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Background Current treatment options for human epidermal growth factor receptor 2 (HER2)‐overexpressing gastric cancer at third‐line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in‐situ hybridization‐negative patients. Here, we report the efficacy and safety of a novel anti‐HER2 antibody RC48 for patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer. Methods Patients with HER2‐overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second‐line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. Results Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%‐33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7‐4.9 months) and 7.9 months (95% CI: 6.7‐9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48‐related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48‐related. Conclusions RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy. RC48 is safe and efficacious for HER2‐overexpressing gastric cancer patients. Patients received trastuzumab showed similar efficacy with trastuzumab‐naïve patients. HER2 status doesn't have significant effect on clinical outcomes.

Background Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin‐dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. Methods This Phase 2 open‐label study enrolled patients with metastatic PDAC who progressed after 1–2 prior therapies. Patients were enrolled in a safety lead‐in (abemaciclib plus galunisertib) followed by a 2‐stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib‐containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression‐free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. Results One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4–1.8), 1.8 months (95% CI: 1.3–1.9), and 3.3 months (95% CI: 1.1–5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. Conclusion In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC. Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This phase 2 randomized study for refractory metastatic PDAC patients showed that the CDK4/6 inhibitor abemaciclib, alone or in combination with the PI3K/mTOR LY3023414, does not improve disease control or progression‐free survival compared to standard chemotherapy.

Background Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand‐foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose‐escalation strategy for elderly refractory mCRC patients. Patients and Methods This open‐label, single‐arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28‐day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug‐related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression‐free survival (PFS). Results A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7–4.9), and the median OS was 7.6 months (95% CI, 6.5–8.7). Treatment‐related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). Conclusion Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose‐escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.

Introduction ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second‐line protease inhibitor (PI)‐based antiretroviral therapy (ART) from 10 low‐ and middle‐income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third‐line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV‐1 RNA ≤200 copies/ml. We report here long‐term outcomes over 144 weeks. Methods Study participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. “Extended Follow‐up” of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow‐up of ≥144 weeks), with HIV‐1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow‐up. Proportion of participants with HIV‐1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow‐up; mean CD4 count changes were estimated using loess regression. Results and Discussion Of 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm3, and HIV‐1 RNA was 4.6 log10 copies/ml. Median follow‐up was 168 weeks (IQR: 156–204); 15 (6%) participants were lost to follow‐up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV‐1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74–85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm3 (95% CI 247–283). Conclusions Third‐line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second‐line PI‐based ART prior to the availability of dolutegravir.

Background Patients with small‐cell lung cancer (SCLC) primarily present with extensive stage (ES) disease and poor 5‐year survival. There are few treatment options and limited data on outcomes in third‐line (3L) ES SCLC to quantify unmet medical needs. This chart review evaluated real‐world (RW) clinical outcomes and treatment patterns in these patients. Methods This retrospective study using electronic medical records included adult patients with ES SCLC (≥ 2 claims for metastasized lung cancer) who received ≥ 3 lines of therapy (LOT) at Cancer Treatment Centers of America (now City of Hope). Patients with other/multiple primary malignancies, non‐SCLC histology, or treated through a clinical trial were excluded. Clinical outcomes included RW physician‐reported response rates, duration of response (DOR), duration of clinical benefit (DoCB), overall survival (OS), and progression‐free survival (PFS), stratified by platinum sensitivity and Eastern Cooperative Oncology Group performance status (ECOG‐PS). Time‐to‐event outcomes were estimated via Kaplan–Meier. Treatment patterns were assessed, including the sequence of regimens by LOT and first‐line (1L) platinum sensitivity status. Results Among 113 eligible patients (median age 58 years), 54% were female, and 46% had a chemotherapy‐free interval after 1L of < 90 days. Tumor shrinkage, complete response, and stable disease were reported in 19%, 1%, and 13% of patients at 3L, respectively. The median DOR, DoCB, OS, and PFS were 2.8, 2.5, 5.8, and 2.4 months in 3L, respectively. Platinum‐resistant versus sensitive patients in 1L had shorter time‐to‐event outcomes. Clinical outcomes were similar regardless of ECOG‐PS status. Platinum‐based chemotherapy rates decreased from 94% and 93% in 1L to 17% and 16% in 3L in platinum‐sensitive and resistant patients, respectively. Conclusion These RW findings validate 3L results from clinical trials, demonstrating the limited clinical benefits with current therapies in 3L ES SCLC, and highlighting the urgent need for novel therapies that improve outcomes in this difficult‐to‐treat patient population.

Background Anlotinib showed significant survival benefits in advanced non‐small cell lung cancer (NSCLC) patients as a third‐ or further‐line treatment in the ALTER0303 trial. We aimed to evaluate the efficacy of anlotinib in patients with different histologies. Methods The ALTER0303 trial was a randomized, open‐label, phase 3 study of anlotinib in NSCLC patients previously treated with at least two lines of chemotherapy or a tyrosine kinase inhibitor (TKI) in 31 centers in China. Patients were randomly assigned at a 2:1 ratio to receive anlotinib (12 mg QD from days 1 to 14 of a 21‐day cycle) or placebo until progression or intolerable toxicity. The primary endpoint was overall survival (OS). We assessed the efficacy of anlotinib in histological subgroups in the full analysis set. Results In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. In the ACC subgroup, the median OS time was significantly improved with anlotinib compared with placebo (9.6 months vs 6.9 months, P = .0051), as was the median progression‐free survival (PFS) time (5.5 months vs 1.4 months, P < .0001). In the SCC subgroup, the median OS time was 10.7 months in the anlotinib group and 6.5 months in the placebo group (P = .2570), and the median PFS time was 4.8 months and 2.7 months (P = .0004), respectively. The common adverse events observed in the SCC and ACC subgroups were similar. Conclusions Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients. In this study, we evaluated the efficacy of anlotinib as third‐ or further‐line treatment for patient with different histological types of NSCLC. In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients.

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.

Introduction As integrase inhibitors become available in low‐ and middle‐income countries (LMICs), they offer the potential to expand extremely limited treatment options available to children and adolescents. In LMICs, only small numbers have used raltegravir, primarily as part of third‐line regimens. Using data from the IeDEA global consortium, we aimed to describe the characteristics of children on raltegravir‐containing regimens and their outcomes. Methods We included data from 1994 to 2017 from children (age <18 years), from East and Southern Africa, Asia and South America, who received cART regimens containing raltegravir for ≥90 days. We describe their characteristics at raltegravir start, and their immunological and virological outcomes. Results and discussion In total, 62 children were included, with median age at raltegravir initiation of 14.3 years (IQR 11.2 to 15.8) and median CD4 count of 276 cells/µL (IQR 68 to 494). Among 40 (65%) with drug resistance testing prior to raltegravir, 71% were resistant to at least one protease inhibitor (PI), and 32% had high‐level resistance to at least one drug class. Most (n = 50; 81%) received raltegravir as part of third‐line cART following PI‐based regimens, and were on regimens containing four or more drugs (n = 47, 76%). By database closure, median duration on raltegravir was 2.0 years (IQR 0.8 to 3.0), 1 (1.6%) patient had died, 6 (9.7%) were lost to follow‐up and 21 (34%) had discontinued raltegravir. Among 15 patients reporting reasons for stopping raltegravir, six discontinued because it was no longer available. Within one year of starting raltegravir, among 53 patients with VL measures, 40 (75%) had VL < 1000 copies/mL, and among 54 with a reported CD4 count, 45 (83%) and 36 (67%) were ≥350 and ≥500 cells/µL, respectively, with median CD4 count increasing to 517.5 cells/µL (IQR 288 to 810). Conclusions Among children in LMICs, the initial use of raltegravir has been primarily for post PI‐based cART. We found good virological and immunological outcomes despite frequent prior triple‐class failure and high levels of drug resistance. Both access to raltegravir and long‐term adherence to regimens with large pill‐burdens remain challenging. Policies which promote earlier access to new drugs and simplify daily regimens for children and adolescents in LMICs are needed.

IntroductionWhile golimumab (GLM) has demonstrated efficacy in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) in several randomized clinical trials with biologic-naïve patients, observational data from biologic-experienced patients are sparse. We aimed to assess the effectiveness of GLM used as the first-, second-, or at least third-line biologic agent in RA, PsA, and AS patients in a real-world setting.MethodsPost hoc analysis of the noninterventional, prospective, 24-month GO-NICE study of RA, PsA, and AS patients who initiated GLM 50 mg subcutaneously once monthly in a real-world setting in Germany.ResultsIn 1454 patients with RA, PsA, or AS, GLM was administered as the first-line (n = 305, 286, 292, respectively), second-line (n = 104, 136, 130, respectively), or at least third-line (n = 64, 79, 58, respectively) biologic agent. In RA patients (n = 473), the time since first diagnosis was 9.7, 10.1, and 14.3 years, respectively. The DAS28 score at BL was 5.0, 4.9, and 5.1 in patients using GLM as a first-, second-, and third-line biologic agent, respectively, and dropped significantly in all groups. After 3 months of treatment, 27.5%, 19.5%, and 14.5% of patients were in remission; the corresponding values after 24 months were 45.3%, 50.0%, and 33.3%, respectively. In PsA patients (n = 501), time since fist diagnosis was 12.4, 13.7, and 13.8 years, respectively. Based on PsARC, a response was achieved at 24 months in the first-, second-, and third-line use of GLM in 76.4%, 51.0%, and 50.0% of the patients. In AS patients (n = 480), the time since first diagnosis was 9.4, 9.8, and 12.4 years in patients using GLM as the first-, second-, and at least third-line biologic agent, respectively. After 24 months of treatment, the mean BASDAI scores decreased significantly (p < 0.001 vs. BL) to 2.1, 2.9, and 2.9 in the patients using GLM as the first-, second-, and at least third-line treatment, respectively.ConclusionsGolimumab is an effective treatment in patients with RA, PsA, and AS, irrespective of any pretreatment with biologic agents.Study RegistrationClinicalTrials.gov NCT01313858.

Summary Introduction The efficacy of currently recommended third‐line therapies for Helicobacter pylori is suboptimal, even that of culture‐guided treatments. Resistance to multiple antibiotics is the major factor related to treatment failure. The aim of this study was to evaluate the effectiveness and safety of a 14‐day therapy using high‐dose of amoxicillin, metronidazole and esomeprazole. Material and methods Multicenter open‐label study as a register in routine clinical practice in patients with two previous failures of eradication therapy. A triple therapy with esomeprazole 40 mg b.d., amoxicillin 1 g t.d.s and metronidazole 500 mg t.d.s for 2 weeks was administered as a third‐line therapy after a first treatment including clarithromycin and a second treatment including a quinolone. Helicobacter pylori status was determined by either histology or 13C‐UBT both before and after treatment. Results A total of 68 patients were included in this study. An interim analysis showed that only three out of eight patients who had received metronidazole in previous eradication regimens were cured (37%, 95% CI 8‐75); as a result, after this interim analysis only metronidazole‐naïve patients were included. The ITT eradication rate in metronidazole‐naive patients was 64% (95% CI 51‐76). Adverse events occurred in 58% of patients, all of them mild‐to‐moderate. Two patients (3%) did not complete >90% of the treatment because of side effects. No severe adverse events occurred. Conclusion Cure rates of this 14‐day schedule using high‐dose esomeprazole, amoxicillin and metronidazole as a third‐line eradication regimen were suboptimal, especially in patients who had received metronidazole in previous failed eradication regimens.