Docetaxel In Patients Research Articles

KRYSTAL-12: A randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRASG12C mutation.

TPS9129 Background: Despite significant advances in chemotherapy and immunotherapy for advanced NSCLC, the majority of pts ultimately develop progressive disease associated with poor outcomes. KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cell growth and proliferation. KRASG12C mutations occur in 14% of NSCLC (adenocarcinoma), and mutations in KRAS are associated with a poor prognosis. Although KRAS has historically been undruggable, recent research into the development of agents that specifically bind mutant KRAS has led to the development of direct inhibitors of KRASG12C. Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to and locks KRASG12C in its inactive state. Adagrasib was optimized for favorable pharmacokinetic (PK) properties, including oral bioavailability, long half-life (̃24 h), and extensive tissue distribution. Initial results have demonstrated encouraging antitumor activity and tolerability of adagrasib monotherapy in pts with NSCLC harboring a KRASG12C mutation. Methods: KRYSTAL-12 is a multicenter, randomized Phase 3 study evaluating the efficacy of adagrasib (600 mg BID) vs docetaxel in pts with advanced NSCLC harboring a KRASG12C mutation who have progressed during or after treatment with a platinum-based regimen and an immune checkpoint inhibitor. The study is designed to demonstrate improvement in the dual primary endpoints of progression-free survival (PFS) and overall survival (OS). Secondary endpoints include safety, objective response rate (ORR) per RECIST 1.1, duration of response (DOR), plasma PK parameters of adagrasib, and patient-reported outcomes (PROs). The study will also explore correlations between gene alterations (at baseline and upon development of treatment resistance) and efficacy. Approximately 450 patients will be randomized in a 2:1 ratio to receive adagrasib or docetaxel and will be stratified by region (United States/Canada vs other countries) and sequential vs concurrent administration of prior platinum-based chemotherapy and anti–PD-1/PD-L1 antibody. The planned sample size is sufficiently powered for the hypothesized treatment effect of the endpoints. Pts will receive study treatment until disease progression, unacceptable adverse events, investigator decision to terminate treatment, or patient withdrawal. This study is currently enrolling and will be open at sites in the United States, Europe, and Asia. Clinical trial information: NCT04685135.

A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01).

TPS9127 Background: Treatment options are limited for patients with advanced/metastatic NSCLC without driver genomic alterations after failure of a platinum-based chemotherapy and immunotherapy; median survival is < 1 year. Datopotamab deruxtecan (Dato-DXd; DS-1062) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. Results from the ongoing phase 1 study (TROPION-PanTumor01; Spira, WCLC 2020) demonstrated an overall response rate (ORR) of 21%, a disease control rate (DCR) of 67%, and a preliminary median progression-free survival (PFS) of 8.2 months (all by blinded independent central review [BICR]), with a manageable safety profile, in patients with NSCLC who were treated with 6 mg/kg of Dato-DXd. This phase 3 study (NCT04656652) will compare the efficacy of Dato-DXd with that of docetaxel as 2/3L therapy in patients with advanced/metastatic NSCLC. Methods: TROPION-Lung01 is an open-label, phase 3, randomized study of Dato-DXd vs docetaxel in patients with advanced/metastatic NSCLC without EGFR, ALK, or other actionable genomic alterations. Patients must have been previously treated with platinum-based chemotherapy and a PD-(L)1 monoclonal antibody in combination or sequentially and have radiographic disease progression on or after the most recent therapy. Those with asymptomatic and stable/treated brain metastases are eligible. A tumor specimen is required for biomarker analyses. Patients (N = 590) are randomized 1:1 to either Dato-DXd 6 mg/kg or docetaxel 75 mg/m2 given intravenously on day 1 of each 3-week cycle. Randomization is stratified by histology (squamous vs nonsquamous), immunotherapy in last regimen (yes vs no), and region (US/Japan/Western Europe vs rest of world). Treatment continues until disease progression or intolerance or other discontinuation criteria are met. The study will be conducted globally at approximately 184 study sites. Dual primary endpoints are PFS by BICR and overall survival. Secondary outcome measures include PFS by investigator, ORR, duration of response, DCR, and time to response (all assessed by BICR and by investigator per RECIST version1.1), patient-reported outcomes, safety, pharmacokinetics, and proportion of patients who develop antidrug antibodies. Biomarkers will be evaluated for potential associations with efficacy. Clinical trial information: NCT04656652.

Second-line nintedanib plus docetaxel for patients with lung adenocarcinoma after failure on first-line immune checkpoint inhibitor combination therapy: Initial efficacy and safety results from VARGADO Cohort C.

9033 Background: The treatment landscape in advanced non-small cell lung cancer (NSCLC) has undergone significant changes, with immune checkpoint inhibitor (ICI) +/- chemotherapy now the preferred first-line (1L) regimen for metastatic, non-mutated NSCLC. However, only limited clinical data are available to guide subsequent treatment selection. Nintedanib (Vargatef), an oral triple angiokinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways, is approved in the EU and other countries in combination with docetaxel for the treatment of advanced adenocarcinoma NSCLC after failure on 1L chemotherapy. Methods: This analysis is part of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) of nintedanib + docetaxel. Here, we present initial efficacy and safety results from 100 patients (pts) with adenocarcinoma NSCLC in Cohort C, who received second-line (2L) nintedanib + docetaxel after failure on prior 1L ICI in combination with chemotherapy. Results: In Cohort C, the median age was 63 years (range: 43–84); 58 pts (58.0%) were men, and 71 pts (71.0%) had ECOG PS 0/1. Ninety-five pts (95.0%) had received prior 1L pembrolizumab-based combination therapy. Thirty-nine pts (39.0%) had progressed within 6 months after the start of 1L therapy, and 66 pts (66.0%) had progressed within 9 months. Objective response rate with 2L nintedanib + docetaxel was 37.3% (22/59 pts), disease control rate was 67.8% (40/59 pts), and median progression-free survival (PFS) was 4.4 months (95% confidence interval [CI]: 2.6–6.6). Among pts who had experienced disease progression < 9 months after the start of 1L therapy (n = 66), median PFS from the start of 2L nintedanib + docetaxel was 4.1 months (95% CI: 2.5–6.6). Among pts with disease progression ≥9 months after the start of 1L therapy (n = 34), median PFS from the start of 2L nintedanib + docetaxel was 8.5 months (95% CI: 2.4–not estimable). Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were observed in 47 pts (47.0%), 37 pts (37.0%) and 28 pts (28.0%), respectively. Conclusions: Initial data from VARGADO Cohort C provide the first evidence that 2L nintedanib + docetaxel has encouraging and clinically meaningful efficacy, and a manageable safety profile in pts with advanced adenocarcinoma NSCLC following progression on 1L ICI in combination with chemotherapy. Clinical trial information: NCT02392455.

CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

Combination of trastuzumab, pertuzumab and docetaxel in patients with advanced non-small cell lung cancer (NSCLC) harboring HER2 mutation: Final results from the IFCT-1703 R2D2 trial.

9015 Background: Human epidermal growth factor receptor 2 ( HER2) exon 20 insertions and mutations are oncogenic drivers found in 1-2% of NSCLC. However, there are no approved therapies for these patients. Many studies suggest that the use of HER2 inhibitors developed for breast cancer patients might be of interest in this setting. The aim of this trial was to prospectively evaluate the interest of a combination of two antibodies against HER2 (trastuzumab and pertuzumab) with docetaxel. Methods: IFCT-1703 R2D2 trial is a multicenter, non-randomized phase 2 study with a two-stage design, a power of 90% and an alpha risk at 5% (one-sided). HER2 mutational status was assessed locally in certified molecular genetic centers. Main other inclusion criteria were advanced NSCLC, progression after ≥ 1 platinum-based chemotherapy, asymptomatic brain metastases, left ventricular ejection fraction (LVEF) ≥ 50%, and PS 0-2. Patients were treated every 3 weeks with pertuzumab at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at a loading dose of 8 mg/kg and 6 mg/kg thereafter; and docetaxel at 75 mg/m². Treatment was given until toxicity or disease progression. The primary outcome was overall response rate (ORR). Other endpoints included duration of response, progression-free survival and safety. NCT number: NCT03845270. Results: From May 2019 to October 2020, 45 patients were enrolled in 17 centers and received study treatment. Median age was 64.5 years (range 31–84), 72% females, 35% smokers, 100% non-squamous histology and 15% with ECOG PS 2. 31.1% patients had brain metastases. PD-L1 was expressed ≥ 1% and ≥ 50% in 36% and 7% of the patients, respectively. No other oncogene driver was found associated with HER2 exon 20 mutation. With a median follow-up of 12 months, 44 (98%) patients were evaluable for the primary endpoint. Overall response rate was 29% (n = 13), stable disease 56% (n = 26). Median PFS was 6.8 months (95% CI[4.0-8.5]). Median duration of treatment in patients with confirmed response (n = 13) was 10 months (95% CI[2.7-14.9]). At the time of data cut-off, 15 patients (33%) were still under treatment. Grade 3/4 treatment-related adverse events (AEs) were observed in 64% of patients. No patient experienced treatment discontinuation because of toxicity. One sudden death was possibly related to treatment. Most frequent grade ≥ 3 AEs were neutropenia (33%), diarrhea (13%) and anaemia (9%). Grade 1/2 dyspnea was observed in 3 (6.7%) patients. No ILD were reported. Variation LVEF was -1.72% on average (min: -18 %; max: 10 %). Conclusions: The triplet trastuzumab, pertuzumab and docetaxel is feasible and active in HER2 pretreated advanced NSCLC. These results confirm the activity of HER2 antibodies-based strategy which should be considered in these patients. Clinical trial information: NCT03845270.

Comparative efficacy of docetaxel versus novel hormonal agent in de novo metastatic hormone-sensitive prostate cancer: Real-world data curated by deidentified chart abstraction.

e17047 Background: The addition of docetaxel or a novel hormonal agent (NHA), such as abiraterone acetate or enzalutamide, has become standard of care for mHSPC, but prospective data for comparative efficacy remains limited. Clinical variables abstracted through natural language processing of free text from patient charts can provide real-world data to answer important clinical questions. Methods: Using an innovative data abstraction process, we retrospectively identified men with de novo mHSPC within deidentified charts from the Mount Sinai Health System treated with either docetaxel or a NHA between January 1, 2014 and April 30, 2019. Dates were chosen to reflect the timeline for which these therapeutic agents received regulatory approval for mHSPC, but also to allow sufficient clinical follow up after treatment initiation. Primary outcome of failure-free survival (FFS), defined as the time to next treatment, was assessed using the Kaplan-Meier method and multivariable Cox proportional hazards models. We additionally performed multivariable analysis to evaluate the prognostic significance of post-treatment PSA nadir on FFS. Results: A total of 94 de novo mHSPC patients that received either docetaxel or an NHA were identified using proprietary Sema4 data abstraction process: 52 received docetaxel, 42 received an NHA. Use of an upfront NHA in mHSPC was associated with a significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p = 0.023). While NHAs were associated with a significantly longer FFS than docetaxel in patients with high metastatic burden of disease (25.12 vs. 9.63 months, p = 0.014), this was not observed in low-volume disease (20.71 vs. 26.5 months, p = 0.9). In multivariable model analysis adjusting for age, baseline PSA, and metastasis burden, docetaxel remains independently associated with worse FFS compared to NHA (HR 1.96, 95% CI 1.12−3.45, p = 0.019). Irrespective of docetaxel or NHA use, lower post-treatment PSA nadir levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, > 0.4ng/ml, respectively; p < 0.001). Conclusions: Clinical variables abstracted from deidentified clinical documentation can efficiently provide relevant and reliable data upon which clinical research can be based. Comparative analysis of real-world data demonstrates superior FFS in de novo mHSPC treated with a NHA as compared to docetaxel. The depth of PSA response holds prognostic value for mHSPC outcomes, regardless of treatment used.

The effects of tislelizumab treatment on the health-related quality of life of non-small cell lung cancer patients who progressed on a prior platinum-containing regimen.

9069 Background: Anti-PD-1/L1 therapies have improved overall survival (OS) by 2-4 months vs docetaxel in patients with advanced non−small cell lung cancer (NSCLC) who progressed after receiving a platinum regimen. Tislelizumab, an anti-PD-1 antibody, has been tested as monotherapy in the RATONALE (NCT 03358875) trial, which found that tislelizumab prolonged OS (median OS difference 5.3 months in ITT population) as compared to docetaxel, improved progression-free survival (median 4.1 vs 2.6 months), as well as overall response rate (ORR difference = 14.9%).Here we report health-related quality of life (HRQoL) of patients receiving tislelizumab vs docetaxel in this clinical trial. Methods: NSCLC patients in this open-label, multicenter Phase 3 study were randomized to either the tislelizumab or docetaxel. HRQoL was measured using the QLQ-C30 global health status/quality of life score (GHS/QoL) from EORTC QLQ-C30 as well as the lung cancer specific subscales of the EORTC QLQ-LC13. Descriptive analysis for the GHS/QoL score was performed for baseline through cycle 10; changes from baseline to cycle 12 were examined for the symptom subscales. Results: 805 patients were randomized to tislelizumab (n = 535) or docetaxel (n = 270). Patients were 77% male with an average age of 60 years (range 28-88 years). The compliance rates were mostly > 98% and were similar across arms. The GHS/QoL score in the tislelizumab arm improved relative to baseline from cycles 5 through 10 while declining in cycles 6 through 10 in the docetaxel arm. The tislelizumab arm showed a reduction from baseline at cycle 12 in the symptom scores of coughing, chest pain, and dyspnea while patients in the docetaxel arm experienced an increase in symptoms. Conclusions: The study results show that tislelizumab monotherapy improved HRQoL in patients who previously failed treatment with a platinum containing chemotherapy; this is especially important as the NSCLC patients treated with tislelizumab not only experienced improvements in OS, but also reductions in their symptomology. Clinical trial information: NCT 03358875.

Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial

IntroductionIn the JAVELIN Lung 200 trial, avelumab (anti-programmed death-ligand 1 [PD-L1] antibody) did not significantly prolong overall survival (OS) versus docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report greater than 2-year follow-up data. MethodsPatients with stage IIIB or IV or recurrent NSCLC with disease progression after platinum-doublet chemotherapy were randomized 1:1 to avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. The primary end point was OS in patients with PD-L1+ tumors (greater than or equal to 1% tumor cell expression; IHC 73-10 pharmDx assay). ResultsOf 792 patients, 529 had PD-L1+ tumors (264 versus 265 in the avelumab versus docetaxel arms, respectively). As of March 4, 2019, median duration of follow-up for OS in the PD-L1+ population was 35.4 months in the avelumab arm and 34.7 months in the docetaxel arm; study treatment was ongoing in 25 (9.5%) versus 0 patients, respectively. In the PD-L1+ population, 2-year OS rates (95% confidence interval [CI]) with avelumab versus docetaxel were 29.9% (24.5%–35.5%) versus 20.5% (15.6%–25.8%); in greater than or equal to 50% PD-L1+ subgroups, 2-year OS rates were 36.4% (29.1%–43.7%) versus 17.7% (11.8%–24.7%) and in the greater than or equal to 80% subgroup were 40.2% (31.3%–49.0%) versus 20.3% (12.9%–28.8%), respectively. Median duration of response (investigator assessed) was 19.1 months (95% CI: 10.8–34.8) versus 5.7 months (95% CI: 4.1–8.3). Safety profiles for both arms were consistent with the primary analysis. ConclusionsAlthough the JAVELIN Lung 200 primary analysis (reported previously) revealed that avelumab did not significantly prolong OS versus docetaxel in patients with platinum-treated PD-L1+ NSCLC, posthoc analyses at 2 years of follow-up revealed that 2-year OS rates were doubled with avelumab in subgroups with higher PD-L1 expression (greater than or equal to 50% and greater than or equal to 80%).

Adjuvant Chemotherapy in High-Risk Prostate Cancer Patients after Primary Local Therapy: Recurrence, Metastasis, and Survival – A Meta-Analysis

Context: Several randomized clinical trials (RCTs) have recently tested adjuvant chemotherapy to high-risk prostate cancer patients (PCA) after primary local therapy. Objective: The aim of the study was to perform a systematic review and meta-analysis of RCTs evaluating the adjuvant chemotherapy in high-risk prostate cancer patients after primary local therapy. The primary endpoint was overall survival (OS). The secondary endpoint was disease-free survival (DFS) and biochemical recurrence-free survival (BRFS). Methods: A systematic review of PubMed/Medline, Embase, and Cochrane databases was performed to identify relevant studies published in English up to March 2020. Six trials were selected for inclusion. Results: There were 7 studies included in the present study. The meta-analysis did not show a significant OS benefit from adjuvant chemotherapy in patients with high-risk prostate cancer after primary local therapy (hazard ratio [HR]: 0.87; 95% confidence interval [CI], 0.72–1.05; p = 0.15). But docetaxel in patients with high-risk prostate cancer after primary local therapy was associated with a slightly OS improvement (HR: 0.79; 95% CI, 0.63–0.98; p = 0.03). It also did not show a significant benefit in DFS and BRFS in patients with high-risk prostate cancer (HR: 0.89, 95% CI, 0.75–1.06, p = 0.18; HR: 0.85, 95% CI, 0.69–1.06, p = 0.16). Conclusions: This meta-analysis shows a slightly OS benefit from docetaxel in patients with high-risk prostate cancer after primary local therapy. It did not show a significant benefit in DFS and BRFS from adjuvant chemotherapy in patients with high-risk prostate cancer.

Pharmacoeconomic analysis of pertuzumab in treatment of HER2-positive breast cancer in Ukraine

Background. The incidence of breast cancer tends to be increasing worldwide in recent years. It is characterized by various clinical manifestations and potential treatment approaches. The choice of treatment strategy, its sequence as well as the efficiency of administered chemotherapy is quite relevant these days.
 Purpose – assessing economic feasibility of targeted therapy with pertuzumab (Perjeta®) in patients with metastatic HER2+ BC from the perspective of the health care system of Ukraine.
 Materials and methods. The treatment outcomes as well as related costs were determined by means of Markov analytical modelling based on a randomized multicenter open clinical study of CLEOPATRA phase III [2]. The model time horizon was 20 years. The alternative schemes of frontline therapy of metastatic HER2+ breast cancer were compared: PTD regimen pertuzumab + trastuzumab + docetaxel and TD regimen trastuzumab + docetaxel. Based on Markov modelling, pharmacoeconomic analysis by means of cost-effectiveness and cost-utility methods was carried out. As an efficiency criterion, LYG amount was used, as a utility criterion − QALY indicator. Direct medical costs were counted, the structure of which had been determined according to the current Protocol. The cost of drugs was calculated in accordance with the Register of wholesale prices for pharmaceuticals of the Ministry of Health of Ukraine; the cost of treatment procedures was determined in accordance with the available price lists of paid medical services provided by licensed medical institutions. Discounting at the level of 3 % per year was applied. Sensitivity analysis of the outcomes was carried out before pertuzumab price changed.
 Results. According to the modelling, the average life expectancy of patients with HER2+ BC, receiving PTD scheme is 15.69 years compared to 13.95 years in the TD group. Along with prolonging life, associated with PTD scheme, its quality increases. Patients in the TD group gain 7.8 QALY on average, while in the PTD group it is 9.24. The total expenses for the simulated (involved into modeling) study period in the PTD group averaged UAH 1 970 369.6 per patient, in the TD group − UAH 732 517.7. ICER (cost of 1 additional life year) and ICUR (cost of 1 additional qualityadjusted life year) incremental coefficients amounted to UAH 710924.6 and UAH 861175.4 respectively.
 Conclusions. 1. Pertuzumab target drug is an effective pharmaceutical when administered to patients with metastatic HER2 + breast cancer. 2. The frontline therapy regimen for patients with metastatic HER2 + breast cancer with pertuzumab being included is more expensive in comparison with trastuzumab + docetaxel regimen; at the same time it makes it possible to achieve better results, i. e. to provide on average extra 1.74 life years and 1.44 QALY in 20-year perspective. 3. Pharmacoeconomic analysis based on Markov model and cost-effectiveness and cost-benefit calculations make it possible to consider pertuzumab (Perjeta®), included into frontline targeted therapy regimen of trastuzumab + docetaxel in patients with metastatic HER2+ breast cancer, as an economically feasible medical technology under current health care conditions in Ukraine.

OA03.05 Phase III Study Comparing Nab-Paclitaxel With Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer

Nanoparticle albumin-bound (nab-) paclitaxel showed promising efficacy for treatment of advanced non–small cell lung cancer (NSCLC) in a phase 2 study. We aimed to assess the efficacy and safety of nab-paclitaxel for previously treated patients with advanced NSCLC. In this multicenter, randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m2) on day 1 or nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival analyzed on an intention-to-treat basis. Adverse events were assessed according to treatment received. Between 22 May 2015 and 12 March 2018, 503 patients were randomly allocated to treatment. Median overall survival was 13.6 months (95% CI, 10.9–16.5) for the 251 patients allocated to docetaxel and 16.2 months (95% CI, 14.4–19.0) for the 252 patients allocated to nab-paclitaxel (hazard ratio, 0.85; 95.2% CI, 0.68–1.07). Median progression-free survival was 4.2 months (95% CI, 3.9–5.0) for the nab-paclitaxel group versus 3.4 months (95% CI, 2.9–4.1) for the docetaxel group (hazard ratio, 0.76; 95% CI, 0.63–0.92; p=0.0042). The objective response rate was 29.9% (95% CI, 24.0–36.2) for the nab-paclitaxel group and 15.4% (95% CI, 10.9–20.7) for the docetaxel group (p=0.0002), and it showed a significant improvement for nab-paclitaxel versus docetaxel regardless of tumor histology. Adverse events of grade ≥3 included febrile neutropenia (55 [22%] of 249 patients in the docetaxel group versus 5 [2%] of 245 patients in the nab-paclitaxel group) and peripheral sensory neuropathy (2 [1%] versus 24 [10%], respectively). The trial showed that nab-paclitaxel was noninferior to docetaxel in terms of overall survival. Nab-paclitaxel should thus be considered a standard treatment option for previously treated patients with advanced NSCLC.

Docetaxel exposure and hematological toxicity in Chinese patients with locally advanced/metastatic nasopharyngeal carcinoma.

This study aimed to describe the area under the plasma concentration-time curve (AUC) and the relationship with hematological toxicity plus clinical responses of docetaxel in patients with nasopharyngeal carcinoma. Furthermore, a suitable docetaxel exposure level would be identified to guide clinical dosing. 96 patients with locally advanced or metastatic nasopharyngeal carcinoma treated with docetaxel-based chemotherapy were enrolled. Docetaxel was measured by turbidimetric immunoassay. Associations between docetaxel exposure and hematologic toxicity, effect, and recurrence time were analyzed. Receiver operating characteristic curve analysis was performed to determine an optimal AUC value to predict the decrease in absolute neutrophil counts. Interpatient variability was large with regard to exposure (AUC) and clearance. The AUC values of 76 patients in course 1 varied more than 4 fold (3.17±0.84 µg×h/mL, ranging from 1.4 to 6.0 µg×h/mL). Clearance was 42.8L/h (ranging from 20.8 to 73.7L/h) with ~3-fold interindividual variability. The incidence of grade 3/4 leukopenia, 3/4 neutropenia, and febrile neutropenia was 46.3, 85.2, and 13.5%, respectively, in course 1. Docetaxel exposure was the only significant predictor (p<0.001) of severe toxicity, including grade 4 neutropenia and febrile neutropenia. A cutoff value of 2.85 µg×h/mL was selected as the target AUC. Higher AUC values were not observed to be associated with better drug effect. The dose was calculated based on individual clearance and a target AUC of 2.85 µg×h/mL, helping to adjust the next cycle of doses and solve interpatient variability.

Differential effect of body mass index (BMI) on outcomes of patients treated with docetaxel in prostate cancer: An exploratory analysis.

129 Background: Docetaxel is a lipophilic drugs with a high affinity for adipose tissue resulting in a higher volume of distribution.There are contradictory data with regards to the differential effect of docetaxel based on BMI in breast cancer patients. However, there are no such data in patients with prostate cancer. A We performed an exploratory analysis to determine if the benefit of docetaxel in patients with metastatic castration resistant prostate cancer (mCRPC) is modified by BMI. Methods: This is a post hoc analysis of data retrieved from the phase III ENTHUSE M1C study that assessed the efficacy and safety of additional zibotentan in combination with docetaxel in patients with mCRPC (ClinicalTrials.gov identifier: NCT00617669). BMI (kg/m2) was categorized as: 18.5 to &lt; 25, lean; 25 to &lt; 30, overweight; and ≥ 30, obese. Cox regression models were constructed to determine the impact of BMI on progression-free survival (PFS) and overall survival (OS) after adjusting for baseline characteristics. Results: A total of 466 patients were eligible for current analysis, of whom 34%, 46% and 20% were &lt; 65 years, 65-74 years and &gt; 75 years, respectively. The median total and free baseline PSA were 99.5 (interquartile range [IQR], 33.6 to 237.0) ng/mL and 13.9 (IQR, 5.4 to 37.4) ng/mL, respectively. There were 31% (n = 145), 46% (n = 213) and 23% (n = 108) lean, overweight and obese patients. Visceral metastasis was present in 52% patients, while the number of bone metastases were 1-3 in 15%, 4 in 5%, 5-20 in 58% and ≥ 21 in 23%. The median number of cycles of docetaxel administered were 10 (IQR, 6-10). The median PFS was 7.3, 7.7 and 8.4 months (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.81 to 1.06; P = .26) for lean, overweight and obese patients, respectively. The median OS was 10.3, 10.7 and 12.4 months (HR, 0.75; 95% CI, 0.63 to 0.89; P = .01) for lean, overweight and obese patients, respectively. After adjusting for baseline and tumor related characteristics, there was no association of BMI with PFS (overweight, HR, 0.92; 95% CI, 0.73 to 1.17; P = .50; obese, HR, 0.90; 95% CI, 0.67 to 1.18; P = .42) while overweight (HR, 0.68; 95% CI, 0.52 to 0.91; P = .01) and obese (HR, 0.61; 95% CI, 0.43 to 0.88; P = .01) patients had significantly better OS as compared with lean patients. Conclusions: The differential effect of docetaxel based on BMI was not observed in patients with mCRPC. Interestingly, obese patients had a significantly longer OS, which warrants further investigation.

Role of free testosterone serum levels during salvage chemotherapy with carboplatin plus weekly docetaxel in patients with docetaxel-refractory, metastatic castration-resistant prostate cancer (mCRPC).

145 Background: Carboplatin plus docetaxel (CD) may be effective in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis and thus lower testosterone levels . In this study, the impact of CD on free and total testosterone (fT, TT) serum levels and the prognostic role of fT and TT were analyzed in mDRPC patients. Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel (35 mg/m2) iv for one hour on days 1, 8, (15) plus prednisone 2x5 mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Results: Of the 118 pts. treated since February 2005, 95.8% had bone, 47.5% lymph node, 28.0% liver and 20.3% lung metastases. Median follow-up time was 14.4 months at the time of the current analysis. The objective response rate (ORR) was 46.4% in the 69 pts. with measureable disease (58.5%). Response of prostate-specific antigen (PSAR ≥ 50%) was observed in 56 (47.9%) patients. Median progression free survival (PFS) was 7.6 months (CI 95% 6.0, 9.1) and median overall survival (OS) was 15.7 months (CI 95% 12.2, 19.2). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (36.4/28.8%). Median FT serum levels were 0.35 pg/mL before and &lt; 0.18 pg/mL during CD treatment (nadir levels, p &lt; 0.001; detection limit &lt; 0.18 pg/mL). In multivariate analyses, LDH &gt; 2xULN, PSAR≥50% and FT nadir levels below the detection limit ( &lt; 0.18 pg/mL) during CD treatment were associated with longer PFS (p &lt; 0.05). Conclusions: These data suggest that CD may be an important salvage treatment option for mDRPC patients by inhibition of the testosterone biosynthesis.

Impact of subsequent immune checkpoint inhibitor treatment on overall survival with avelumab vs docetaxel in platinum-treated advanced NSCLC: Post hoc analyses from the phase 3 JAVELIN Lung 200 trial

ObjectivesThe JAVELIN Lung 200 phase 3 trial did not meet its primary endpoint of improving overall survival (OS) with avelumab vs docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report post hoc analyses assessing the effects of subsequent immune checkpoint inhibitor (ICI) treatment on OS. Material and methodsPatients with stage IIIB/IV NSCLC progressed following platinum-doublet therapy were randomized to receive avelumab or docetaxel. OS was analyzed in the PD-L1+ population (≥1% of tumor cells) and full analysis set (PD-L1+ or PD-L1−). Effects of subsequent ICI (after permanent discontinuation of study treatment) on OS were analyzed using a preplanned naive sensitivity analysis and post hoc inverse probability of censoring weighting (IPCW) analysis. Subgroups with or without subsequent ICI treatment were analyzed using descriptive statistics. ResultsIn the avelumab and docetaxel arms, a subsequent ICI was received by 16/396 (4.0 %) and 104/396 (26.3 %) after a median of 10.5 months (range, 3.9–20.4) and 5.7 months (range, 0.1–24.4), respectively. Some subgroups showed trends for higher subsequent ICI treatment, including patients with non-squamous NSCLC (avelumab arm, 4.3 % vs docetaxel arm, 32.1 %) or with a baseline ECOG performance status of 0 (6.3 % vs 31.3 %); those enrolled in the early recruitment wave (11.6 % vs 54.3 %), or enrolled in the US/Western Europe (2.8 % vs 45.5 %) or Asia (11.0 % vs 35.4 %); and non-white patients (10.1 % vs 35.0 %). The hazard ratio for OS with avelumab vs docetaxel was lower in the IPCW analysis than in the naive sensitivity analysis (PD-L1+ population: 0.80 [95 % CI, 0.62−1.04] vs 0.86 [95 % CI, 0.68−1.09], respectively). ConclusionIn the JAVELIN Lung 200 trial, avelumab showed clinical activity as second-line treatment for patients with advanced NSCLC. Post hoc analyses suggest that the primary OS analysis may have been confounded by subsequent ICI use in the docetaxel arm. ClinicalTrials.gov identifier: NCT02395172.

MO01.32 CodeBreaK 200: A Phase 3 Multicenter Study of Sotorasib, a KRAS(G12C) Inhibitor, versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS p.G12C Mutation

Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation is an oncogenic driver mutation that occurs in approximately 13% of NSCLC and is often associated with poor prognosis. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRAS(G12C) by locking it in its inactive GDP-bound state. Results from the first-in-human trial of sotorasib (CodeBreak 100, NCT03600883) demonstrated a favorable safety profile and promising and durable antitumor activity in patients with KRAS p.G12C mutant advanced NSCLC.

EX4 Bayesian MULTI-Parameter Evidence Synthesis to Improve LONG TERM Survival Extrapolation with EARLY Follow up DATA from Nivolumab NSCLC Studies

Immuno-oncology therapies can be associated with responses that are delayed but durable and related to long-term survival. This may lead to complex hazard functions which standard parametric models fail to accurately model with often only early trial data available for HTA assessments. We used Bayesian multi-parameter evidence synthesis (B-MPES), a method which enables incorporation of external evidence, to provide long-term survival extrapolations in comparison to standard parametric models. We assessed the performance of B-MPES using databases with minimum follow up of 1- to 5-years from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and non-squamous (CheckMate-057) NSCLC. A natural cubic spline model was used to combine overall survival data from each trial with Surveillance, Epidemiology, and End Results (SEER) cancer registry data. Cumulative hazard plots were examined to identify spline knot locations. Performance of the survival extrapolations with 1-, 2-, and 3-year dataset-based B-MPES models were compared with the validated standard parametric model (SPM) for the 5-year dataset using restricted mean survival time (RMST). Additional comparisons against best fit SPMs with earlier data will also be presented. The estimated RMST (95% CI) in months for nivolumab from the 2-, 3-, and 5-year datasets of CheckMate-017 over a 20-year horizon were 24.0 (19.0-29.5), 25.2 (20.7-30.7), and 30.5 (23.0-35.9), respectively, with B-MPES models and 30.5 (21.4-43.6) with the validated 5-year SPM. For CheckMate-057, the estimated 20-year RMST from the 2-, 3-, and 5-year datasets were 22.4 (19.0-26.1), 32.8 (28.2-37.9), and 35.5 months (28.6-44.4), respectively, with B-MPES and 28.6 months (23.5-34.5) with the 5-year validated SPM. We demonstrate that incorporating data from external data sources using B-MPES, yields comparable results to 5-year SPMs using earlier datasets. For CheckMate-057, B-MPES fitted to 3- and 5-year datasets yields more favorable survival extrapolations than the 5-year SPM.

PCN258 Using Mixture Cure Models to Improve Survival Extrapolations from EARLY Follow-up DATA for Nivolumab in NSCLC

Selecting appropriate parametric models to extrapolate long-term survival based on limited follow up trial data may improve the reliability of HTA evidence. Using data from two phase 3 trials in 2L NSCLC, we assess whether mixture cure models (MCMs) improve survival extrapolation relative to standard methods. The analyses were based on datasets with minimum of 5 years of follow up from trials comparing nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and non-squamous (CheckMate-057) NSCLC. MCMs assume a fraction of patients are cured by treatment, with uncured and cured patients subject to separate survival curves. We estimated MCMs on 1-3 year databases and assessed the survival extrapolations against the validated standard parametric models (SPM) using the 5-year dataset. Validation of models was facilitated by comparing the restricted mean survival time (RMST) over 20-years. Additional comparisons against SPMs from earlier datasets will be presented. For CheckMate-017, MCMs fitted to the 1-year (PFS) and 3-year (OS) datasets were the earliest datasets modeled to yield results comparable to the 5-year validated SPM. For CheckMate-057, the 2-year (PFS) and 3-year (OS) datasets were the earliest datasets modeled to yield results comparable to the 5-year validated SPM. For CheckMate-017, the 20-year RMST estimate for PFS from the 1-year data was 25.5 vs 22.9 months for the 5-year SPM, and the 3-year OS MCM was 30.2 vs 30.5 for the 5-year SPM. For CheckMate-057, the 20-year RMST for the 2-year PFS MCM was 23.6 vs 19.0 for the 5-year SPM, and the 3-year OS MCM was 27.5 vs 28.6 for the 5-year SPM We demonstrate that the use of MCMs for modeling survival with early follow-up in NSCLC patients could anticipate validated standard survival extrapolations with extended follow-up.

Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials

The phase 2 POPLAR and phase 3 OAK studies of the anti-programmed death-ligand 1 (PD-L1) immunotherapy atezolizumab in patients with previously treated advanced NSCLC revealed significant improvements in survival versus docetaxel (p = 0.04 and 0.0003, respectively). Longer follow-up permits evaluation of continued benefit of atezolizumab. This study reports the final overall survival (OS) and safety findings from both trials.POPLAR randomized 287 patients (atezolizumab, 144; docetaxel, 143) and OAK randomized 1225 patients (atezolizumab, 613; docetaxel, 612). The patients received atezolizumab (1200 mg fixed dose) or docetaxel (75 mg/m2) every 3 weeks. Efficacy and safety outcomes were evaluated.A longer OS was observed in patients receiving atezolizumab versus docetaxel in POPLAR (median OS = 12.6 mo versus 9.7 mo; hazard ratio = 0.76, 95% confidence interval [CI]: 0.58-1.00) and OAK (median OS = 13.3 versus 9.8 mo; hazard ratio = 0.78, 95% CI: 0.68-0.89). The 4-year OS rates in POPLAR were 14.8% (8.7-20.8) and 8.1% (3.2-13.0) and those in OAK were 15.5% (12.4-18.7) and 8.7% (6.2-11.3) for atezolizumab and docetaxel, respectively. Atezolizumab had improved OS benefit compared with docetaxel across all PD-L1 expression and histology groups. Most 4-year survivors in the docetaxel arms received subsequent immunotherapy (POPLAR, 50%; OAK, 65%). Of the 4-year survivors, most had Eastern Cooperative Oncology Group performance status of 0 and nonsquamous histological classification and approximately half were responders (POPLAR: atezolizumab, seven of 15; docetaxel, three of four; OAK: atezolizumab, 24 of 43; docetaxel, 11 of 26). Treatment-related grade 3/4 adverse events occurred in 27% and 16% of atezolizumab 4-year survivors in POPLAR and OAK, respectively.Long-term follow-up suggests a consistent survival benefit with atezolizumab versus docetaxel in patients with previously treated NSCLC regardless of PD-L1 expression, histology, or subsequent immunotherapy. Atezolizumab had no new safety signals, and the safety profile was similar to that in previous studies.

402P Efficacy and safety of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC)

Immuno-checkpoint inhibitors (ICIs) has become standard second line therapy for advanced NSCLC patients (pts). However, early progression remained a major challenge with ICIs monotherapy. The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting. Our study aims to explore if the combination of a PD-1 inhibitor with chemotherapy can provide additional clinical benefits in previously treated advanced NSCLC pts. Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would be enrolled in this single-arm phase II study. EGFR/ALK positive pts must be TKIs failure or intolerable. Eligible pts would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. The primary end point is progression-free survival (PFS) per RECIST v1.1. Secondary end points included overall response rate (ORR), duration of response (DOR), overall survival, and safety. From 10/2019 to 4/2020, 28 pts were enrolled. Most were male (75%) and adenocarcinoma (85.7%). 21.4% pts had brain metastasis at baseline. Median follow-up was 5.1m (range 2.4-8.1) as of data cut-off (6/17/2020). 42.9% (12/28) pts were still on study treatment. PFS data was immature with only 35.7% (10/28) events. Estimated median PFS was 5.5m (95%CI 3.6-NE). Of the 25 evaluable pts, ORR is 24% (95%CI 9%, 45%), DCR is 92% (95%CI 74%, 99%). Median DOR was not reached (95% 1.28m, NA). Overall, 60.7% (17/28) pts had experienced treatment emergent adverse events (TEAEs), including 17.9% (5/28) grade 3-4 cases. No AEs led to treatment discontinuation or death. The most common TEAEs were leukopenia (50%), neutropenia (28.6%), alopecia (17.9%), lymphopenia (14.3%) and fatigue (14.3%). This first report of a PD-1 inhibitor plus chemotherapy in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. Enrollment is ongoing and more data will be presented.