Second-line Systemic Treatment Research Articles

Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching.

BACKGROUNDStarting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available.AIMTo evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time.METHODSA retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups.RESULTSFifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors.CONCLUSIONThis multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.

Lenvatinib Plus Programmed Cell Death Protein-1 Inhibitor Beyond First-Line Systemic Therapy in Refractory Advanced Biliary Tract Cancer: A Real-World Retrospective Study in China.

BackgroundCurrently, no second-line systemic treatment regimen has been recommended in advanced biliary tract cancer (BTC). Cumulative clinical evidence showed that systemic treatment with tyrosine kinase inhibitors (TKIs) in combination with immunotherapy may shed light on the dim clinical outcome in advanced BTC.ObjectiveThe aim of this study is to evaluate the anticancer efficacy of lenvatinib plus programmed cell death protein-1 (PD-1) antibody in patients with BTC who progressed after first-line cisplatin/gemcitabine (CisGem) chemotherapy.MethodsPatients with advanced BTCs who progressed after CisGem were recruited. A combination regimen of lenvatinib (8/12 mg daily) plus PD-1 antibody (200/240 mg injection every 3 weeks) was prescribed. Clinicopathological information and therapeutic outcome, including tumor subtypes, biomarkers, treatment duration, adverse events (AE), progression-free survival (PFS), and overall survival (OS), were recorded and estimated.ResultsA total of 351 patients with BTCs were reviewed and 74 were recruited eventually: 35 had intrahepatic cholangiocarcinoma (47.3%), 4 had extrahepatic cholangiocarcinoma (5.4%), and 35 had gallbladder cancer (47.3%). The median administered cycles of PD-1 antibody were 6.43 (95% CI: 5.83–7.04) cycles, and the median duration of lenvatinib medication was 21.0 weeks (95% CI: 18.04–23.93). Twenty-eight patients (37.83%) experienced detectable objective response per RECIST1.1 within a median follow-up duration of 15.0 months. The objective response rate (ORR) was 20.27% (95% CI: 10.89%–29.65%), and the disease control rate (DCR) was 71.62% (95% CI: 61.11%–82.14%). The median PFS and OS were 4.0 months (95% CI: 3.5–5.0) and 9.50 months (95% CI: 9.0–11.0), respectively. Seventy-three patients (98.64%) reported AEs and 39 (52.70%) experienced ≥grade 3 AEs. In subgroup analyses, tumoral PD-L1 expression ≥50% and tumor mutation burden (TMB) ≥2.5 Muts/Mb were associated with prolonged PFS.ConclusionLenvatinib plus PD-1 antibody treatment shows an active trend towards improving survival in patients with advanced BTCs after failure with CisGem chemotherapy. The treatment-related AEs are worthy of attention and are manageable.

First- and Second-Line Palliative Systemic Treatment Outcomes in a Real-World Metastatic Pancreatic Cancer Cohort.

Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor survival rate, which can be improved by systemic treatment. Consensus on the most optimal first- and second-line palliative systemic treatment is lacking. The aim of this study was to describe the use of first- and second-line systemic treatment, overall survival (OS), and time to failure (TTF) of first- and second-line treatment in metastatic PDAC in a real-world setting. Patients with synchronous metastatic PDAC diagnosed between 2015 and 2018 who received systemic treatment were selected from the nationwide Netherlands Cancer Registry. OS and TTF were evaluated using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard analyses. The majority of 1,586 included patients received FOLFIRINOX (65%), followed by gemcitabine (18%), and gemcitabine + nab-paclitaxel (13%) in the first line. Median OS for first-line FOLFIRINOX, gemcitabine + nab-paclitaxel, and gemcitabine monotherapy was 6.6, 4.7, and 2.9 months, respectively. Compared to FOLFIRINOX, gemcitabine + nab-paclitaxel showed significantly inferior OS after adjustment for confounders (hazard ratio [HR], 1.20; 95% CI, 1.02-1.41), and gemcitabine monotherapy was independently associated with a shorter OS and TTF (HR, 1.98; 95% CI, 1.71-2.30 and HR, 2.31; 95% CI, 1.88-2.83, respectively). Of the 121 patients who received second-line systemic treatment, 33% received gemcitabine + nab-paclitaxel, followed by gemcitabine (31%) and FOLFIRINOX (10%). Based on population-based data in patients with metastatic PDAC, treatment predominantly consists of FOLFIRINOX in the first line and gemcitabine with or without nab-paclitaxel in the second line. FOLFIRINOX in the first line shows superior OS compared with gemcitabine with or without nab-paclitaxel.

Optimizing systemic therapy for advanced hepatocellular carcinoma: the key role of liver function.

The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment sequence. Hepatic decompensation, which does not always coincide with disease progression, is part of this complex dynamically evolving system, and must be promptly recognized and adequately managed to allow the patient to continue in the therapeutic course. The purpose of this review is to highlight and summarize the evidence on the efficacy and safety of systemic agents, with a focus on the impact of underlying cirrhosis, and to suggest new clinical outcomes for randomized controlled trials for advanced HCC to better assess the net health benefit in this specific setting.

Outcomes of Patients with Metastatic Melanoma-A Single-Institution Retrospective Analysis.

Simple SummaryApproximately 15% of patients diagnosed with locally advanced malignant melanoma will relapse. Currently, anti-PD-1 and anti-CTLA4 antibodies and BRAF/MEK inhibitors are the mainstay of treatment of advanced, inoperable or disseminated malignant melanoma. A group of 52 patients treated for disseminated malignant melanoma in 2013–2018 was subjected to a retrospective analysis. Overall survival, time to relapse after surgery, time to first disease progression after first-line treatment and time to second progression after second-line treatment were assessed. Factors such as age of the patients, type of progression, stage, blood parameters and the treatment used were analyzed for their influence on prognosis. The study showed that the BRAF V600 mutation is an independent prognostic factor for the recurrence of malignant melanoma after surgery. Patients with this mutation had a longer progression-free time compared to patients undergoing monotherapy with anti-PD-1/PD-L1 antibodies (p = 0.046). The type of treatment used had no effect on overall survival (Z = 0.23, p > 0.05).Background: This study assessed risk factors and the results of treatment with anti-PD-1 antibodies and BRAF/MEK inhibitors for advanced malignant melanoma. Methods: A retrospective analysis was performed on 52 patients treated with immunotherapy and BRAF/MEK inhibitors for disseminated malignant melanoma. Results: The median follow-up was 31 months (6–108 months). The median PFS1 was 6 months (1–44 months). Second-line systemic treatment was applied in 27 patients (52%). The median PFS2 was 2 months (0–27 months), and the median OS was 31 months (6–108 months). Among the analyzed risk factors, only the presence of the BRAF mutation was statistically significant for disease recurrence after surgery. In patients undergoing anti-BRAF/MEK therapy, the median PFS1 was 7 months, and in patients undergoing mono-immunotherapy, 4 months. The 12- and 24-month PFS1 rates in the group treated with BRAF inhibitors were 29 and 7%, respectively, and in patients treated with mono-immunotherapy 13 and 0%, respectively (Z = 1.998, p = 0.04). The type of treatment used had no effect on OS (Z = 0.237, p > 0.05). Conclusion: Patients with the V600 mutation should be closely monitored. In the event of disease recurrence, treatment with BRAF/MEK inhibitors should be considered. The type of treatment used has no effect on OS.

Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

Durable objective response to sorafenib and role of sequential treatment in unresectable hepatocellular carcinoma.

Background:The response rate to sorafenib is limited for unresectable hepatocellular carcinoma (HCC). Little is known about the long-term outcomes of objective responders. The role of second-line therapies on the survival of sorafenib-responders is unclear. We aimed to delineate the long-term outcomes and the role of subsequent treatment after responding to sorafenib.Methods:From September 2012 to December 2019, 922 patients who received sorafenib treatment for unresectable HCC were retrospectively reviewed. Of these, 21 (2.3%) achieved a complete response (CR) and 54 (5.9%) had a partial response (PR) based on mRECIST criteria. Factors associated with survivals were analyzed.Results:During the median follow-up of 35.3 months, the median duration of response was 18.3 months (range: 2.3–45.5) for patients achieving CR and 10.0 months (range: 1.9–60.3) for PR. The median overall survival (OS) was 39.5 months [95% confidence interval (CI): 28.4–50.5] including values not yet estimable for CR and 25.8 months for PR. Patients who experienced treatment-related adverse events (TRAEs) had better median OS than those without (44.9 versus 18.1 months, p = 0.003). Eventually, 53 patients developed tumor progression; 30 patients received second-line systemic treatment including nivolumab (n = 8), regorafenib (n = 15), and chemotherapy (n = 7). Sorafenib–nivolumab sequential therapy provided the best median OS versus sorafenib–regorafenib and sorafenib–chemotherapy in these patients (55.8, 39.5, and 25.5 months), respectively.Conclusions:The response is durable for advanced HCC patients with CR or PR to sorafenib. Subsequent immunotherapy seems to provide the best survival. This information is important for characterizing outcomes of sorafenib-responders and the choice of sequential treatment.

First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials

Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.

Optimal Sequence and Second-Line Systemic Treatment of Patients with RAS Wild-Type Metastatic Colorectal Cancer: A Meta-Analysis.

Although several sequential therapy options are available for treating patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the optimal sequence of these therapies is not well established. A systematic review and meta-analysis of 13 randomized controlled trials and 4 observational studies were performed, resulting from a search of the Cochrane Library, PubMed, and Embase databases. Overall survival (OS) did not differ significantly in patients with RAS-WT failure who were administered a second-line regimen of changed chemotherapy (CT) plus anti-epidermal growth factor receptor (EGFR) versus only changed CT, changed CT plus bevacizumab versus changed CT plus anti-EGFR, or changed CT versus maintaining CT plus anti-EGFR after first-line therapy with CT, plus bevacizumab. However, OS was significantly different with a second-line regimen that included changed CT plus bevacizumab, versus only changing CT. Analysis of first-line therapy with CT plus anti-EGFR for treatment of RAS-WT mCRC indicated that second-line therapy of changed CT plus an anti-EGFR agent resulted in better outcomes than changing CT without targeted agents. The pooled data study demonstrated that the optimal choice of second-line treatment for improved OS was an altered CT regimen with retention of bevacizumab after first-line bevacizumab failure. The best sequence for first-to-second-line therapy of patients with RAS-WT mCRC was cetuximab-based therapy, followed by a bevacizumab-based regimen.

British Association of Dermatologists guidelines for the management of people with cutaneous lupus erythematosus 2021.

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of cutaneous lupus erythematosus (CLE) in the presence or absence of systemic lupus erythematosus (SLE) in adults, young people and children. The document aims to: offer an appraisal of all relevant literature up to December 2020, focusing on any key developments address important, practical clinical questions relating to the primary guideline objective. provide guideline recommendations and if appropriate research recommendations.

Second-Line Treatment Options for Hepatocellular Carcinoma: Current Landscape and Future Direction.

Hepatocellular carcinoma is a leading cause of mortality worldwide, and its incidence is rising. The last few years have witnessed a proliferation of available systemic therapeutic options, with the approval of multiple agents, including immune checkpoint inhibitors and drugs targeting vascular endothelial growth factor, such as cabozantinib, regorafenib, and ramucirumab. Most recently, the combination of atezolizumab plus bevacizumab has resulted in the longest overall survival yet known in hepatocellular carcinoma, therefore changing the preferred first-line treatment from the previous options of sorafenib and lenvatinib. The aim of this review is to summarize the available clinical data for the current second-line systemic treatment options and the future perspectives in the treatment landscape of hepatocellular carcinoma.

The Optimal Second-Line Systemic Treatment Model for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: A Bayesian Network Meta-Analysis.

BackgroundThe optimal second-line systemic treatment model for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains controversial. A Bayesian network meta-analysis (NMA) was performed to address this issue with regard to efficacy and toxicity.MethodsBy searching MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science, we extracted eligible studies. Efficacy, represented as overall survival (OS) and progression-free survival (PFS), and overall toxicity, represented as ≥ grade 3 severe acute events (sAE), were assessed to compare the following 7 treatment models through an NMA: standard-of-care therapy (SoC), single targeted therapy different from SoC (ST), double targeted therapy (DT), targeted therapy combined with chemotherapy (T+C), single immune checkpoint inhibitor therapy (SI), double immune checkpoint inhibitor therapy (DI) and single chemotherapy different from SoC (SC). Rank probabilities according to the values of the surface under the cumulative ranking curve (SUCRA) were separately determined for efficacy and toxicity.ResultsIn total, 5285 patients from 24 eligible studies were ultimately screened, with 5184, 4532 and 4026 involved in the NMA of OS, PFS and sAE, respectively. All qualifying studies were absent from first-line immune checkpoint inhibitor therapy. In terms of OS, SI was superior to the other treatments, followed by DI, ST, T+C, SoC, DT and SC. Other than SI and SC, all treatments tended to be consistent, with hazard ratios (HRs) close to 1 between groups. For PFS, ST ranked first, while DT ranked last. For the toxicity profiles, compared with the other models, SI resulted in the lowest incidences of sAE, with statistical significance over SoC (odds ratio [OR] 0.31, 95% credible interval [CrI] 0.11 to 0.90), ST (OR 0.23, 95% CrI 0.06 to 0.86) and DT (OR 0.11, 95% CrI 0.02 to 0.53), while DT was the worst. When the SUCRA values of OS and sAE were combined, a cluster plot illustrated the superiority of SI, which demonstrated the best OS and tolerability toward sAE.ConclusionFor R/M HNSCC patients without immune checkpoint inhibitors in the first-line setting, SI may serve as the optimal second-line systemic treatment model, demonstrating the best OS and least sAE.

The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma.

In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.

P-72 A patient preference study on risk thresholds to switch between daily tablets and biweekly infusions in second-line treatment for advanced hepatocellular carcinoma

There are various available second-line (2L) systemic treatments for unresectable hepatocellular carcinoma (HCC) utilizing different route of administration (eg, tablets and intravenous [IV] infusions) and having different safety profiles. Therefore, patient preferences should be considered in treatment decisions. However, there are insufficient data regarding patient preferences in the real-world setting in the US. The objectives of this study were to determine patients’ preferences for mode of administration and risk of adverse events (AEs) for regorafenib (4 tablets once daily [QD]) and ramucirumab (once in 2 weeks [Q2W] IV for 30/60 minutes) with similar efficacy profile but different AE profiles, and to determine the proportion of patients who preferred ramucirumab over regorafenib.

Efficacy of PSMA PET-Guided Radiotherapy for Oligometastatic Castrate-Resistant Prostate Cancer

PurposeTo assess the outcome of radiotherapy (RT) to all PSMA ligand positive metastases for patients with castrate-resistant prostate cancer (mCRPC).Patients and methodsA total of 42 patients developed oligometastatic mCRPC and received PSMA PET-guided RT of all metastases. The main outcome parameters were biochemical progression-free survival (bPFS), and second-line systemic treatment free survival (SST-FS).ResultsA total of 141 PSMA ligand-positive metastases were irradiated. The median follow-up time was 39.0 months (12-58 months). During the follow-up five out of 42 (11.9%) patients died of progressive mPCa. Five out of 42 (11.9%) patients showed no biochemical responses and presented with a PSA level ≥10% of the baseline PSA at first PSA level measurement after RT and were classified as non-responders. The median PSA level before RT was 4.79 ng/mL (range, 0.4-46.1), which decreased significantly to a median PSA nadir level of 0.39 ng/mL (range, <0.07-32.8; p=0.002). The median PSA level at biochemical progression after PSMA ligand-based RT was 2.75 ng/mL (range, 0.27-53.0; p=0.24) and was not significantly different (p=0.29) from the median PSA level (4.79 ng/mL, range, 0.4-46.1) before the PSMA ligand-based RT. The median bPFS was 12.0 months after PSMA ligand PET-based RT (95% CI, 11.2-15.8) and the median SST-FS was 15.0 months (95% CI, 14.0-21.5).ConclusionIn well-informed and closely followed-up patients, PSMA PET-guided RT represents a viable treatment option for patients with oligometastatic mCRPC to delay further systemic therapies.

Post-progression outcomes of NSCLC patients with PD-L1 expression ≥ 50% receiving first-line single-agent pembrolizumab in a large multicentre real-world study

BackgroundTreatment sequencing with first-line immunotherapy, followed by second-line chemotherapy, is still a viable option for NSCLC patients with PD-L1 expression ≥50%. MethodsWe evaluated post-progression treatment pathways in a large real-world cohort of metastatic NSCLC patients with PD-L1 expression ≥ 50% treated with first-line pembrolizumab monotherapy. ResultsOverall, 974 patients were included. With a median follow-up of 22.7 months (95%CI: 21.6–38.2), the median overall survival (OS) of the entire population was 15.8 months (95%CI: 13.5–17.5; 548 events). At the data cutoff, among the 678 patients who experienced disease progression, 379 (55.9%) had not received any further treatment, and 359 patients (52.9%) had died. Patients who did not receive post-progression therapies were older (p = 0.0011), with a worse ECOG-PS (p < 0.0001) and were on corticosteroids prior to pembrolizumab (p = 0.0024). At disease progression, 198 patients (29.2%) received a switched approach and 101 (14.9%) received pembrolizumab ByPD either alone (64 [9.4%]) or in combination with local ablative treatments (37 [5.5%]) (LATs). After a random-case control matching according to ECOG-PS, CNS metastases, bone metastases, and (previous) best response to pembrolizumab, patients receiving pembrolizumab ByPD plus LATs were confirmed to have a significantly longer post-progression OS compared to patients receiving pembrolizumab ByPD alone 13.9 months versus 7.8 months (p = 0.0179) 241 patients (35.5%) among the 678 who had experienced PD, received a second-line systemic treatment (regardless of previous treatment beyond PD). As compared to first-line treatment commencement, patients’ features at the moment of second-line initiation showed a significantly higher proportion of patients aged under 70 years (p = 0.0244), with a poorer ECOG-PS (p < 0.0001) and having CNS (p = 0.0001), bone (p = 0.0266) and liver metastases (p = 0.0148). ConclusionsIn the real-world scenario NSCLC patients with PD-L1 expression ≥50% treated with first-line single-agent pembrolizumab achieve worse outcomes as compared to the Keynote-024 trial. Poor post-progression outcomes are major determinants of the global results that should be considered when counselling patients for first-line treatment choices.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastric cancer

Gastric cancer with peritoneal metastases is associated with an extremely poor prognosis. Developed multimodal treatment concepts, which include a combination of perioperative systemic treatment and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), show promising results with respect to improvement of the long-term survival. This article contains areview of the literature of published studies on the topic of gastric cancer and peritoneal metastasis. The prognosis of patients with gastric cancer peritoneal carcinomatosis shows an extremely limited median survival of 7months under palliative second-line systemic treatment. The median survival time increased to 12months with cytoreductive surgery and in combination with HIPEC showed a positive effect on survival in individual studies. Treatment recommendations for patients with peritoneal metastases of gastric cancer should be carried out by experts in surgical reference centers.

Phase III study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy.

TPS372 Background: There is an unmet need for treatment options in the second-line or later setting following anti–PD-1/L1 or VEGF tyrosine kinase inhibitor (TKI) therapy in patients with advanced RCC. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). Promising antitumor activity has been reported for the first-in-class small molecular HIF-2α inhibitor, MK-6482, in heavily pretreated patients with ccRCC and patients with VHL disease–associated RCC. HIF-2α also regulates VEGF gene expression and plays a role in resistance to anti-VEGF therapy. Therefore, combining MK-6842 with a VEGF receptor TKI, such as lenvatinib, is an attractive treatment option in the advanced RCC setting. Methods: This is a randomized, open-label, active-controlled, multicenter phase III trial evaluating the efficacy and safety of MK-6482 + lenvatinib compared with cabozantinib in patients with advanced ccRCC who have progressed on prior anti–PD-1/L1 therapy (NCT04586231). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or metastatic ccRCC; disease progression on or after first- or second-line systemic treatment with an anti–PD-1/L1 therapy (monotherapy or in combination with other agent[s]) for locally advanced or metastatic disease, the immediately preceding line of treatment must be an anti–PD-1/L1 therapy; no more than 2 prior systemic regimens, with only 1 prior anti–PD-1/L1 therapy; measurable disease per RECIST v1.1; and Karnofsky performance status ≥70%. Patients must provide tissue for biomarker analysis. Approximately 708 patients will be randomly assigned in a 1:1 ratio to receive MK-6482 120 mg orally once daily (QD) + lenvatinib 20 mg orally QD or cabozantinib 60 mg orally QD. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are International mRCC Database Consortium prognostic scores (0, 1-2, or 3-6), number of prior lines of therapy (1 or 2), and geographic region (North America, Western Europe, or rest of the world). Imaging will be assessed by CT or MRI every 8 weeks through week 80, then every 12 weeks thereafter. The dual primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Secondary end points are objective response rate and duration of response per RECIST v1.1 as assessed by BICR, and safety. Safety and tolerability will be evaluated using a tiered approach. Clinical trial information: NCT04586231 .

Treatment patterns and survival in patients with late-stage hepatocellular carcinoma in France: A retrospective database analysis.

288 Background: The prognosis for patients with late-stage hepatocellular carcinoma (HCC) is poor, with only one systemic treatment option available for patients until 2017. Aim: To describe treatment patterns and survival of French patients following diagnosis of late-stage HCC (Barcelona Clinic Liver Cancer classification B, C or D), using a comprehensive nationwide claims database, SNDS. Methods: The SNDS database was searched from 1 January 2015 to 31 December 2017 for patients with a diagnosis of HCC (ICD-10: C220) and late-stage disease, defined by the identification of transcatheter arterial chemoembolization (TACE) or radioembolization (TARE), HCC systemic therapy and/or best supportive care (BSC). Patients were followed up for a maximum of 2 years. Results: 17,298 patients (mean age: 68.7 years (SD: 11.3), 82.6% male) were identified, with 72.4% diagnosed at late stage. During follow-up, 29.6% of patients were treated with TACE or TARE, and 27.1% received systematic therapy (sorafenib in 99.5% of cases). The median duration of systemic treatment was 7.9 (95% CI: 7.4-8.5) months. In 62.5% of cases, this treatment was discontinued at 12 months; this proportion fell to 40.3% when using mortality as a competitive risk. Survival since diagnosis of late stage HCC differed according to the type of first treatment received. Median overall survival was 23.7, 11.9, 7.4 and 1 month in patients initially receiving TACE, TARE, systemic therapy or no treatment, respectively. Conclusions: These results confirm the high clinical burden of late-stage HCC over this period and the need for second-line systemic treatments to improve patient outcomes.

Prognostic Factors of Survival with Aflibercept and FOLFIRI (fluorouracil, leucovorin, irinotecan) as Second-line Therapy for Patients with Metastatic Colorectal Cancer.

Background: Aflibercept and fluorouracil, leucovorin, irinotecan (FOLFIRI) is commonly used as a second-line treatment for metastatic colorectal cancer (CRC). However, the biomarkers to guide the choice of this regimen from among treatment options remain unclear.Patients and Methods: We performed exploratory analyses to validate potential prognostic factors for patients receiving aflibercept plus FOLFIRI as a second-line systemic treatment for metastatic CRC between January 2015 and July 2019. Patient characteristics, histopathologic data, laboratory and radiologic data, and treatment outcomes were collected and reviewed.Results: Included were 52 patients: 50 (96.2%) received bevacizumab plus fluorouracil, leucovorin, oxaliplatin (FOLFOX) as prior first-line treatment. Among the 52 patients receiving aflibercept and FOLFIRI, four complete responses and 21 partial responses were observed in analyzed patients for an overall response rate of 48.1%. Median progression-free survival (PFS) was 7.0 months and overall survival (OS) was 16.8 months. Response to first-line treatment (median PFS, 8.0 versus 4.2 months), left-side location of primary tumor (7.9 versus 4.9 months), low baseline CEA level (8.0 versus 5.9 months), and no RAS/RAF mutation (9.9 versus 6.4 months) were remained significant prognostic factors for PFS in the multivariate backward stepwise Cox regression model, and the latter three factors were also significantly related to OS.Conclusions: Significant prognostic factors for PFS with aflibercept plus FOLFIRI as second-line therapy were extracted and validated in the multivariate OS model. These findings could provide useful information for selecting patients for aflibercept plus FOLFIRI as second-line therapy.