Progression-free Survival Curves Research Articles

Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucose positron emission tomography uptake in non-small cell lung cancer.

The epithelial-to-mesenchymal transition (EMT) phenotype-based subsets of circulating tumor cells (CTCs) might be predictors of tumor progression. We evaluated the clinical properties of different phenotypic CTCs in patients with non-small cell lung cancer (NSCLC). Secondly, we explored the association between different phenotypic CTCs and the uptake of 18F-fluorodeoxyglucose (FDG) by the primary tumor on a positron emission tomographic (PET) scan. Venous blood samples from 34 pathologically confirmed Stage IIB-IVB NSCLC patients were collected prospectively. CTCs were immunoassayed using a SE-i·FISH®CTC kit. We identified CTCs into cytokeratin positive (CK+) and cytokeratin negative (CK-) phenotypes. CTC classifications were correlated with the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Overall survival (OS) and progression-free survival (PFS) curves were produced using the Kaplan-Meier method. CTCs were detected in 91.2% of NSCLC patients. CTC counting was associated with TNM stage (P = 0.014) and distant metastasis (P = 0.007). The number of CK-CTCs was also positively associated with TNM stage (P = 0.022) and distant metastasis (P = 0.007). Both total CTC counting and CK-CTC counting did not show association with SUVmax value (P = 0.959, P = 0.903). Kaplan-Meier survival analysis demonstrated that patients with ≥ 7 CTCs had shorter OS (P = 0.003) and PFS (P = 0.001)relativeto patients with < 7 CTCs). Notably, the number of CK-CTCs can act as independent risk factors for PFS (P = 0.044) and OS (P = 0.043) in NSCLC patients. However, SUVmax value was not associated with OS (P = 0.895) and PFS (P = 0.686). The CTC subpopulations could be useful evidence for testing metastasis and prognosis in NSCLC patients. The SUVmax value of the primary tumor was not related to prognosis in patients with NSCLC.

Incremental cost-effectiveness analysis of tyrosine kinase inhibitors in advanced non-small cell lung cancer with mutations of the epidermal growth factor receptor in Colombia

ABSTRACT Objective To estimate the cost-effectiveness of sequences starting with tyrosine kinase inhibitors (TKI), afatinib and osimertinib, for the treatment of epidermal growth factor receptor (EGFR) mutation-positive (Exon 19 deletion or L858R) non-small cell lung cancer (NSCLC), stages IIIB – IV in Colombia. Methods A partitioned survival model was designed, using information from global and progression-free survival curves. For first and second-generation TKI, second line treatment was assumed according to the presence of T790M mutation to define the use of osimertinib or chemotherapy. The cost of the states without progression and post-progression was estimated using the base case approach, identified through consultation with clinical experts. Results The cost of treatment starting with afatinib in the first line was of 222,247 USD (1 USD = 3171.99 COP) and produced 1.36 QALYs. The strategy with afatinib was dominant with respect to that of first line TKI (227,289 USD and 1.34 QALY). The strategy with osimertinib resulted in more QALYs and higher costs, with ICERs of 35,062 USD, exceeding the current willingness to pay threshold for Colombia. Conclusions Treatment starting with afatinib in the first line is dominant with respect to the strategy with first line TKI. The ICER of osimertinib sequence exceeds the threshold when compared with afatinib one.

Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Splenic Marginal Zone Lymphoma

IntroductionSplenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin lymphoma usually with a good prognosis, but no clear metabolic behavior at fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). The aim of our analysis was to investigate the prognostic role of baseline 18F-FDG PET/CT parameters in SMZL. Materials and MethodsWe retrospectively included 42 patients who received 18F-FDG-PET/CT before any treatments, and PET images were evaluated visually and semi-quantitatively by measuring lesion to liver (L-L) maximum standardized uptake volume (SUVmax) ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume, and total lesion glycolysis. Progression-free (PFS) and overall survival (OS) curves were plotted according to the Kaplan-Meier method. ResultsIn all patients, an increased splenic FDG uptake (higher than the background) was identified, showing the presence of diffuse spleen uptake in 35 patients and focal uptake in the remaining 7 patients. At a median follow-up of 51 months, relapse or progression of disease occurred in 23 patients with an average time of 38.1 months from the baseline 18F-FDG PET/CT, and death occurred in 4 patients with an average time of 26.8 months. The estimated 2-year PFS and OS rates were 78% and 90%, respectively, whereas 5-year PFS and OS rates were 63% and 82%, respectively. At multivariate analysis, only L-L SUV R and L-BP SUV R were independent prognostic factors for PFS. In addition, no significant association was discovered for OS, considering all features. ConclusionsL-L SUV R and L-BP SUV R were independently correlated with PFS.

Potential insights from population kinetic assessment of progression-free survival curves.

Progression-free survival (PFS) curves follow first order kinetics on exponential decay nonlinear regression analysis (EDNLRA). Some exhibit 1-phase-decay, some have 2-phase-decay, some are convex. We digitized, performed EDNLRA and generated log-linear plots for 887 published PFS curves for incurable solid tumors treated with various systemic therapies. Proportion of curves fitting 2-phase-decay varied by therapy (p < 0.0001). For 13 therapies, >64 % of PFS curves had 2-phase-decay. This included epidermal growth factor receptor inhibitors in unselected lung cancer patients (some with, some without mutations), immune checkpoint inhibitors, interferon, breast cancer hormonal therapies, and selected others, suggesting 2 distinct, potentially identifiable subpopulations with differing progression rates. For 22 other therapies, <25 % of PFS curves had 2-phase-decay. Only 1 therapy was in the mid-range. Small cell lung and colon carcinomas were particularly likely to yield highly convex curves (p < 0.006), probably from discontinuation of effective therapies. PFS curve shape may yield biological and clinical insights.

Antibiotics Modulate Chemotherapy Efficacy in Patients with Esophageal Cancer.

PurposeAccumulating evidence suggests that microbiota dysbiosis induced by antibiotic administration plays a crucial role in regulating the efficacy and toxicity of cancer therapy. We explored the influence of antibiotic administration on the efficacy of chemotherapy in patients with esophageal cancer (EC).Patients and MethodsEC patients were stratified into two groups: antibiotic-treated group and control group. The antibiotic-treated group included patients who received antibiotics within 60 days before or after chemotherapy initiation, and the control group included patients who did not receive antibiotics within 60 days before or after chemotherapy initiation. Progression-free survival (PFS) and overall survival (OS) curves were constructed using the Kaplan–Meier method. The Cox proportional hazards model was used for univariate and multivariate analyses.ResultsThe rate of primary progressive disease in the antibiotic-treated group was significantly higher than that in the control group (36.58% vs 10.45%, p = 0.002) as calculated using the chi-square test. Further, antibiotic administration was associated with shorter PFS (6.7 vs 14.6 months, hazard ratio (HR): 2.545, 95% confidence interval (CI): 1.554–4.168, p < 0.001) and reduced OS (15.0 vs 21.0 months, HR: 2.007, 95% CI: 1.213–3.319, p = 0.007) in univariate analysis. Subsequent multivariate analysis indicated that antibiotic administration was a significant independent prognostic factor for PFS (HR: 2.350, 95% CI: 1.423–3.882, p = 0.001) and OS (HR: 1.900, 95% CI: 1.140–3.167, p = 0.014).ConclusionAntibiotic administration was associated with reduced chemotherapy efficacy and poor prognosis in patients with EC.

Assessing long-term survival improvement of immune-checkpoint inhibitors (ICI) anticancer agents approved by the Food and Drug Administration: A meta-analysis of randomized controlled trials (RCTs).

e15062 Background: Conventional anticancer drugs have been developed to improve overall survival (OS) and/or progression-free survival (PFS) in the palliative intent setting. However, long-term survival is often limited by acquired biologic resistance. In contrast to conventional anticancer drugs, ICIs putatively preserve long-term survival in a small subset of patients. However, in the absence of a gold-standard definition, long-term survival improvement has not been adequately quantified. Long-term survival rate difference has been proposed as a method of quantifying long-term survival. However, there a paucity of literature demonstrating statistical improvements in survival rate. Therefore, the objective of the study was to quantify the improvement in long-term survival rate in OS and PFS improvement in ICIs compared with non-ICIs. Methods: The FDA Hematology/Oncology Approvals &amp; Safety Notification web page was searched for RCTs cited in oncology drug approvals between 01-2011 and 06-2019. The most recent OS and PFS updates were used when available. OS and PFS curves were digitized to reconstruct pseudo individual patient data as per established methods. Survival rate improvement at 1, 2 and 3 years were calculated as differences between the experimental arm and control arm. Survival rate improvements across RCTs at 1, 2 and 3 years were pooled using a random-effects model and the results were compared between ICI and non-ICIs. Subgroup analyses were conducted for melanoma and non-small cell lung cancer. Results: We identified 130 RCTs (22 ICIs, 108 non-ICIs) for analysis. The absolute OS rate improvement was 9.5% in ICIs and 4.9% in non-ICIs at 1-year (difference = 4.6%, p &lt; 0.001), 10.3% in ICIs and 4.9% in non-ICIs at 2-years (difference = 5.3%, p &lt; 0.001), and 10.2% in ICIs and 5.1% in non-ICIs at 3-years (difference = 4.6% p 0.006). The absolute PFS rate improvement was 10.3% in ICIs and 17.7% in non-ICIs at 1-year (difference = -7.3% p &lt; 0.001), and 8.9% in ICIs and 15.5% in non-ICIs at 2-years (difference = -6.6% p &lt; 0.001). Conclusions: Long-term OS survival rate improvements, while statistically significant were only modestly higher in ICIs compared to non-ICIs. PFS survival rate differences were statistically lower in ICIs compared to non-ICIs. While ICIs represent an important shift towards long-term survival, greater emphasis should be placed on rigorously evaluating long-term survival rate improvement and reporting of future novel therapies.

Assessing the potential cost-effectiveness of the addition of atezolizumab to first-line platinum chemotherapy in advanced urothelial cancer: Implications for value-based pricing.

5031 Background: Data from interim analysis of IMvigor130 trial showed that 1st line treatment of advanced urothelial cancer (aUC) with atezolizumab (Atezo) + platinum-based chemotherapy (PBC) significantly improved progression-free survival (PFS), but not overall survival (OS), vs PBC. Switch maintenance anti-PD(L)1 after completion of PBC as 1st line therapy is an alternate strategy, recently reported to significantly prolong OS. We aimed to compare cost-effectiveness of combined treatment (Atezo+PBC) vs PBC based on IMvigor130. Methods: We used a partitioned-survival model to evaluate the potential cost-effectiveness of treatment with A) Atezo+PBC (gemcitabine with cisplatin or carboplatin) or B) PBC alone with checkpoint inhibitor pembrolizumab at progression (standard-of-care). PFS and OS curves were extracted from IMvigor 130 and parametric models were fit to approximate outcomes with Atezo+PBC with the hazard ratio (HR) from the trial used to project outcomes for PBC alone. We used a health-care payer perspective with a two-year time horizon. Model outputs — costs, life-years, quality-adjusted life years (QALYs) — were used to calculate an incremental cost-effectiveness ratio (ICER). A scenario analysis evaluated the “value-based price” needed for Atezo+PBC to be cost-effective; a one-way sensitivity analysis was also performed. Results: Results of the cost-effectiveness analysis are summarized in the table. The mean projected incremental cost of Atezo+PBC compared to PBC was $59,604 for a mean incremental gain of 0.09 life-years and 0.07 QALYs. This resulted in an ICER of $629,755/life-year and $895,800/QALY, respectively. A 33% reduction would be needed in the price of atezolizumab to make Atezo+PBC cost-effective at an ICER of $150,000/QALY. Results were sensitive to cost of pembrolizumab at progression, the cost of Atezo+PBC, and the OS HR between Atezo+PBC and PBC. Conclusions: Combined chemoimmunotherapy with atezolizumab and PBC would likely not be cost-effective for the first-line treatment of aUC. However, with a price rebate of 33%, it would approach being cost-effective at a widely used cost-effectiveness threshold. [Table: see text]

Extensive small cell lung cancer (SCLC) chemotherapy: A population kinetics assessment.

e21101 Background: Most progression-free (PFS) and overall survival (OS) curves fit exponential decay models on nonlinear regression analysis (NLRA). Log-linear curve shape varies with tumor &amp; therapy type: straight line vs inflection to right (2 phase decay due to 2 distinct subpopulations with differing sensitivities) vs convex (downward inflection, eg due to stopping therapy that is slowing tumor growth).1 We compared SCLC to other cancers. Methods: As previously described,1 we did NLRA of published PFS &amp; OS curves for etoposide-platinum in SCLC. We also assessed various therapies in other cancers. We calculated PFS &amp; OS half-lives and classified curves by log-linear shape. Results: Of 18 evaluable SCLC PFS curves, 14 (78%) were highly convex &amp; 18 (100%) were moderately or highly convex, compared to 35/888 (4%) highly convex &amp; 186 (21%) moderately or high convex curves for other cancers (p &lt; 0.0001). Of 24 evaluable SCLC OS curves, 12 (50%) were highly convex &amp; 24 (100%) were moderately or highly convex, compared to 15/363 (4%) being highly convex &amp; 87 (24%) moderately or highly convex for other cancers (p &lt; 0.0001). In SCLC, 6 vs 4 cycles induction therapy minimally changed PFS half-life (median across studies 5.5 vs 5.2 months, p = 0.27) or OS half-life (9.5 vs 10.4 months, p = 0.06). PFS half-life correlated with OS half-life for other cancers (n 320, Spearman r 0.81, p &lt; 0.0001) but not for SCLC (n 18, r 0.04, p = 0.86). Post progression survival (PPS) correlated positively with PFS half-life for other cancers (n 376, r 0.68, p &lt; 0.0001) but correlated negatively for SCLC (n 18, r -0.43, p = 0.07). SCLC PFS curves had an initial downward inflection at a median of 2.9 months (where 87% of patients are still progression-free), followed by a 2nd inflection point at 4.5 months (where 71% are still progression-free). Median PFS half-life was 14.6 months prior to the 1st inflection point vs 1.9 months after the 2nd inflection point. Our analysis methods1 suggest that after the 2nd PFS inflection point, 23% of patients would progress by the next scan if scans are done every 3 weeks, while 40% would progress by the next scan if they are done every 6 weeks. Conclusions: PFS &amp; OS curves for SCLC are more often highly convex than for other cancers since SCLC is sensitive to chemotherapy but progresses rapidly after induction therapy is completed. Giving 6 rather than 4 induction cycles makes no OS difference. New maintenance strategies are needed. Very short PFS half-lives post induction suggest that frequent follow up scans should be done for patients who are candidates for 2nd line therapy. 1. Stewart. Cancer Med 2019; 8:6871

PIK3CA mutation status and progression-free survival in advanced hormone receptor positive (HR+)/ human endocrine receptor negative (HER2–) metastatic breast cancer (mBC): A meta-analysis of published clinical trials.

1069 Background: Approximately 40% of HR+/HER2- mBC patients harbor PIK3CA mutation. Associations between PIK3CA mutation status and clinical outcomes among patients with HR+/HER2- mBC have been heterogeneous across clinical trials. We synthesized available evidence from clinical trials to estimate the association between PIK3CA status and progression-free survival (PFS) using a meta-analysis adjusting for study design differences. Methods: Randomized clinical trials reporting PFS stratified by PIK3CA status in HR+/HER2- mBC were identified via a systematic literature review. Trial arms receiving PIK3CA targeted therapies were excluded. Median PFS, 6-, 12- and 18-month PFS rates, and data on trial design features were extracted. Associations between PIK3CA status and PFS were estimated adjusting for study follow-up duration, PIK3CA testing method (ctDNA vs tissue ) and study treatment using multi-level random effects meta-regression. Results: The analyzed data included 3,238 patients from 33 study arms across 11 trials ( PIK3CA mutated (MT): 1,386, wild type (WT): 1,852). PIK3CA mutation was overall associated with shorter median PFS (difference [95% CI] (months): -2.15 [-4.14, -0.15]) with substantial heterogeneity across studies ( I2 = 98.34%). The direction of this association was robust to adjustment for study treatment (-1.27 [-2.22, -0.32]). The association was stronger for ctDNA testing (-2.16 [-3.65, -0.66]; N (total patients): 1,876) than for tissue testing (-0.65 [-2.2, 0.91]; N: 998). Findings were similar for 6-month PFS rates (absolute rate difference -9.17% [-14.22, -4.12], N: 3,179; MT: 1,366, WT: 1,813). Associations were directionally consistent but not statistically significant at 12 months (N = 2,487; MT: 1,056, WT: 1,431) and 18 months (N = 1,745; MT: 811, WT: 934), potentially due to the decreasing precision towards the tails of the PFS curves and significant heterogeneity across studies. Conclusions: Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS, especially when ctDNA testing was used. These findings suggest a negative prognostic value of PIK3CA mutation in patients with HR+/HER2- mBC.

POLO: Quality-adjusted (QA) progression-free survival (PFS) and patient (pt)-centered outcomes with maintenance olaparib in pts with metastatic pancreatic cancer (mPaC).

4626 Background: In the Phase III POLO trial (NCT02184195), maintenance olaparib significantly prolonged PFS vs placebo in pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPaC (median 7.4 vs. 3.8 months). The aim of maintenance treatment is to extend PFS and survival without compromising health-related quality of life due to adverse events. The duration of time spent without symptoms or toxicities (TWiST) and the QA-PFS were assessed in a post hoc analysis of the POLO trial. Methods: Patients were randomized 3:2 to receive maintenance olaparib (tablets; 300 mg bid) or placebo. Restricted mean (RM)-PFS was calculated by estimating the area under the Kaplan–Meier PFS curve between randomization and 29.8 months after randomization (maximum follow-up for the placebo arm in POLO). Patient-centered outcomes were assessed by QA-PFS (derived from the product of the EQ-5D-5L single-index utility score from randomization to disease progression and RM-PFS) and TWiST (RM-PFS minus time with toxicity after randomization). Results: RM-PFS was significantly longer with olaparib, with a between-treatment difference of 4.8 months ( P=0.009; Table). Over this period, no significant or meaningful differences in mean EQ-5D-5L index were observed between treatment groups. The corresponding mean QA-PFS was significantly longer with olaparib vs placebo. TWiST analysis demonstrated a benefit with olaparib over placebo (Table): between-arm difference, 3.8 months ( P=0.039) for the primary analysis (criteria 1: grade ≥2 nausea, vomiting or fatigue). Sensitivity analysis (criteria 1 plus abdominal pain, diarrhea, decreased appetite or constipation) also revealed a trend toward benefit with olaparib (difference: 3.4 months, P=0.062). Conclusions: Consistent with the primary PFS analysis of the POLO trial, RM-PFS and QA-PFS were significantly longer with maintenance olaparib than with placebo. As demonstrated by the findings of the TWiST analyses, the PFS benefit observed with olaparib in pts with a gBRCAm and mPaC persists even when symptoms of toxicity are considered. Clinical trial information: NCT02184195 . [Table: see text]

Population-adjusted indirect treatment comparison (PAITC) of maintenance PARP inhibitor (PARPi) with or without bevacizumab versus bevacizumab in women with newly diagnosed ovarian cancer (OC).

6052 Background: In patients (pts) with newly diagnosed OC, bevacizumab (B), PARPi, and PARPi + B have shown benefit as maintenance treatment options after platinum chemotherapy response. Phase III trials have demonstrated longer median progression-free survival (PFS) with PARPi + B (PAOLA-1, olaparib [O]; NCT02477644) vs placebo (P) + B and with PARPi alone (PRIMA, niraparib [N]; NCT02655016) vs P. As there are no randomized head-to-head trials comparing PARPi + B vs PARPi, or PARPi vs B, we performed indirect treatment comparison across these regimens. Methods: Unanchored PAITC was performed with individual pt data (IPD) from a PAOLA-1 subset comprising pts with stage IV disease, stage III with residual disease after primary surgery, inoperable stage III disease, or any patient who received neoadjuvant chemotherapy. Propensity weights were used to match the baseline (BL) characteristics of the PRIMA population. PRIMA dataset was reconstructed using published PFS curves. Both datasets were pooled; treatment efficacy was assessed by weighted Cox regression and Kaplan–Meier methods. PAITC was performed in all pts (biomarker unselected) and the homologous recombination repair deficiency positive (HRD+; cut-off 42) subgroup. Results: 595/806 (266/387 HRD+) PAOLA-1 pts were included. After matching, the effective sample size (ESS) for PAOLA-1 was 532 (242 HRD+; weights 0.241–2.37). Weighted BL data were balanced across cohorts. Conclusions: In biomarker-unselected and HRD+ pts, PAITC suggests that adding O to B significantly improved PFS vs. N or B alone. In biomarker-unselected pts, PAITC results show no significant difference in PFS between N and B. In HRD+, improved efficacy with N appears to translate into improved PFS vs. B alone, although follow-up was &lt;2 years (14 vs 22 months, respectively). Results are hypothesis generating and could guide randomized trial design. Clinical trial information: NCT02477644 and NCT02655016. [Table: see text]

PCN85 COST-EFFECTIVENESS OF OLAPARIB AS A MAINTENANCE TREATMENT OPTION FOR NEWLY DIAGNOSED BRCA-MUTATED OVARIAN CANCER WHO ARE IN RESPONSE AFTER FIRST-LINE PLATINUM-BASED CHEMOTHERAPY IN PANAMA

SOLO1 was an international, Phase III, randomised, double-blind, placebo-controlled trial that assessed the efficacy and safety of olaparib (OLA) versus placebo in patients with newly diagnosed advanced BRCA-mutated ovarian cancer who were in response (complete or partial) following first-line platinum-based chemotherapy. The acquisition cost of new oncology drugs is a concern for payors in emerging markets. This study aimed to evaluate the cost-effectiveness of OLA therapy in this new indication versus routine surveillance (RS) in the Panamian population, using national estimates of costs and treatment patterns. A three-state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of OLA versus RS from a payer perspective. Progression-free survival (PFS) and overall survival (OS) curves were estimated using data from SOLO1 and extrapolated using parametric survival models for Panama. Mortality and morbidity rates for the groups were modelled based on assumptions validated with local clinicians. Health state utilities and adverse event frequencies were obtained from SOLO1 study. Drug costs were provided by the Panamian Institute of Oncology (ION). Healthcare resource usage and costs were based on local clinician input and local publications. A 1.5% discount rate was applied to costs and outcomes. Maintenance treatment with OLA in first line setting after platinum based chemotherapy compared to routine surveillance as currently practiced was associated with an ICER of $ $35,512 per QALY. This ICER is lower than the WHO-WTP threshold of three times GDP per capita of $$48,736 and the willingness-to-pay (WTP) analysis showed an estimated 100% probability to be cost-effective. The results were robust to univariate sensitivity analysis, with all variables having a non-significant impact. OLA is a cost-effective treatment option for patients with newly diagnosed BRCA-mutated ovarian cancer, who are in response (complete or partial) after first-line platinum-based chemotherapy in Panama.

PCN96 OLAPARIB COST-EFFECTIVENESS AS A MAINTENANCE TREATMENT OPTION FOR NEWLY DIAGNOSED BRCA-MUTATED OVARIAN CANCER WHO ARE IN RESPONSE AFTER FIRST-LINE PLATINUM-BASED CHEMOTHERAPY IN COSTA RICA

SOLO1 was an international, Phase III, randomised, double-blind, placebo-controlled trial that assessed the efficacy and safety of Olaparib (OLA) versus placebo in patients with newly diagnosed advanced BRCA-mutated ovarian cancer who were in response (complete or partial) following first-line platinum-based chemotherapy. The acquisition cost of new oncology drugs is a concern for payors in emerging markets. This study aimed to evaluate the cost-effectiveness of OLA therapy in this new indication versus routine surveillance (RS) in the Costa Rican population, using national estimates of costs and treatment patterns. A three-state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of OLA versus RS from a payer perspective. Progression-free survival (PFS) and overall survival (OS) curves were estimated using data from SOLO1 and extrapolated using parametric survival models for Costa Rica. Mortality and morbidity rates for the groups were modelled based on assumptions validated with local clinicians. Health state utilities and adverse event frequencies were obtained from SOLO1 study. Drug costs were provided by the Caja Costarricense de Seguro Social (CCSS) Healthcare resource usage and costs were based on local clinician input and local publications. A 1.5% discount rate was applied to costs and outcomes. Maintenance treatment with OLA in first line setting after platinum based chemotherapy compared to routine surveillance as currently practiced was associated with an ICER of $37,004. per QALY. This ICER is lower than the WHO-WTP threshold of three times GDP per capita of $37,026 and the willingness-to-pay (WTP) analysis showed an estimated 99% probability to be cost-effective. OLA is a cost-effective treatment option for patients with newly diagnosed BRCA-mutated ovarian cancer, who are in response (complete or partial) after first-line platinum-based chemotherapy in Costa Rica

Relationship between the efficacy of immunotherapy and characteristics of specific tumor mutation genes in non-small cell lung cancer patients.

BackgroundImmune checkpoint inhibitors (ICIs) have greatly improved the prognosis and overall management of non‐small cell lung cancer (NSCLC) patients, but in the long term less than 20% of patients benefit from treatment with ICIs. Therefore, it is necessary to guide the choice of immunotherapy population through biomarkers in order to maximize the benefit for NSCLC patients. This article mainly explores the relationship between the efficacy of immunotherapy and specific tumor mutation gene characteristics in an NSCLC population.MethodsThis was a prospective analysis of patients with advanced NSCLC who visited the Department of Respiratory Medicine of Peking Union Medical College Hospital from March 2018 to June 2019 and were instructed to use PD‐1 inhibitors. The follow‐up deadline was 31 December 2019. The tumor pathological tissues were tested for tumor mutation genes, and the patients were evaluated for efficacy according to RECIST 1.1. The patients were divided into the durable benefit group (DCB) and the nonsustainable benefit group (NDB). DCB/NDB was used as the outcome variable. Various statistics methods were used to explore the independent predictors of long‐term benefits associated with immunotherapy and to draw a progression‐free survival curve for the relevant predictors.ResultsA total of 44 patients were examined for tumor mutation genes in pathological tissues; 20 in the DCB group and 24 in the NDB group. Specific gene mutations occurred in TP53 38.64%, KRAS 31.82%, EGFR 20.45%, BRCA 20.45%, ERBB (excluding EGFR) 18.18%, PTEN 15.91%, CDK4/6 13.64%, POLE 11.36%, MET 11.36%, PIK3CA 9.10%, FGFR 9.10%, BRAF 9.10%, JAK 9.10%, ALK 6.82%, POLD1 4.55%, BLM 4.55%. Chi‐square test results showed that there were statistically significant differences between DCB and NDB groups with eight mutations such as KRAS. Logistic regression showed that the KRAS mutation was statistically significant (P < 0.001). Two accuracy indicators, Random Forest Classification of Mean Decrease Gini and Mean Decrease Accuracy, evaluated the importance of the impact of different gene mutations on the outcome. Under two different measures, the variables were all KRAS mutations. It is suggested that the mutation of the KRAS gene is an independent predictor of the long‐term benefit of immunotherapy.ConclusionsThe mutation of KRAS gene in tumor tissues is an independent predictor of the long‐term benefit of immunotherapy, and the predictive ability is better.

Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer.

Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4weeks. Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3months were Gr < 0.76 and SumTLs < 31.0mm. Further, Gr < 0.76 and SumTLs < 31.0mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.

Pretreatment neutrophil-to-lymphocyte ratio is a predictive biomarker for EGFR TKI-treated patients with advanced EGFR-mutant Non-small cell lung cancer.

BackgroundNeutrophil-lymphocyte ratio (NLR) has been reported as a prognostic biomarker in various cancers, but its prognostic value for advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs) remains unclear. To address this issue, we performed a retrospective study to investigate the clinical value of NLR in these patients.MethodsAll data were collected from medical records. Sixty-five cases with stage IIIB-IVB EGFR-mutant NSCLC treated with EGFR-TKIs were enrolled. The pretreatment NLR was analyzed for associations with disease control rate (DCR) and progression-free survival (PFS). The primary outcomes of interest were DCR and PFS. All the data were analyzed using SPSS 23.0. The PFS curves were plotted by Kaplan-Meier analysis and log-rank test. Univariate and multivariate Cox regression analyses were used to determine the factors affecting PFS.ResultsThe results indicated that, compared with those with lower NLR (<2.57), the patients with a higher NLR (≥2.57) showed a significantly shorter PFS (8.8 vs. 12.2 months, P<0.01), and decreased DCR by the end of 8, 10 months after TKIs treatment (62.5% vs. 93.3%, P=0.014; 38.5% vs. 77.8%, P=0.037). COX multivariate analysis showed that NLR was an independent prognostic factor for PFS (P<0.001).ConclusionsElevated NLR is significantly associated with lower DCR, shorter PFS, and might act as a meaningful biomarker for predicting the efficacy of TKIs treatment and the prognosis of advanced EGFR-mutant NSCLC. High-quality prospective clinical trials with longer follow-up are needed to further confirm the results.

Comparison of progression-free and overall survival between endometrial cancer patients treated with laparoscopic and open surgical techniques

Introduction: Recently published unfavourable results of endoscopic radical surgery for early-stage cervical cancer compared to open surgery raises the need for auditing treatment results of endoscopic staging surgery for endometrial cancer. Aim: Comparison of progression-free and overall survival (PFS and OS) between endometrial cancer patients treated with laparoscopic (LSC) and open surgical techniques. Method: Retrospective analysis was performed to compare clinicopathological and survival data of endometrial cancer patients who had either laparoscopic or open staging surgery between 2013 and 2019 at the Gynaecological Oncology Unit of the University of Debrecen, Hungary. Distribution of the most relevant prognostic factors were compared with χ2 and t-tests. Frequencies of progressive disease and disease-specific deaths were compared in the Cox-model, while progression-free and overall survival curves were compared with the Kaplan-Meier method. Results: The frequency of endometrioid, serous papillary, mixed Müllerian, adenosquamous and other histological types in the laparoscopic and open groups were similar (p = 0.3356). The frequency of grade 1, 2 and 3 tumours in the endoscopic and open groups showed significant differences (p = 0.0036). Pathological stage-distribution (IA, IB, II, IIIA, IIIB, IIIC1, IIIC2) of endoscopic cases and open cases was also statistically different (p = 0.0048). The mean number of removed lymph-nodes was higher in the open surgery group (14.3 vs. 9,3, p<0.0001). The frequency of recurrence did not show significant difference between the two groups, in contrast to the frequency of disease-specific deaths (2/120 vs. 29/345, p = 0.01; 2/120 vs. 17/345, p = 0.12). In the Cox-model, progression-free survival and overall survival showed a hazard ratio favouring laparoscopic surgery, however, the range of 95% confidence intervals showed no statistical significance (PFS LSC vs. open: HR = 0.36, 95% CI = 0.084-1.538; OS LSC vs. open: HR = 0.603, 95% CI = 0.135-2.693). Conclusion: Progression-free and overall survival of endoscopically staged endometrial cancer is not worse than those of patients staged with open surgery. Orv Hetil. 2020; 161(10): 382-388.

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti‐PD‐1 monotherapy

Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3-5 sessions, 20-26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.

Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy

Objective: To compare radiation-induced toxicity and dosimetry parameters in patients with locally advanced nasopharyngeal cancer (LANPC) treated with a mixed-beam (MB) approach (IMRT followed by proton therapy boost) with an historic cohort of patients treated with a full course of IMRT-only.Material and methods: Twenty-seven patients with LANPC treated with the MB approach were compared to a similar cohort of 17 patients treated with IMRT-only. The MB approach consisted in a first phase of IMRT up to 54–60 Gy followed by a second phase delivered with a proton therapy boost up to 70–74 Gy (RBE). The total dose for patients treated with IMRT-only was 69.96 Gy. Induction chemotherapy was administrated to 59 and 88% and concurrent chemoradiotherapy to 88 and 100% of the MB and IMRT-only patients, respectively. The worst toxicity occurring during the entire course of treatment (acute toxicity) and early-late toxicity were registered according to the Common Terminology Criteria Adverse Events V4.03.Results: The two cohorts were comparable. Patients treated with MB received a significantly higher median total dose to target volumes (p = .02). Acute grade 3 mucositis was found in 11 and 76% (p = .0002) of patients treated with MB and IMRT-only approach, respectively, while grade 2 xerostomia was found in 7 and 35% (p = .02) of patients treated with MB and IMRT-only, respectively. There was no statistical difference in late toxicity. Local progression-free survival (PFS) and progression-free survival curves were similar between the two cohorts of patients (p = .17 and p = .40, respectively). Local control rate was 96% and 81% for patients treated with MB approach and IMRT-only, respectively.Conclusions: Sequential MB approach for LANPC patients provides a significantly lower acute toxicity profile compared to full course of IMRT. There were no differences in early-late morbidities and disease-related outcomes (censored at two-years) but a longer follow-up is required to achieve conclusive results.

Correlation of tumor mutation with efficacy in patients with gastric cancer who received nivolumab and ramucirumab combination therapy.

413 Background: Nivolumab (Nivo) plus ramucirumab (Ram) showed promising efficacy in the second-line chemotherapy for advanced gastric cancer (AGC) in NIVORAM study with the 44% of objective response rate (ORR) and 38.6% of 6-month progression free survival (PFS) rate. We investigated the correlation of tumor mutation load and efficacy. Methods: Patients received Nivo (3mg/kg, Q2W) in combination with Ram (8mg/kg, Q2W) until unacceptable toxicity or disease progression. Tissue samples were collected before the treatment, and analyzed for tumor mutation load using Oncomine Tumor Mutation Load Assay. Efficacy included ORR, overall survival (OS), PFS and duration of response. OS and PFS curves were estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazards model. Results: By the data cut off of December 15, 2018, the median follow duration on therapy was 13.7 month. Thirty AGC pts who obtained tissue sample were analyzed. Median tumor mutation load (TML) was 6.755 mutation/Mb (range 0.84-19.67). Higher TML (cut-off median) related to better tendency of efficacy with ORR (40.0% vs 20.0%), PFS (5.32 vs 2.33 months) and OS (18.1 vs 10.6 months). 6-month PFS rate was better in TML higher group (48%) compared to TML lower group (18%). In multivariate analysis, higher TML showed 2.030 of hazard ratio (95% CI; 0.849-4.855, p-0.112) for PFS, and 1.915 (95% CI; 0.578-6.343, p=0.287) for OS. Conclusions: The patients with higher tumor mutation load have a better tendency for OS and PFS, among AGC patients who received Nivo and Ram combination therapy. Clinical trial information: NCT02999295.