Second-line Therapy In Patients Research Articles

Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study.

383 Background: The anti–PD-1 antibody pembro showed efficacy and manageable safety in the global phase 2 KEYNOTE-224 and phase 3 KEYNOTE-240 studies of patients (pts) with previously treated advanced HCC, a population of high unmet need. KEYNOTE-394 is a randomized, double-blind, phase 3 study conducted in Asia to evaluate the efficacy and safety of pembro vs placebo, both given with BSC, as second-line therapy for previously treated advanced HCC (NCT03062358). Methods: Eligible pts in Asia with confirmed advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomized 2:1 to pembro 200 mg or placebo Q3W for ≤35 cycles plus BSC per local guidelines. The primary endpoint was OS. Secondary endpoints were PFS, ORR, DOR, DCR, and TTP, all assessed per RECIST v1.1 by blinded independent central review, and safety. Treatment differences were assessed using the stratified log-rank test (OS and PFS) or the stratified Miettinen & Nurminen method (ORR). The P value boundary for OS superiority at final analysis (FA) was 0.019307. If OS was superior, PFS and ORR superiority at the second interim analysis (IA2; primary analysis timepoint for these endpoints) could be tested at boundaries of 0.013447 and 0.009139, respectively. Results: 453 pts were randomized to pembro (N = 300) or placebo (N = 153). Baseline characteristics were generally balanced between arms; 90.7% had received sorafenib as first-line therapy. As of the June 30, 2021 cutoff date for FA, median study follow-up was 33.8 mo (range 18.7-49.0). At FA, pembro significantly improved OS vs placebo (HR 0.79, 95% CI 0.63-0.99, P = 0.0180); median (95% CI) OS was 14.6 mo (12.6-18.0) for pembro vs 13.0 mo (10.5-15.1) for placebo and 24-mo OS rate was 34.3% vs 24.9%. At IA2, pembro significantly improved PFS (HR 0.74, 95% CI 0.60-0.92, P = 0.0032) and ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P = 0.00004); median (95% CI) PFS was 2.6 mo (1.5-2.8) for pembro vs 2.3 mo (1.4-2.8) for placebo, 12-mo PFS rates were 15.9% vs 1.4%, and ORR was 12.7% vs 1.3%. At FA, ORR was 13.7% vs 1.3%, median DOR was 23.9 mo vs 5.6 mo, DCR was 52.7% vs 47.7%, and median TTP was 2.7 mo vs 1.7 mo (HR 0.72, 95% CI 0.58-0.90). At FA, treatment-related AEs occurred in 66.9% of pts in the pembro arm and 49.7% in the placebo arm, including 14.4% and 5.9% with grade 3-5 events. 3 pts (1.0%) in the pembro arm and 0 in the placebo arm died of treatment-related AEs. Conclusions: Pembro plus BSC significantly improved OS, PFS, and ORR compared with placebo plus BSC as second-line therapy for patients from Asia with advanced HCC. The pembro safety profile was as expected. Overall, results were consistent with those previously observed in KEYNOTE-224 and KEYNOTE-240 and thus add to the body of evidence supporting the use of pembro as second-line therapy for advanced HCC. Clinical trial information: NCT03062358.

Natural history of patients with advanced cholangiocarcinoma and FGFR2 gene fusions/rearrangements.

391 Background: Cholangiocarcinoma (CCA) is a rare malignancy associated with poor survival. Molecular profiling is important to inform treatment choices and FGFR2 fusions or other rearrangements are common, occurring in 10–16% of patients with intrahepatic CCA (iCCA). There is limited real-world data on the natural history of patients with advanced CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. The primary objective of this retrospective, observational natural history study was to compare real-world overall survival in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2 from the index date of diagnosis of advanced CCA to date of death. A secondary objective was to analyze overall survival in the subgroup of patients with CCA and FGFR2 fusions/rearrangements from the index date of start of second-line therapy to date of death. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database. Data originated from approx. 280 US cancer clinics (̃800 sites of care). Patients were ≥18 years of age, had chart-confirmed advanced CCA, comprehensive genomic profiling demonstrating FGFR2 fusion/rearrangement, and had ≥2 visits within the Flatiron Health network since January 1, 2011. Results: As of May 2020, 571 patients met the inclusion criteria; 75 patients with FGFR2 fusions/rearrangements (median age 63 years; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 patients with WT FGFR2 (median age 65 years; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median overall survival from the index date of diagnosis was numerically higher, but not statistically different, for patients with FGFR2 fusions/rearrangements vs. WT FGFR2 (12.1 months [95% CI 8.5−17.1] vs. 7.1 months [95% CI 5.7−8.8]; log rank p = 0.184). 50 patients with FGFR2 fusions/rearrangements (median age 62 years; 70% female; 94% iCCA; 70% stage IV at diagnosis) received second-line therapy. Median real-world overall survival from the index date of second-line therapy was 8.5 months (95% CI 4.1−12.4 months). Conclusions: These real-world overall survival findings did not demonstrate a survival advantage for patients with CCA and FGFR2 fusions/rearrangements vs. WT FGFR2 receiving therapies for advanced disease, although a non-significant trend towards longer overall survival was observed in patients with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of overall survival after adjusting for potential prognostic covariates. An additional analysis is ongoing to compare overall survival from the start of second-line therapy in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with WT FGFR2.

Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis

BackgroundMost patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. AimTo evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. MethodsRetrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. ResultsOverall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. ConclusionsPatients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment.

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia

In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study. Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level. In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P= 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively. Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.

116TiP KEYNOTE-B98: Phase Ib/II study of pembrolizumab plus investigational agents as second-line treatment for anti–PD-1/PD-L1-refractory extensive-stage small cell lung cancer (ES-SCLC)

Immune checkpoint inhibitors plus platinum chemotherapy are first-line standard-of-care therapy for ES-SCLC. Treatment options for patients who progress after first-line therapy have limited efficacy. The anti–PD-1 monoclonal antibody (mAb) pembrolizumab has demonstrated antitumor activity as monotherapy in patients who have received prior therapy for advanced SCLC in the KEYNOTE-028 and KEYNOTE-158 studies. KEYNOTE-B98 (NCT04938817) is a randomized, phase 1b/2, rolling-arm, multicenter, open-label study evaluating pembrolizumab plus investigational agents as second-line therapy in patients with anti–PD-1/PD-L1 refractory ES-SCLC.

Safety and cost-effectiveness of ponatinib versus other tyrosine kinase inhibitors as second-line therapy in patients with chronic myeloid leukemia in the United States

To evaluate the cost-effectiveness of ponatinib compared with second-line TKIs in the treatment of adult patients with CML who failed, or were intolerant to, first-line TKIs. A Markov state transition model was conducted. Model transition, adverse-effect probabilities, utility data and medical costs were obtained from clinical trials and literature. Measurements included medications, follow-ups, adverse events, allogeneic stem cell transplantation and quality-adjusted life years (QALYs). Univariable and Bayesian multivariable probabilistic sensitivity analyses were conducted using Monte Carlo simulations. Dasatinib resulted in an ICER of $79,086/QALY compared to nilotinib. Ponatinib yielded an ICER of $176,278/QALY and $141,563/QALY compared to dasatinib and nilotinib, respectively. Dasatinib was the optimal treatment at a $100,000/QALY threshold. The probability (36%–40%) for ponatinib or dasatinib optimal treatment was associated with thresholds of $160,000–$180,000/QALY. Dasatinib and ponatinib can be considered cost-effective options and provide clinical benefits compared to other second-line TKIs for CML in the US.

Efficacy and Safety of Ruxolitinib in the Treatment of Elderly Patients with Policythemia Vera Resistant/Intolerant to Hydroxyurea

▪Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts.Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts.Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy.Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start.No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1).Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04).Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs.As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60).Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs.Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. [Display omitted] DisclosuresLatagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Apatinib plus S-1 for previously treated, advanced gastric or gastro-oesophageal junction adenocarcinoma: a phase 2, single-arm, prospective study.

The current management of advanced gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. We investigated the efficacy and safety of the combination therapy of apatinib and S-1, considering the potential advantage of home-based treatment without hospital admission, in patients with platinum-refractory gastric or gastro-oesophageal junction adenocarcinoma. In this open-label, single-arm, phase 2 trial, in each 21-day cycle, eligible patients received apatinib at an initial dose of 500 mg once daily continuously and S-1 at a dose of 40-60 mg twice daily on days 1-14 until the trail was discontinued disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoints were progression-free survival. The secondary endpoints were objective response rates, disease control rates, and safety, and overall survival. This study was registered at ClinicalTrials.gov, NCT04338438. Between April 2015 and May 2019, we included 37 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma refractory to first-line platinum-containing therapy. At the data cutoff, the 6-month progression-free survival was 31.5%, the median progression-free survival and overall survival were 4.2 (95% CI: 3.50-4.90) months and 8.2 (95% CI: 4.69-11.71) months, respectively. Of 37 eligible patients, 8 (21.6%) patients reached objective responses, 31 (83.8%) patients reached disease control. Grade 3 or 4 adverse events occurred in 8 (21.6%) patients, including hand-foot syndrome, hypertension, and diarrhea, etc. The combination of Apatinib and S-1 showed promising efficacy and manageable toxicity as a home-based, second-line therapy in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, especially for the elder patients with poor performance status. NCT04338438.

Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181

BackgroundSafe and effective treatments for advanced esophageal cancer are an unmet need in Japan. We report results of a subgroup analysis of Japanese patients enrolled in KEYNOTE-181, a randomized, open-label, phase 3 study of pembrolizumab versus chemotherapy as second-line therapy for patients with advanced or metastatic esophageal cancer whose disease progressed after standard first-line therapy.MethodsPatients were randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks or investigator’s choice of paclitaxel, docetaxel, or irinotecan. Efficacy was evaluated in all Japanese patients and in those with programmed death ligand 1 combined positive score ≥ 10.ResultsOf the 152 Japanese patients enrolled (pembrolizumab, n = 77; chemotherapy, n = 75), 150 (98.7%) had squamous cell carcinoma and 79 (52.0%) had combined positive score ≥ 10. At the final analysis, median overall survival was improved among all patients (12.4 vs 8.2 months with pembrolizumab and chemotherapy, respectively; hazard ratio, 0.68; 95% CI 0.48–0.97) and patients with combined positive score ≥ 10 (12.6 vs 8.4 months; hazard ratio, 0.68; 95% CI 0.42–1.10). Fewer patients had any-grade (74.0% vs 95.9%) or grade 3–5 (16.9 vs 50.0%) treatment-related adverse events with pembrolizumab than with chemotherapy.ConclusionConsistent with the global trial results, second-line pembrolizumab therapy showed a survival benefit and a favorable safety profile compared with chemotherapy in Japanese patients with advanced esophageal cancer.

PD-1/PD-L1 Immune Checkpoint Inhibitors after Platinum-based Chemotherapy in Metastatic or Locally Advanced Urothelial Bladder Carcinoma: A Systematic Review and Meta-analysis

Objective: This study aimed to assess the effect of anti-programmed cell death-1/programmed cell death-ligand-1 (PD-1/PD-L1) agents compared with second-line therapy in patients with metastatic or locally advanced urothelial bladder carcinoma following previous platinum-containing chemotherapy.Material and Methods: We systematically searched three electronic databases. The protocol of the study was registered in Prospero (CRD42019142494). Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the certainty of evidence (CoE) was estimated.Results: The search results initially found 8168 publications. For qualitative synthesis, two publications were included. Pooled results indicated that patients treated with anti-PD-1/PD-L1 agents had significantly prolonged overall survival (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.7-0.9; I2 21.0%; moderate CoE). According to positive PD-L1 expression, PD-1/PD-L1 inhibitors had significantly more survival than chemotherapy (HR 0.75; 95% CI 0.5-0.9, I2 57.0%, low CoE). Furthermore, there was no significant difference in adverse events (AE) between the anti-PD-1/PDL1 agents and second-line chemotherapy (risk ratio 0.68; 95% CI 0.3-1.4; I2 97.0%, low CoE).Conclusion: The present meta-analysis and systematic review provide strong evidence that anti-PD-1/PD-L1 agents could improve overall survival and have similar results in AEs compared with second-line chemotherapy. Further studies will confirm the power of immunotherapy for the treatment of metastatic or locally advanced urothelial bladder carcinoma.

Recent Updates in the Treatment of Erythema Multiforme.

Erythema multiforme (EM) is an immune-mediated condition that classically presents with discrete targetoid lesions and can involve both mucosal and cutaneous sites. While EM is typically preceded by viral infections, most notably herpes simplex virus (HSV), and certain medications, a large portion of cases are due to an unidentifiable cause. EM can be confused with other more serious conditions like Stevens–Johnson syndrome (SJS); however, clinical research has provided significant evidence to classify EM and SJS as separate disorders. Treatment of EM is highly variable, depending on the etiology, the involvement of mucosal sites, and the chronicity (acute vs. recurring) of the disease. If the etiology or causal medication/infection is identified, then the medication is stopped and/or the infection is treated prior to initiating symptomatic treatment. Treatment for acute EM is focused on relieving symptoms with topical steroids or antihistamines. Treatment for recurrent EM is most successful when tailored to individual patients. First line treatment for recurrent EM includes both systemic and topical therapies. Systemic therapies include corticosteroid therapy and antiviral prophylaxis. Topical therapies include high-potency corticosteroids, and antiseptic or anesthetic solutions for mucosal involvement. Second-line therapies for patients who do not respond to antiviral medications include immunosuppressive agents, antibiotics, anthelmintics, and antimalarials

275P A phase II study of LAG525 in combination with spartalizumab (PDR001), PDR001 and carboplatin (Carbo), or Carbo, as first- or second-line therapy in patients (Pts) with advanced (Adv) triple-negative breast cancer (tnbc)

In TNBC, despite high initial response to chemotherapy (CT), many pts relapse, and options for treating recurrence are limited. Combining immunotherapy and CT may synergise to enhance therapeutic efficacy. Here we evaluate LAG525, an anti-LAG-3 antibody (ab), with PDR001, an anti-PD-1 ab, and/or carbo in pts with adv TNBC.

Racotumomab in Non-Small Cell Lung Cancer as Maintenance and Second-Line Treatment.

Racotumomab is a therapeutic vaccine based on a monoclonal anti-idiotypic antibody developed by the Molecular Immunology Center in Havana, Cuba, that is registered in Cuba and Argentina for treatment of non-small cell lung cancer. It induces a specific humoral and cellular immune response against the N-glycolyl GM3 (NeuGcGM3) ganglioside present in tumor cells, thereby provoking the death of these cells. Evaluate racotumomab vaccine use as switch maintenance and second-line therapy for patients with inoperable non-small cell lung cancer in routine clinical practice, outside the framework of clinical studies, and assess the overall survival, stage-specific survival and safety in these patients. A descriptive, retrospective study was carried out in patients diagnosed with non-small cell lung cancer not suitable for surgical treatment, who received racotumomab as a part of switch maintenance or second-line treatments. Overall survival was defined from diagnosis and from the first immunization, until death. We included 71 patients treated with racotumomab, 57.7% (41/71) of whom were in stages IIIB and IV of non-small cell lung cancer. Of the patients, 84.5% (60/71) had no adverse events, and 15.5% (11/71) had mild adverse reactions. The median overall survival was 24.5 months, calculated from the first immunization, 17.2 months for those who received racotumomab as switch maintenance and 6.8 months for patients who had progressed after the first line of treatment. Racotumomab in routine clinical practice prolonged overall survival in patients with non-small cell lung cancer treated in switch maintenance, and in stage IV patients who received the treatment as second-line therapy. The vaccine was well tolerated.

P-194 Study of efficacy and safety of combination of octreotide acetate LAR with lenvatinib as second-line therapy in patients with advanced G1-G2 NETs of non-pancreatic origin

There is a documented role of tyrosine kinase inhibitors e.g. sunitinib, axitinib, etc. in grade 2 NET. Lenvatinib is a multikinase inhibitor which includes inhibition of VEGFR-1,2,3, platelet-derived growth factor receptor α (PDGFRα), KIT and RET, as well as FGFR1-4. The aim of this study was to assess the efficacy and toxicity of lenvatinib and octreotide acetate LAR combination in patients with advanced G1-2 extra-pancreatic NETs.

Clinical Benefits of Achieving Deep Remission to Second-Line Therapy in Patients with Relapse/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) - a Real-World Study

▪Introduction: Deep remission to first-line chemoimmunotherapy for chronic lymphocytic leukemia (CLL), especially undetectable minimal residual disease (MRD-), was associated with longer progression-free (PFS) and overall survival (OS). (Kovacs 2016, Kwork 2016) Patients with relapsed/refractory (R/R) CLL represent a more difficult and complex population to treat. The benefits of achieving deep response to second-line therapy in R/R CLL have not been reported. This study aimed to describe patient characteristics, PFS, and OS in patients with R/R CLL who achieved clinical complete remission (CCR) from second-line therapy compared to patients who did not achieve CCR in a real-world setting.Methods: Patient-level data was abstracted from medical charts by 85 oncologists/hematologists in the United States between April and June 2017. Data were collected for adult patients with R/R CLL who initiated a second-line pharmacological therapy between January 1, 2010 and Augusts 31, 2015. Data on disease progression, mortality, and best response to second-line therapy was reported by the treating oncologists/hematologist; iwCLL 2008 criteria were provided to guide assessment of treatment response. Patients were categorized into two cohorts based on best response to second-line therapy: patients who achieved CCR (CCR cohort) and patients who did not achieve CCR (non-CCR cohort). The non-CCR cohort included patients with partial remission (PR), stable disease (SD) and progressive disease (PD). Sample size for each response cohort (i.e., CCR, PR, SD, and PD) was determined a priori based on distribution of responses seen in clinical trials. PFS and OS were compared between the CCR and non-CCR cohorts using Cox proportional analyses. Exploratory analyses compared outcomes between patients with and without MRD- among those who achieved a CCR or PR and had an MRD assessment. Multivariate models adjusted for potential differences in demographic and clinical characteristics between CCR and non-CCR cohorts (i.e., gender, age at R/R CLL diagnosis, del [17p] status, Rai staging and ECOG status at second-line therapy initiation) and between cohorts with and without MRD- (i.e., gender, age at R/R CLL diagnosis, chronic renal failure, and ECOG status).Results: Data was collected on 306 patients with R/R CLL - 153 patients with CCR and 153 patients who did not achieve CCR (102 patients with PR, 40 with SD, and 11 with PD). Most common regimens received in second-line therapy were novel targeted therapies (CCR cohort: 42.5%; non-CCR cohort: 52.3%) and combination of rituximab and bendamustine (CCR cohort: 27.5%; non-CCR cohort: 19.6%). Most patients were male (70.6%). Patients in the non-CCR cohort were older (median of 66 vs. 63 years old) than patients in the CCR cohort; a higher proportion of patients in the non-CCR cohort had a Rai stage of III-IV (62.1% vs. 50.3%), an ECOG status of 2+ (33.9% vs. 13.1%), and del (17p) (26.1% vs. 13.1%) at second-line therapy initiation compared to the CCR cohort. The median observation period after second-line therapy initiation was 26.8 months in the CCR cohort and 23.1 months in the non-CCR cohort. Compared to patients in the CCR cohort, patients in the non-CCR cohort had an over 2-fold higher hazard of progression/death (adjusted hazard ratio [HR]=2.85, p<0.05) and an over 3-fold higher hazard of death (adjusted HR=3.13, p<0.05). Among patients who achieved CCR or PR (n = 255), 78 patients achieved MRD- and 86 patients did not; 13(17%) patients who achieved MRD- and 23 (27%) patients who did not achieve MRD- progressed/died. Patients without MRD- had an over 2-fold higher hazard of progression/death (adjusted HR=2.11, p<0.05) compared to patients with MRD-. Overall survival was not significantly different among patients with an MRD assessment.Conclusion: Results from thisreal-world study suggest that among patients with R/R CLL, achieving deep response in second-line treatment is associated with improved PFS and OS. Given the findings from this study, achieving deep response should be considered as an endpoint for treatment in patients who are receiving first salvage therapy. [Display omitted] DisclosuresWierda:Genzyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Karyopharm: Research Funding; Merck: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Juno: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding. Gauthier:AbbVie Inc.: Other: I am an employee of Analysis Group Inc., which received consulting fees from AbbVie for this study; Analysis Group, Inc: Employment. Meissner:AbbVie Inc.: Employment, Equity Ownership, Other: I am an employee of AbbVie, Inc and may own AbbVie and/or Abbott stock. Guerin:Analysis Group, Inc: Employment; Novartis: Other: I am an employee of Analysis Group, which received consulting fees from Novartis; AbbVie Inc.: Other: I am an employee of Analysis Group, which received consulting fees from AbbVie . Samp:AbbVie, Inc.: Employment, Equity Ownership, Other: I am an employee of AbbVie, Inc and may own AbbVie and/or Abbott stock.

Glucagon-Like Peptide 1 Receptor Agonists, Carotid Atherosclerosis, and Cardiovascular Outcomes.

Glucagon-like peptide 1 receptor agonists (GLP-1 RA) represent an integral part of the arsenal used in clinical practice to improve cardiovascular outcomes in patients with diabetes. Large-scale randomized controlled trials have shown that liraglutide, dulaglutide, albiglutide, and semaglutide all reduce the risk of cardiovascular events in patients with diabetes and either established atherosclerotic cardiovascular disease (ASCVD) or high-risk characteristics (1–4). In contrast, exenatide and lixisenatide improved glycemic control but did not have a sizable impact on cardiovascular events in clinical trials (5,6), suggesting that glycemic control and cardiovascular outcomes are at least partly uncoupled. A meta-analysis including 42,920 participants from five randomized trials demonstrated that GLP-1 RA as a drug class are associated with a significant 13% reduction in the risk of the composite of myocardial infarction, stroke, or cardiovascular death in patients with diabetes and established ASCVD (7). GLP-1 RA are recommended in patients with diabetes and established ASCVD or at high risk of ASCVD (8). They are also indicated as second-line therapy in patients without ASCVD (or without indicators of high risk) who do not meet treatment goals with lifestyle modifications and metformin alone, and they are preferred to insulin if injectable therapy is needed (8). Although the …

МИНИ-ФОТОФЕРЕЗ – ЭКСТРАКОРПОРАЛЬНЫЙ ФОТОФЕРЕЗ, НЕ ТРЕБУЮЩИЙ ЛЕЙКАФЕРЕЗА: ОПЫТ КЛИНИЧЕСКОГО ИСПОЛЬЗОВАНИЯ

Extracorporeal photopheresis (ECP) has proven effectiveness for treatment of several diseases, including acute and chronic graft-versus-host disease (GVHD) after allogenic transplantation of hematopoietic blood stem cells. The standard ECP requires leukapheresis to obtain a mononuclear cell fraction. The possibility of using leukapheresis is limited by the requirements for vascular access and the somatic status of the patient. There is a relatively new method of performing ECF, called «mini-photopheresis» (mini-ECF), in which a fraction of mononuclear cells is isolated from a dose of whole blood obtained by the exfusion method. The article presents preliminary results of using mini-ECP in patients with acute and chronic GVHD. Materials and methods of research: the study included 11 patients with acute (7 patients) and chronic (4 patients) GVHD who received mini-ECP therapy from June 2018 to January 2021. Leukocyte fractions rich in mononuclear cells were prepared from the dose of whole blood of patients. The resulting fraction was diluted with 0,9% NaCl solution to less than 3% hematocrit. The cellular product was then injected with an 8-Methoxyperalene and programmed with UV spectrum A. Autologous erythrocytes and the finished cellular product were injected into the patient after irradiation. Results: 6 out of 7 patients (85,7%) with acute GVHD has responded to mini-ECP therapy. In patients with chronic GVHD, the response rate to mini-ECP therapy was 25%. In both groups there are no significant differences found in the number of leukocytes count per body mass in the finished cellular product. The correlation between the presence and severity of response to mini-ECP therapy with the number of leukocytes in the finished cellular product was not determined. None of the patients had adverse reactions and complications associated with mini-ECP therapy. Conclusion: mini-ECP is an attractive alternative for treatment of patients with steroid-resistant or steroid-dependent GVHD who cannot undergo leukapheresis. Our results are preliminary, but promising. We will continue to use this method as a second-line therapy for patients with contraindications to leukapheresis.

RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

Apatinib plus paclitaxel versus placebo plus paclitaxel as second-line therapy in patients with gastric cancer with peritoneal carcinomatosis: A double-blind, randomized phase II trial.

e16022 Background: Individuals with gastric cancer who present with peritoneal metastasis (PM) have poor prognosis. VEGF and VEGFR-2-mediated angiogenesis can increase vascular permeability, mesothelial cell permeability and promote peritoneal metastasis and ascites formation. This study assessed whether apatinib, a small-molecule VEGFR-2 tyrosine kinase inhibitor, in combination with paclitaxel would improve survival in patients with gastric cancer with PM as second-line therapy. Methods: This was a randomized, placebo-controlled, double-blind phase 2 trial. Recruitment of the trial was stopped after 44 patients due to poor accrual. Patients aged 18 years or older with gastric adenocarcinoma with PM and disease progression after first-line chemotherapy (platinum plus fluoropyrimidine) were randomly assigned in a 1:1 ratio to receive apatinib or placebo 500 mg oral once daily plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR) and safety profiles. Results: Between January 2017 and January 2019, 44 patients were randomly assigned to treatment (21 in Paclitaxel/apatinib group while 23 in Paclitaxel/placebo group). Median PFS was significantly longer in apatinib plus paclitaxel group than in placebo plus paclitaxel group (4.67 months [95% CI, 3.90 to 9.13 months] vs 4.07 months [95% CI, 1.93 to 5.00 months]; hazard ratio 0.46 [95% CI, 0.22 to 0.97]; P=0.037). There was no significant difference between the two groups in median OS (8.57 months vs. 9.03 months; P=0.85), ORR (19.0% vs. 4.3%; P=0.290) and DCR (76.2% vs. 52.2%, P=0.098). Apatinib group showed a higher incidence of proteinuria (38.1% vs. 4.3%; P=0.016), while no significant difference was found in the incidence of grade 3 or higher drug-related adverse events. Conclusions: Compared with placebo plus paclitaxel, the combination of apatinib with paclitaxel as second-line therapy significantly improved median PFS with an acceptable safety profile in patients with gastric cancer with peritoneal metastasis. Clinical trial information: NCT03144843. [Table: see text]

A randomized phase II trial of oral vinorelbine as second-line therapy for patients with malignant pleural mesothelioma.

8507 Background: All patients with malignant pleural mesothelioma (MPM) eventually relapse following standard chemotherapy. However, there is no standard treatment option in this setting. Vinorelbine, exhibits useful clinical activity but has not been formally evaluated in a randomised clinical trial, despite its widespread off-label use worldwide. BRCA1 regulates spindle assembly checkpoint in MPM and predicts vinorelbine sensitivity in preclinical models [1,2], suggesting that BRCA1 negative patients may be chemoresistant. Methods: VIM, a Cancer Research UK funded, investigator-initiated randomised controlled phase 2 multi-centre UK trial, enrolled patients with MPM who had progressed after first-line chemotherapy. Pts were randomised 2:1 to either vinorelbine (60mg/m2 weekly Q21d escalating to 80mg/m2 from cycle 2) + active supportive care (ASC) versus ASC until disease progression, unacceptable toxicity or withdrawal of consent. The primary outcome was progression free survival (PFS) defined as the time from randomisation to any progression (based on Modified RECIST criteria for assessment of response in malignant pleural mesothelioma) or death. The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints were overall survival (OS), tolerability and safety. Results: Between May 2016 and Oct 2018, 154 patients were recruited from 10 UK sites and randomised to vinorelbine + ASC (n=98) or ASC alone (n=56). In the Intention-to-treat analysis, after 129 events, median PFS was 4.2 months (m) for vinorelbine + ASC compared to 2.8m for ASC alone (Hazard Ratio (HR) 0.59; 95% CI: 0.41 to 0.85; one-sided p = 0.0017). 108 deaths were reported. Median OS was 9.3m for vinorelbine + ASC compared to 9.1m for ASC alone (HR=0.79; 95% CI: 0.53 to 1.17; two-sided p = 0.24). Toxicity data and subgroup analyses including the impact of BRCA1 deficiency will be presented. Conclusion: The trial met its primary endpoint. Vinorelbine demonstrates useful clinical efficacy in relapsed MPM, supporting its off-label use, as a treatment option for patients with relapsed MPM.[1] Busacca et al, J Pathol 2012, 227(2), 200. [2] Busacca et al, Mol Cancer Res, 2021, 20(2) 379. Clinical trial information: NCT02139904.