Combination Treatment with an Antibody–Drug Conjugate (A1mcMMAF) Targeting the Oncofetal Glycoprotein 5T4 and Carboplatin Improves Survival in a Xenograft Model of Ovarian Cancer The article Combination Treatment with an Antibody–Drug Conjugate (A1mcMMAF) Targeting the Oncofetal Glycoprotein 5T4 and Carboplatin Improves Survival in a Xenograft Model of Ovarian Cancer, written by Y. Louise Wan, Puja Sapra, James Bolton, Jia Xin Chua, Lindy G. Durrant and Peter L. Stern, was originally published under a CC BY-NC 4.0 license, but has now been made available under a CC BY 4.0 license.

Acknowledgement to Referees

Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab Abstract Background Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS). Objective Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC). Methods Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6 weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis. Results Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6 weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and OS (grade 1–2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66–1.24]; grade 3+, HR 1.02 [95% CI 0.67–1.55]; P = 0.803) or PFS (grade 1–2, HR 0.98 [95% CI 0.74–1.28]; grade 3+, HR 0.93 [95% CI 0.64–1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1–2, HR 0.96 [95% CI 0.76–1.20]; grade 3+, HR 2.72 [95% CI 1.67–4.44]; P = 0.001) and PFS (grade 1–2, HR 1.01 [95% CI 0.83–1.23]; grade 3+, HR 2.22 [95% CI 1.43–3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS. Conclusions Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS. Clinical trial registration No. NCT01183780.

Treatment Sequencing and Clinical Outcomes in BRAF -Positive and BRAF -Negative Unresectable and Metastatic Melanoma Patients Treated with New Systemic Therapies in Routine Practice Abstract Background Although BRAF/MEK inhibitors are generally considered to be equally effective whether given before or after immunotherapy, no prospective trial has confirmed this hypothesis and contradictory data have been published in the melanoma field. Objective We aimed to investigate the outcomes of patients with metastatic melanoma depending on the first-line treatment. Patients and Methods In this ambidirectional cohort, single-center study, we included 253 consecutive melanoma patients treated in our institution with an anti-PD1 antibody or BRAF/MEK inhibitors, who started first-line treatment between December 2015 and March 2018. Kaplan–Meier estimator, log-rank test, and Cox proportional hazard model were used in this analysis. Results First-line median progression-free survival (PFS) for all patients was 5.7 months (m), 6.9 m on anti-PD-1 therapy and 5.6 m for combination targeted therapy. Patients with BRAF mutated melanoma had 6.0 m median PFS on immunotherapy. At a median follow-up of 23.2 m with 149 events, in BRAF wild-type patients treated with anti-PD1, median overall survival (OS) was 18.1 m. BRAF mutated patients treated with first-line BRAF/MEK inhibitors had 11.7 m median OS. High neutrophil to lymphocyte ratio, high LDH level, ECOG > 0, and the presence of brain metastases negatively impacted PFS and OS. Conclusions In BRAF mutated patients with normal LDH, first-line immunotherapy seems a more effective approach. We have demonstrated that although BRAF mutation is a negative prognostic factor in stage IV melanoma, the use of two different systemic treatment modalities allows achievement of comparable survival in BRAF mutated and BRAF wild-type patients.

Addition of Bevacizumab to First-Line Palliative Chemotherapy in Patients with Metastatic Small Bowel Adenocarcinoma: A Population-Based Study Abstract Background Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce. Objective The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA. Patients and methods Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated. Results In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06–9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3 months, compared to 9.1 months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5 months with and 6.4 months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65–1.59). Conclusions Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Atezolizumab First-Line Combination Therapy: A Review in Metastatic Nonsquamous NSCLC Abstract Atezolizumab (Tecentriq®), a humanized, anti-programmed cell death ligand-1 (PD-L1) monoclonal antibody, in combination with bevacizumab, carboplatin and paclitaxel (ABCP) or with carboplatin and nab-paclitaxel (ACnP) has been approved as first-line treatment for metastatic nonsquamous NSCLC, based on results from the randomized IMpower150 and IMpower130 studies in chemotherapy-naïve patients with nonsquamous metastatic NSCLC. In IMpower150, ABCP prolonged progression-free survival (PFS) and overall survival (OS) relative to BCP, regardless of EGFR or ALK status, liver metastases at baseline or PD-L1 expression levels. In IMpower130, ACnP prolonged PFS and OS relative to CnP in patients without EGFR or ALK genetic aberrations. ABCP and ACnP had manageable tolerability profiles, which were consistent with the profile of the individual components of the regimen. Immune-related adverse events with ABCP and ACnP were largely mild or moderate in severity, and most were reversible with interruption of atezolizumab and initiation of appropriate treatment. Current evidence indicates that ABCP and ACnP are valuable emerging first-line treatment options for metastatic nonsquamous NSCLC.

Therapy Line and Associated Predictors of Response to PD-1/PD-L1-Inhibitor Monotherapy in Advanced Non-small-Cell Lung Cancer: A Retrospective Bi-centric Cohort Study Abstract Background Evidence on PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy for advanced non-small-cell lung cancer (NSCLC) is mainly based on clinical trials in first- or second-line settings. Objective We aimed to investigate response and prognostic factors with special regard to third- or later-line therapy. Patients and Methods We retrospectively analyzed all patients who had received ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab for advanced NSCLC. Computed tomography evaluations were analyzed using response evaluation criteria in solid tumors (RECIST, version 1.1). Kaplan–Meier analyses were conducted to calculate progression-free (PFS) and overall (OS) survival; the impact of influencing variables was evaluated using uni- and multivariate Cox-regression analyses. Results Among 153 patients (59% men, mean age 66 years), median PFS was 4 months [mo; 95% confidence interval (95% CI) 3–5], OS was 13 mo (10–17), and objective response rate (ORR) was 22%. Therapy line ≥ 3 was associated with significantly inferior PFS (p = 0.003) and OS (p = 0.001). In first-line therapy PFS, OS, and ORR were 7 mo (3–11), 17 mo [9–not evaluable (n.e.)], and 36%; in second-line 4 mo (3–7), 18 mo (13–n.e.) and 19%, and in ≥ third-line 2 mo (1–3), 9 mo (4–12), and 13%. PFS was significantly influenced by PD-L1 expression in first-line therapy (p = 0.006). In ≥ third-line patients, Eastern Cooperative Oncology Group (ECOG) performance status significantly affected PFS and OS (both p < 0.001). Conclusions Third- or later-line single-agent anti-PD-1/PD-L1 therapy is less efficacious as compared to first- and second-line treatment. In that setting, ECOG performance status predominates known predictors like PD-L1 expression or presence of an alteration in EGFR or ALK.

Regorafenib-Induced Hypothyroidism as a Predictive Marker for Improved Survival in Metastatic or Unresectable Colorectal Cancer Refractory to Standard Therapies: A Prospective Single-Center Study Abstract Background Tyrosine kinase inhibitor-induced hypothyroidism is associated with favorable survival in patients with various cancers. Objective We aimed to investigate the incidence of regorafenib-induced hypothyroidism and assess its prognostic value in patients with metastatic or unresectable colorectal cancer (CRC) receiving regorafenib. Patients and Methods This study included 68 patients treated at Asan Medical Center (Seoul, Republic of Korea) between 2014 and 2016 with metastatic or unresectable CRC refractory to standard therapies. Regorafenib (160 mg/day on days 1–21 followed by a 7-day break) was administered. Results The median patient age was 58 (range 26–72) years; 61.8% of patients were male. Among the 68 patients, 50 (73.5%) showed hypothyroidism; 39 (57.4%) had subclinical and 11 (16.2%) had symptomatic hypothyroidism. Overall, the objective response rate (ORR) and disease control rate (DCR) were 7.4% and 70.6%, respectively; both were significantly higher in patients with symptomatic or subclinical hypothyroidism than in euthyroid patients (ORR 27.3% vs. 5.1% vs. 0.0%, P = 0.001; DCR 100% vs. 76.9% vs. 38.9%, P = 0.001). Median progression-free survival (PFS) and overall survival (OS) were longer in patients with symptomatic hypothyroidism than in those with subclinical hypothyroidism (median PFS 9.1 vs. 3.8 months, P = 0.018; median OS: 19.2 vs. 9.4 months, P = 0.012) or with euthyroid status (median PFS 9.1 vs. 1.8 months, P < 0.001; median OS 19.2 vs. 4.7 months, P = 0.001). Symptomatic hypothyroidism was a significant protective factor for PFS (hazard ratio (HR) = 0.37, P = 0.006) and OS (HR = 0.35, P = 0.007); no other adverse events were associated with survival. Conclusions Regorafenib-induced hypothyroidism frequently occurs in patients with metastatic CRC receiving regorafenib and is associated with improved survival. Thyroid function status should be actively monitored in CRC patients receiving regorafenib.

Subcutaneous Trastuzumab: A Review in HER2-Positive Breast Cancer Abstract A subcutaneous (SC) formulation of trastuzumab, a potent humanized anti-Human Epidermal growth factor Receptor 2 (HER2) receptor monoclonal antibody, with a recombinant hyaluronidase (Herceptin Hylecta™; Herceptin®) is indicated in the USA and EU for the treatment of HER2-positive breast cancer. In the phase III pivotal HannaH trial, SC trastuzumab was noninferior to the standard intravenous (IV) formulation of trastuzumab with respect to trough drug concentrations and pathological complete response in patients with HER2-positive early breast cancer. Other clinical outcomes, including event-free survival and overall survival rates, were generally similar between the formulation groups. SC trastuzumab had a manageable tolerability profile in patients with HER2-positive early or metastatic breast cancer, with the safety profile being generally similar to that of the IV formulation. In the phase III PrefHER and MetaspHER trials, more patients preferred SC over IV trastuzumab and more healthcare professionals expressed satisfaction with the SC formulation. Relative to IV trastuzumab, SC trastuzumab offers a quicker and more convenient dosage regimen, thereby potentially improving patient convenience, providing economic benefit and optimizing the use of medical resources. Thus, given the high preference for SC trastuzumab and its generally similar efficacy and tolerability profile to that of the IV formulation, SC trastuzumab is the preferred treatment of choice in patients receiving trastuzumab for the treatment of HER2-positive early or metastatic breast cancer.

Dynamics of Plasma EGFR T790M Mutation in Advanced NSCLC: A Multicenter Study Abstract Background Droplet digital polymerase chain reaction (ddPCR) is an emerging technology for quantitative cell-free DNA oncology applications. However, a ddPCR assay for the epidermal growth factor receptor (EGFR) p.Thr790Met (T790M) mutation suitable for clinical use remains to be established with analytical and clinical validations. Objective We aimed to develop and validate a new ddPCR assay to quantify the T790M mutation in plasma for monitoring and predicting the progression of advanced non-small-cell lung cancer (NSCLC). Methods Specificity of the ddPCR assay was evaluated with genomic DNA samples from healthy individuals. The inter- and intraday variations of the assay were evaluated using mixtures of plasmid DNA containing wild-type EGFR and T790M mutation sequences. We assessed the clinical utility of the T790M assay in a multicenter prospective study in patients with advanced NSCLC receiving tyrosine kinase inhibitor (TKI) treatment by analyzing longitudinal plasma DNA samples. Results We set the criteria for a positive call when the following conditions were satisfied: (1) T790M mutation frequency > 0.098% (3 standard deviations above the background signal); (2) at least two positive droplets in duplicate ddPCR reactions. Among the 62 patients with advanced NSCLC exhibiting resistance to TKI treatment, 15 had one or more serial plasma samples that tested positive for T790M. T790M mutation was detected in the plasma as early as 205 days (median 95 days) before disease progression, determined by imaging analysis. Plasma T790M concentrations also correlated with intervention after disease progression. Conclusions We developed a ddPCR assay to quantify the T790M mutation in plasma. Quantification of longitudinal plasma T790M mutation may allow noninvasive assessment of drug resistance and guide follow-up treatment in TKI-treated patients with NSCLC. Trial Registration Clinical Trials.gov identifier: NCT02804100.