Validity and Efficiency of Progression-Free Survival-2 as a Surrogate End Point for Overall Survival in Advanced Cancer Randomized Trials.

PURPOSE: Progression-free survival (PFS)-2, defined as the time from randomization to progression on second-line therapy, is potentially a more reliable surrogate than PFS for overall survival (OS), but will require longer follow-up and a larger sample size. We sought to compare the validity and efficiency, defined as proportional increase in follow-up time and sample size, of PFS-2 to PFS. METHODS: We performed an electronic search to identify randomized trials of advanced solid tumors reporting PFS, PFS-2, and OS as prespecified end points. Only studies that had protocols that defined measurement of PFS-2 and follow-up for patients after first disease progression were included. We compared correlations in the relative treatment effect for OS with PFS and PFS-2. We reconstructed individual patient data from survival curves to estimate time to statistical significance (TSS) of the relative treatment effect. We further computed the sample size (person-year [PY] follow-up) required to reach statistical significance. RESULTS: Across the 42 analysis units and 21,255 patients, the correlation of the relative treatment effect between OS and PFS-2, r, was 0.70 (95% CI, 0.41 to 0.80) and r = 0.46 (95% CI, 0.26 to 0.74) for OS and PFS. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS with PFS-2 were 16.59 (95% CI, 4.48 to not reached [NR]), 10.0 (95% CI, 2.2 to NR), and 4.31 (95% CI, 2.92 to 13.13) months, respectively. The median difference in PYs required to reach statistical significance for PFS-2 over PFS was 156 (95% CI, 82 to 500) PYs, equivalent to an estimated median 12.7% increase in PYs. CONCLUSION: PFS-2 offers improved correlation with OS than PFS with a modest increase in follow-up time and sample size. PFS-2 should be considered as a primary end point in future trials of advanced cancers.

Efficacy and safety of 'Second Adjuvant' therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy.

BACKGROUND: Anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for 'second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of 'second adjuvant' BRAF/MEKi. PATIENTS AND METHODS: Patients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive 'second adjuvant' therapy (no second adjuvant group). RESULTS: 73 patients were included; 61 who received 'second adjuvant' therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). CONCLUSION: This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

PURPOSE: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields. METHODS: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included. RESULTS: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa. CONCLUSIONS: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging.

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab.

BACKGROUND: The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. METHOD: To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. RESULTS: Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61-27.81) in patients without diabetes, 10.23 months (95% CI: 5.81-14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04-78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02-44.85) in patients without diabetes, 22.12 months (95% CI: 14.41-29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29-72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04-0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. CONCLUSIONS: LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained.

Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma.

Importance: Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. Objective: To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). Main Outcomes and Measures: Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. Results: Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. Conclusions and Relevance: In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.

Angiogenesis Inhibitors and Immunomodulation in Renal Cell Cancers: The Past, Present, and Future.

Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development.

PD-L1 expression as a prognostic marker in patients treated with chemotherapy for metastatic non-small-cell lung cancer.

Background: In metastatic non-small-cell lung cancer (mNSCLC), PD-L1 expression is associated with benefit from immune checkpoint inhibitor (ICI) therapy. However, the significance of PD-L1 expression in chemotherapy-treated patients is uncertain. Methods: Using the chemotherapy control arm of first-line randomized trials, a meta-analysis of the association between efficacy outcomes and PD-L1 status was performed, stratified by assay due to inter-assay differences. Results: Across 12 trials and 4378 patients, overall survival (OS) was superior in high PD-L1 versus negative tumors and low versus negative according to 22C3/28-8 assays. When classified by SP142 assay, no significant difference in response or survival was seen between PD-L1 groups. Conclusion: In mNSCLC, high PD-L1-expressing tumors are associated with longer OS and improved objective rate when treated with chemotherapy. Inter-assay variability impacts outcome results.

Biomarkers are naturally occurring cancer traits that can predict certain events. PD-L1 expression is a biomarker used in advanced lung cancer to predict benefit from immunotherapy. However, the association between PD-L1expression and chemotherapy is unclear. The authors analyzed data from 14 large clinical trials and found that PD-L1 expression could also be used to define a type of lung cancer that responds better to chemotherapy.

The validity of progression-free survival 2 as a surrogate trial end point for overall survival.

BACKGROUND: Overall survival (OS) is the gold-standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression-free survival 2 (PFS-2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta-analytic approach, the authors aimed to assess the association between OS and PFS-2 and compare this with progression-free survival 1 (PFS-1) and the objective response rate (ORR). METHODS: An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS-2 as a prespecified end point. Correlations between OS and PFS-2, OS and PFS-1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. RESULTS: Thirty-eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS-2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval [CI], 0.08-0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00-0.13) and PFS-1 (r = 0.21; 95% CI, 0.00-0.33) were poor. The findings for PFS-2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63). CONCLUSIONS: Across diverse tumors and therapies, the treatment effect on PFS-2 correlated moderately with the treatment effect on OS. PFS-2 performed consistently better than PFS-1 and ORR, regardless of postprogression treatment and postprogression survival. PFS-2 should be included as a key trial end point in future randomized trials of solid tumors.

Combination chemotherapy with NAB® -paclitaxel and capecitabine for patients with advanced biliary tract cancer (NAP-CAPABIL Pilot Study).

BACKGROUND:  Advanced biliary tract cancer (ABTC) is a highly aggressive malignancy, with a 5-year overall survival of < 10%. Although preliminary evidence suggests a role of targeted treatments or immunotherapy in a subset of patients, chemotherapy remains the standard second-line treatment in the majority. We conducted a pilot study of second-line chemotherapy with capecitabine and nab-paclitaxel after failure of gemcitabine and platinum. METHODS: Eligible patients had histologically proven, unresectable biliary tract cancer, which had progressed on a gemcitabine/platinum doublet. In this single-arm, multicenter trial, all patients received capecitabine (825 mg/m2 bd PO D1-14 q21d) and nab-paclitaxel (125 mg/m2 IV D1,8 q21d) until progression or unacceptable toxicity. The primary objective was feasibility of delivering the proposed regimen, with secondary objectives of disease control measures and QOL outcomes. RESULTS: Ten patients were enrolled between 2015 and 2016 from four cancer centers in NSW. Treatment was generally well tolerated with grade III toxicities in five patients (including infection, cholangitis, obstruction, and intestinal perforation) and no grade IV toxicity. Median treatment duration was 4.3 months, with a disease control rate of 80% (8/10), and median progression-free and overall survival of 5.7 and 12.1 months, respectively. Quality of life data and specimens for translational research have been collected. CONCLUSIONS: Our pilot study demonstrates that combination of capecitabine and nab-paclitaxel is feasible as a second-line treatment in ABTC. Adequate safety and promising early efficacy signals make further assessment of the combination in a formal phase II or III trial reasonable. CLINICAL TRIAL INFORMATION: ACTRN12615000504516.

Immunotherapy-related gastritis: Two case reports and literature review.

Immunotherapy is increasingly defining a role in a wide variety of tumours such that as use becomes more ubiquitous, so too will the complications. A relatively rare complication of immunotherapy use is immune-related gastritis. In this case series, we present two cases of immunotherapy-related gastritis from our institution and undertake a comprehensive review and analysis of the literature around this less common adverse event.

Disseminated intravascular coagulation complicating diagnosis of ROS1-mutant non-small cell lung cancer: A case report and literature review.

Disseminated intravascular coagulation (DIC) is a rare paraneoplastic complication in advanced solid malignancies, with success of treatment and survival dependent on treatment of the underlying malignancy. Best estimates suggest an incidence of 1.6-6.8% in cancer, with risk factors being advanced disease, older age, and adenocarcinoma, especially of lung origin. Few cases, however, have reported on an association between DIC and oncogene-addicted lung cancers, especially those containing ROS proto-oncogene 1 (ROS1) mutations, however precedent exists to suggest increased prothrombotic rates in tumors harboring this mutation. We present a young woman with ROS1-mutant non-small-cell lung cancer who presented in DIC and subsequently developed complications of both hemorrhage and thrombosis. Following initiation of targeted treatment, rapid resolution of laboratory coagulation derangement was observed and clinical improvement quickly followed. This event underscores the need for rapid evaluation of lung molecular panels and the dramatic resolution of life-threatening illness that can occur with institution of appropriate therapy. This case contributes to growing evidence for a possible underlying link between oncogene addicted tumors and abnormalities of coagulation.

Leukocytoclastic vasculitis associated with use of aromatase inhibitors.

Leukocytoclastic vasculitis is an uncommon but important complication of aromatase inhibitor use which may have cosmetic and systemic ramifications. We present a case in which this reaction was observed and aim to compare the characteristics of patients and trajectory of disease in order to assist with early identification and treatment.

Predictive value of PD-L1 and other clinical factors for chemoimmunotherapy in advanced non-small-cell lung cancer.

We investigate if PD-L1 expression and other clinical characteristics predict chemoimmunotherapy (CIT) benefits versus chemotherapy in advanced non-small-cell lung cancer. We performed a meta-analysis of randomized controlled trials of CIT versus chemotherapy identified through electronic searches. In seven randomized controlled trials (n = 4170), CIT prolonged progression-free survival over chemotherapy (hazard ratio [HR]: 0.62; 95% CI: 0.58-0.67; p < 0.00001). The treatment benefits differed between PD-L1-high (HR: 0.41; 95% CI: 0.34-0.49) and PD-L1 low (HR: 0.63; 95% CI: 0.55-0.72; interaction-p = 0.00002) and PD-L1-high and PD-L1-negative (HR: 0.72; 95% CI: 0.65-0.80; interaction-p < 0.00001). Similar benefits were observed regardless of gender, EGFR/ALK status and histological subtype. PD-L1 status is predictive of CIT benefit and may assist patient selection and design of future trials.

Accuracy of Clinician Predictions of Future Self-Harm: A Systematic Review and Meta-Analysis of Predictive Studies.

Assessment of a patient after hospital-treated self-harm or psychiatric hospitalization often includes a risk assessment, resulting in a classification of high risk versus low risk for a future episode of self-harm. Through systematic review and a series of meta-analyses looking at unassisted clinician risk classification (eight studies; N = 22,499), we found pooled estimates for sensitivity 0.31 (95% CI: 0.18-0.50), specificity 0.85 (0.75-0.92), positive predictive value 0.22 (0.21-0.23), and negative predictive value 0.89 (0.86-0.92). Clinician classification was too inaccurate to be clinically useful. After-care should therefore be allocated on the basis of a needs rather than risk assessment.