‐line chemotherapy for wild‐type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first‐line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76–1.77], respectively. Progression‐free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78–1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor‐A (VEGF‐A) levels and worse in those with low levels (P for interaction = 0.016). Second‐line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.     

Final results of the CAVE trial in RAS wild type metastatic colorectal cancer patients treated with cetuximab plus avelumab as rechallenge therapy: Neutrophil to lymphocyte ratio predicts survival

BackgroundHigh neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic factor in metastatic colorectal cancer (mCRC). Here we provide final results of CAVE mCRC trial, of cetuximab plus avelumab rechallenge in chemo-refractory mCRC patients and investigated the predictive role of NLR.MethodsAll the 77 patients enrolled were included in the analysis. A cut-off of 3 was used to correlate baseline NLR with with overall survival (OS) and with progression free survival (PFS), in intention to treat (ITT) and in circulating tumor DNA (ctDNA) RAS/BRAF Wild Type (WT) patients.ResultsIn ITT population, NLR <3 (49%) group had median overall survival (mOS) of 17.8 months, vs. 8.9 months in NLR ≥ 3 group (51%) [HR 0.50, (CI 95% 0.3-0.8), P = .006]. Median progression free survival (mPFS) was 3.9 months in NLR <3 group and 3.5 months in NLR≥3 [HR 0.79, (CI 95% 0.5-1.24), P = .3]. In ctDNA RAS/BRAF WT population, mOS was 22 months in NLR <3 group (48%), vs. 8.9 months in NLR ≥3 group (52%), [HR 0.38, (CI 95% 0.19-0.75), P = .005]. A trend towards increased mPFS was observed in patients with NLR <3 versus NLR ≥3: 5.3 vs. 3.6 months [HR: 0.79, (CI 95% 0.44-1.4), P = .43]. In contrast, NLR did not correlate either with PFS or OS in ctDNA RAS/BRAF mutated patients.ConclusionIn the exploratory analysis of the CAVE mCRC trial, baseline NLR <3 significantly correlated with improved survival and may represent a potential predictive biomarker of cetuximab plus avelumab rechallenge activity in ctDNA RAS/BRAF WT patients, that must be confirmed in randomized studies.     

Safety and efficacy study of oral metronomic vinorelbine combined with trastuzumab (mNH) in HER2-positive metastatic breast cancer: a phase II trial

Purpose

We conducted a single-arm prospective phase II trial to evaluate the efficacy and safety of oral metronomic vinorelbine combined with trastuzumab (mNH) in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer (MBC) patients.

Methods

HER2-positive MBC patients received oral vinorelbine 40 mg thrice a week and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoints were objective response rate (ORR), clinical benefit rate (CBR; CR?+?PR?+?SD for?≥?24 weeks). The secondary endpoints were progression-free survival (PFS), tolerability, and overall survival (OS).

Results

Twenty patients with HER2-positive MBC were enrolled, with a median of 1 prior chemotherapy regimens for MBC. Median age was 61.5 years (95% Confidence Interval (CI) 48.6–63.1). Visceral involvements presented in 14 patients (70.0%). ORR was 20.0%, and CBR was 75% with 4 PR (20.0%) and 11 SD (55.0%). The median PFS (mPFS) and median OS (mOS) were 7.4 months (95% CI 3.2–11.5) and 45.8 months (95%CI: not reached), respectively. The mPFS was 17.7 months (95%CI not reached) and 5.8 months (95%CI 5.6–5.9) in mNH as first-line and?≥?second-line therapy (log rank p?=?0.03), respectively. The most common grade 1 adverse events (AEs) included nausea (15%), leukopenia (15%), ALT/AST elevation (15%), diarrhea (10%), and peripheral neuropathy (10%). Grade 2 adverse events included leukopenia (5%) and neutropenia (10%). No grade 3/4 AEs were observed.

Conclusions

Oral metronomic vinorelbine combined with trastuzumab is a well-tolerated and effective anti-tumor regimen for HER2-positive MBC.

     

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

BackgroundRapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Materials and MethodsArchival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).ResultsFifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005).ConclusionsA low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.