Phase II study of trifluridine/tipiracil in metastatic breast cancers with or without prior exposure to fluoropyrimidines.

BACKGROUND: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study. METHODS: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability. RESULTS: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications. CONCLUSION: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC.

Management of Oncogene Driven Locally Advanced Unresectable Non-small Cell Lung Cancer.

INTRODUCTION: The current standard of care of locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation, followed by consolidation durvalumab. However, there is evidence that the efficacy of chemoradiation and also immunotherapy in many oncogene-positive LA-NSCLC are attenuated, and dependent on the subgroup. AREAS COVERED: We will firstly review the outcomes of standard-of-care therapy in oncogene-driven LA-NSCLC. We looked at various oncogene driven subgroups and the tumor microenvironment that may explain differential response. Finally, we review the role of targeted therapy in the treatment of LA-NSCLC. EXPERT OPINION: Each oncogene-positive subgroup should be treated as its own entity, and continued efforts should be undertaken to incorporate targeted therapy, which is likely to yield superior survival outcomes if trial design can be optimized and toxicities can be managed.

Advances in the management of non-small-cell lung cancer harbouring EGFR exon 20 insertion mutations.

Epidermal growth factor receptor (EGFR) mutation is one of the key oncogenic mutations in non-small-cell lung cancer with adenocarcinoma histology. Exon 19 deletions and exon 21 L858R substitutions account for 90%, while EGFR exon 20 insertions constitute 4-10% of EGFR mutations and are the third most prevalent activating EGFR mutations. EGFR exon 20 insertions are associated with decreased sensitivity to EGFR tyrosine kinase inhibitors and, until recently, effective targeted therapy against these tumours remained an unmet clinical need and chemotherapy was the only treatment of choice available. The approval of amivantamab and mobocertinib for patients who have progressed after chemotherapy represents an important step forward in the management of these patients. Here in this review, we summarize the epidemiology, structure and the tumour microenvironment of EGFR exon 20 insertion and also review the systemic treatments, including targeted therapies and ongoing clinical trials in EGFR exon 20 insertion mutations, as well as detection methods for EGFR exon 20 insertion. Lastly, resistant mechanisms and future directions are addressed.

Real-world assessment of attenuated dosing anti-PD1 therapy as an alternative dosing strategy in a high-income country (as defined by World Bank).

The rising cost of oncological drugs poses a global challenge to patients, insurers, and policy makers, with the leading drugs worldwide by revenue from immune checkpoint inhibitors (ICIs). Despite its cost, ICI is marked as a paradigm shift, offering the potential of a long-term cure. To reduce cost, an attenuated dose of ICI based on pharmacological principles can be used while maintaining efficacy. This real-world study aims to examine the prescribing patterns, the effect of financial constraints, and the outcomes in non-small cell lung cancer (NSCLC). All patients receiving palliative intent ICI treatment for advanced NSCLC between January 2014 and April 2021 in National University Hospital, Singapore were recruited. Demographics, prescription trends, factors affecting the prescription of attenuated dose ICI (AD ICI) versus standard dose ICI (SD ICI), and the effect of dose on survival outcomes, toxicities, and costs were examined. Two hundred seventy-four received ICI. The majority of them were treated in first-line setting. One hundred sixty-two (59%) of patients received AD ICI, whereas 112 (41%) received SD ICI. Patients who did not have a supplemental private as-charged health insurance plan were more likely to have received AD ICI (OR: 4.53 [2.69-7.61] p < 0.001). There was no difference in progression-free survival (PFS) and overall survival (OS)-adjusted HR 1.07 CI [0.76, 1.50] p = 0.697 and HR 0.95 CI [0.67, 1.34] p = 0.773, respectively, between patients who received AD versus SD ICI. A cost minimization analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of USD 7,939,059 over 7 years. Our study provides evidence for AD-ICI as a promising strategy to maximize the number of patients who can be treated with ICI. This has the potential to make significant economic impact and allow more patients to benefit from novel therapies.

Real-world outcomes from use of CDK4/6 inhibitors in the management of advanced/metastatic breast cancer in Asia.

Background: Oestrogen receptor positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer (BC) is the most frequently diagnosed BC subtype. Combinations of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with anti-oestrogen therapy have led to improved survival compared with anti-oestrogen therapy alone for advanced/metastatic BC. The evaluation of CDK4/6i in the real-world facilitates treatment planning, insights into the incidence of drug toxicities, dose modifications including dose delays (DDs) and dose reductions (DRs) and improves prognostic accuracy in subgroups, for example geriatric patients, who are under-represented in clinical trials. Methods: This multi-centre study analysed retrospective and prospective data from 456 patients treated with CDK4/6i between January 2015 and December 2020. We examined patient characteristics, variation in prescribing practices, efficacy and toxicity outcomes. Results: In all, 456 patients were included in this study. The median age was 59 (range: 24-92). In total, 85 (19%) were ⩾70 years old. In all, 122 (27%) and 119 (26%) of patients were treated in the first-line and second-line settings, respectively. In total, 25 (5%), 31 (7%) and 145 (32%) of patients had brain, peritoneum and liver metastasis, respectively, at the time of CDK4/6i initiation. On univariate analysis, heavily pre-treated patients and those with distant metastases, involving the liver, brain or peritoneum, had significantly shorter progression-free survival (PFS) and 24-month overall survival (OS). Elderly patients (⩾70) had a shorter PFS; OS results were not mature. Majority of patients (n = 362, 80%) initiated treatment with the United States FDA-approved starting dose of CDK4/6i. In all, 330 (72%) had at least one DD and 217 (48%) patients required at least one DR, but these dose modifications were not associated with poorer survival outcomes. Patients age ⩾70 were more likely to require dose modifications leading to a lower treatment dose. The most common reason for DD/DR was neutropenia (60%) and the incidence of febrile neutropenia was only 2%. Conclusions: Our study indicates CDK4/6i is effective and safe. Age ⩾ 70, distant metastases to liver, peritoneal or brain were negative prognostic factors. Age ⩾ 70 was associated with significantly increased requirement for dose modification; however, this did not impact survival outcomes. These findings provide reassurance that survival outcomes are not adversely affected in elderly patients when DD/DR is indicated.

Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer.

BACKGROUND: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting. METHOD: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. RESULTS: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis. CONCLUSION: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

Atypical Response Patterns in Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors-Navigating the Radiologic Potpourri.

BACKGROUND: Atypical response patterns have been a topic of increasing relevance since the advent of immune checkpoint inhibitors (ICIs), challenging the traditional RECIST (Response Evaluation Criteria in Solid Tumors) method of tumor response assessment. Newer immune-related response criteria can allow for the evolution of radiologic pseudoprogression, but still fail to capture the full range of atypical response patterns encountered in clinical reporting. METHODS: We did a detailed lesion-by-lesion analysis of the serial imaging of 46 renal cell carcinoma (RCC) patients treated with ICIs with the aim of capturing the full range of radiologic behaviour. RESULTS: Atypical response patterns observed included pseudoprogression (n = 15; 32.6%), serial pseudoprogression (n = 4; 8.7%), dissociated response (n = 22; 47.8%), abscopal response (n = 9; 19.6%), late response (n = 5; 10.9%), and durable response after cessation of immunotherapy (n = 2; 4.3%). Twenty-four of 46 patients (52.2%) had at least one atypical response pattern and 18 patients (39.1%) had multiple atypical response patterns. CONCLUSIONS: There is a high incidence of atypical response patterns in RCC patients receiving ICIs and the study contributes to the growing literature on the abscopal effect. The recognition of these interesting and overlapping radiologic patterns challenges the oncologist to tweak treatment options such that the clinical benefits of ICIs are potentially maximized.

Low-dose pembrolizumab in the treatment of advanced non-small cell lung cancer.

A dose of 200 mg 3-weekly of pembrolizumab was approved by the Food and Drug Administration (FDA) as treatment for advanced non-small cell lung cancer (NSCLC) without oncogenic drivers. This is despite evidence showing no difference in efficacy with 2 mg/kg. Our study aimed to assess the efficacy of a lower fixed dose of 100 mg, which is closer to 2 mg/kg weight-based dose in an average-sized Asian patient. All patients receiving pembrolizumab for advanced NSCLC from January 2016 to March 2020 in National University Hospital, Singapore, were included in this retrospective observational study. The effect of pembrolizumab 100 mg (Pem100) vs 200 mg (Pem200) upon survival outcomes, toxicity and cost were examined. One hundred fourteen patients received pembrolizumab. Sixty-five (57%) and 49 (43%) received Pem100 and Pem200, respectively. There was no difference in progression-free survival (PFS) and overall survival (OS) between Pem100 vs Pem200 as a single agent (PFS: 6.8 vs 4.2 months, hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.36-1.46, P = .36; 9 month OS: 58% vs 63%, HR 1.08, 95% CI 0.48-2.41, P = .86) and when combined with chemotherapy (9-month PFS: 60% vs 50%, HR0.84, 95% CI 0.34-2.08, P = .71; 9-month OS: 85% vs 58%, HR 0.27, 95% CI 0.062-1.20, P = .09). No significant difference in response rate or ≥G3 immune-related toxicities between Pem100 and Pem200 was observed. A cost minimisation analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of SGD4,290,912 and cost saving per patient of SGD39,942 in the Pem100 group. A 100 mg of pembrolizumab appears to be effective with reduction in cost. A randomised trial should be done to investigate a lower dose of pembrolizumab.

Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience.

BACKGROUND: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. METHODS: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. RESULTS: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. CONCLUSION: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.

Immune checkpoint inhibition for non-small cell lung cancer in patients with pulmonary tuberculosis or Hepatitis B: Experience from a single Asian centre.

BACKGROUND: The importance of immune-checkpoint inhibitors (ICI) can no longer be understated since its move to front-line treatment in non-small cell lung cancer (NSCLC) in recent years. However, the safety and efficacy of ICI in special populations such as those with infections like tuberculosis (TB) and hepatitis B (HBV) remain unknown as they are routinely excluded from clinical trials. METHODS: Records of patients with advanced NSCLC who were treated with ICI from January 2014 to June 2019 at a single Asian centre were reviewed. Those with a history of HBV and/or TB were selected. In this group, safety and treatment outcomes including overall survival (OS), progression-free survival (PFS) and response rate were reported and compared against control. RESULTS: 191 patients received ICI, 47 (24.6%) had a history of TB/HBV. The median PFS in those with a history of TB/HBV was 5.7 months (95% CI 3.9-7.6), compared to 3.1 months (95% CI 2.4-3.8) in control (HR 0.61, 95% CI 0.39-0.93, p = 0.021). Median OS was 15.6 months (95% CI 10.2-21.0) compared to 11.1 months (95% CI 7.6-14.7 months) in the control group (HR 0.58, 95% CI 0.34-0.99, p = 0.046). Adverse events of any grade (G) were similar in both groups; slightly more patients with TB/HBV experienced G3 or higher adverse events. Four patients developed TB after initiation of ICI, none with previously documented TB experienced reactivation. Of the 42 patients with a history of HBV, eight had inactive chronic HBV and six had detectable viral load. None of the 34 patients who were previously exposed to HBV had reactivation. CONCLUSION: The use of ICI appears to be safe and efficacious in patients with TB/HBV infection. Prospective studies are required to identify those at risk in order to optimise care to these groups of patients.

The evolving immuno-oncology landscape in advanced lung cancer: first-line treatment of non-small cell lung cancer.

Lung cancer is the most common cancer and leading cause of cancer death. While targeted therapies have redefined treatment options for non-small cell lung carcinoma (NSCLC) with genetic aberrations such as epidermal growth factor and anaplastic lymphoma kinase, many patients do not harbour these oncogenic drivers. Cancer immunology has enabled the development of immune modulators that has dramatically altered the therapeutic landscape of advanced NSCLC. The success of immune-checkpoint inhibitors in pretreated NSCLC has led to the conduct of multiple studies exploring their role in the first-line setting. This article provides an overview of the evolving landscape of immune-checkpoint inhibitors with a focus on the programmed cell-death 1 (PD-1; pembrolizumab, nivolumab) and programmed cell-death ligand 1 (PD-L1; atezolizumab, durvalumab, avelumab) immune-checkpoint inhibitors as single agent or in combination with either chemotherapy or with another immune-checkpoint inhibitor in the treatment of NSCLC, the challenges faced, as well as future perspectives.