Background-Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid PFS surrogate in newly diagnosed multiple myeloma (NDMM).Materials and Methods-We searched abstracts in PubMed, The American Society of Hematology (ASH) and the European Hematology Association (EHA) for "myeloma", "minimal residual disease", and "clinical trial". Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRDtested populations were required. Meta-analysis was performed by principles outlined at the 2013 FDA workshop on MRD in AML. 1 For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD positive.
Purpose: MET gene amplification is associated with poor prognosis in gastric/gastroesophageal junction/esophageal
Introduction: The use of lenalidomide (LEN) and bortezomib (BTZ) in newly diagnosed multiple myeloma (MM) patients (pts), along with continuous or maintenance therapy paradigm have improved survival outcomes. However, many pts progress while on these agents or discontinue them due to toxicity. There is a need for novel, efficacious, and tolerable regimens that can treat MM pts who are exposed or refractory to LEN or BTZ. The proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab have both been approved as single agents or as components of combination regimens for the treatment of RRMM. The combination of carfilzomib, dexamethasone, and daratumumab has been shown to be efficacious and safe in RRMM in the phase 1 study MMY1001 (Chari, Blood 2019). We present results from the primary analysis of CANDOR, a multicenter, phase 3, randomized study comparing carfilzomib, dexamethasone, and daratumumab (KdD) vs carfilzomib and dexamethasone (Kd) in RRMM pts. Methods: RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Pts were randomized 2:1 to KdD or Kd. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 wks for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), minimal residual disease (MRD) negative-complete response at 12 months (threshold, 10-5 cells), overall survival (OS), time to response, and safety. Results: 466 pts (KdD: 312; Kd: 154) from 102 sites worldwide were randomized. Baseline characteristics were balanced between the two arms. Median age was 64 years. Of the randomized pts, 42.3% and 90.3% received previous LEN- and BTZ-containing regimens, respectively. 33% of pts were LEN-refractory. The primary endpoint of PFS was met after a median follow-up of 16.9 mo and 16.3 mo for the KdD and Kd arms, respectively. Median PFS was not reached for the KdD arm vs 15.8 mo for the Kd arm (HR, 0.63; 95% CI, 0.46-0.85; P=0.0014; Figure). PFS HRs favored KdD vs Kd across prespecified subgroups. Importantly, median PFS (KdD vs Kd) was not reached vs 12.1 mo in the LEN-exposed group (HR, 0.52; 95% CI, 0.34-0.80), and was not reached vs 11.1 mo in the LEN-refractory group (HR, 0.45; 95% CI, 0.28-0.74). Median time to first response was 1 mo in the KdD and Kd arms. ORR was 84.3% vs 74.7% (P=0.0040), and the rate of complete response or better was 28.5% vs 10.4%. MRD-negative complete response rate at 12 mo was 12.5% for KdD vs 1.3% for Kd (P<0.0001). Median OS was not reached in either arm at a median follow-up time of 17 mo (HR, 0.75; 95% CI, 0.49-1.13; P=0.08). Median treatment duration was longer in the KdD than Kd arm (70.1 vs 40.3 wks). The incidence of grade ≥3 AEs was 82.1% and 73.9% in the KdD and Kd arms, respectively. Serious AEs occurred in 56.2% (KdD) and 45.8% (Kd). The rate of treatment discontinuation due to AEs was similar in both arms (KdD, 22.4%; Kd, 24.8%). The frequency of grade ≥3 cardiac failure was 3.9% (KdD) and 8.5% (Kd); rate of cardiac failure event leading to K discontinuation was similar in the arms (3.9% and 4.6%). 5 deaths were reported as treatment-related, all in the KdD arm (pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest [n=1 each]). Additional efficacy endpoints, including key subgroup analyses will be presented. Conclusion: KdD resulted in a significant PFS benefit over Kd, with a 37% reduction in the risk of progression or death. Pts treated with KdD achieved deeper responses, with a nearly 10-times higher MRD negative-complete response rate vs Kd-treated pts. The PFS benefit of KdD was maintained across prespecified clinically important subgroups, particularly among LEN-exposed and LEN-refractory pts. AEs were generally manageable and the incidence of AEs leading to treatment discontinuation was similar in the arms. Overall, KdD was associated with a favorable benefit-risk profile and represents an efficacious new regimen for RRMM, including for LEN-exposed and/or LEN-refractory pts. Figure Disclosures Usmani: AbbVie: Other: Personal fees; SkylineDx: Consultancy, Other: Grant, Personal fees, Research Funding; GSK: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Grant, Personal fees, Research Funding; MundiPharma: Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; Sanofi: Other: Grant, Personal fees, Research Funding, Speakers Bureau; Pharmacyclics: Other: Grant, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Other: Grant, Research Funding; Array Biopharma: Grant, Personal fees, Research Funding; Amgen: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau. Quach:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Other: investigator initiated clinical study; Grant, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: investigator initiated clinical study; Grant, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Other: Free drug for investigator-initiated study, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:Glicomimetics: Other: Personal fees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Adaptive: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Landgren:Takeda: Other: Grants, Independent Data Monitoring Committee (IDMC); Rising Tides Foundation: Other: Grants; Amgen: Other: Grant, Personal fees; Seattle Genetics: Other: Grants; NIH: Other: Grants; FDA: Other: Personal fees; Glenmark: Other: Grants; MMRF: Other: Independent Data Monitoring Committee (IDMC); IMF: Other: Grants; LLS: Other: Grants; Perelman Family Foundation: Other: Grants; Karyopharm: Other: Grants; Adaptive: Other: Personal fees; Binding Site: Other: Personal fees; Celgene: Other: Grant, Personal fees; BMS: Other: Personal fees; Cellectis: Other: Personal fees; Juno: Other: Personal fees; Pfizer: Other: Personal fees; Merck: Other: Independent Data Monitoring Committee (IDMC); Janssen: Other: Grants, Personal fees, Independent Data Monitoring Committee (IDMC). Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; GSK: Honoraria; AbbVie: Honoraria. Siegel:Novartis: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy; GSK: Honoraria. Yang:Amgen: Employment, Equity Ownership. Klippel:Amgen: Employment, Equity Ownership. Zahlten-Kumeli:Amgen: Employment, Equity Ownership. Dimopoulos:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi Oncology: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis Pharma: Research Funding; BMS: Consultancy; Celgene: Consultancy, Honoraria. OffLabel Disclosure: carfilzomib dexamethasone, and daratumumab triplet for relapsed or refractory multiple myeloma
Although the relationships between CXCR4 and EGFR expression and survival in non‑small cell lung cancer (NSCLC) have been studied independently, dual CXCR4/EGFR tumor status and its relationship with survival has not been previously investigated. In the present study, we examined the relationship between CXCR4 expression, EGFR expression and dual CXCR4/EGFR expression and survival in patients with NSCLC (n=125) using immunohistochemical techniques. Overall survival was estimated using Kaplan-Meier and Cox proportional hazards models adjusting for patient age, tumor stage and type of treatments. Patients with CXCR4-positive tumors were significantly associated with distant metastasis and tended to have poorer prognosis compared to patients with CXCR4-negative tumors (HR=2.172, 95% CI=1.229‑3.839). No significant association between EGFR expression and survival was found; however co-expression of CXCR4/EGFR was a significant prognostic factor of worse overall survival (HR=2.741, 95% CI=1.330‑5.741). Furthermore, we showed that EGF enhanced the expression of CXCR4 in NSCLC cells through the PI-3K pathway, and treatment of NSCLC cells with EGFR phosphorylation inhibitor, AG1478, resulted in downregulation of the expression of CXCR4. These results suggest an important interaction between CXCR4 and EGFR intra-cellular pathways that may activate signals of tumor progression and may provide a valid explanation for the poor overall survival rate of patients whose co-expression of CXCR4 and EGFR is detected in tissue sections. Based on EGFR and CXCR4 expression, new molecular subtypes of NSCLC established in the present study can be used for customization of NSCLC treatment. Our results also showed that EGFR and CXCR4 are potential therapeutic targets for NSCLC and that simultaneous inhibition of EGFR and CXCR4 in NSCLC patients with concomitant expression of both CXCR4 and EGFR may be an effective treatment strategy.
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