•Immune checkpoint inhibitors can induce immune-related adverse events (irAEs), potentially life-threatening.•There is evidence suggesting a potential association between toxicities and clinical ...benefit.•This systematic review showed that there appears to be an association between the development of irAEs and anti-tumor effect by ICI.•This systematic review provides real-world data showing increased likelihood of response to ICI and improved progression free-survival, overall survival and response rate in patients who experienced an irAE, across all solid tumors and regardless of type of ICI.
The use of immune checkpoint inhibitors (ICIs) has become standard therapy in many tumor sites. The aim of this study is to systematically review the literature to determine whether the incidence of immune-related adverse events (irAEs) after the use of ICIs is associated with clinical outcomes in all solid malignancies.
Embase and PubMed were searched from January 1st, 2000 until March 14, 2020 for relevant studies assessing the relationship between irAEs and treatment efficacy. Outcome measures of interest included: incidence of irAEs, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).
Of 3384 unique citations, 51 studies met inclusion criteria. Studies included melanoma (n = 21), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancers (n = 1). In patients with metastatic melanoma (n = 1474), the development of irAEs (irAE + versus irAE-) was associated with better weighted average OS (15.24 months (95% CI 9.95 to 20.5) versus 8.94 months (95% CI 7.76 to 10.1), HR = 0.46 (n = 640, CI 0.35–0.62, p < 0.00001), PFS (17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68), HR = 0.51 (n = 1763, CI 0.42–0.63, p < 0.00001), and ORR (37.67% (95% CI 32.8 to 42.5) versus. 23.44% (95% CI 17.8 to 29.1). Similarly, in lung cancer patients, the ORR (irAE + versus. irAE-) was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6). The weighted average PFS and OS were 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) with HR = 0.46 (n = 1575, CI 0.39–0.54, p < 0.00001) and 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) HR = 0.40 (n = 1085, CI 0.30–0.51, p < 0.00001), respectively. Improved treatment efficacy in patients who developed irAEs was also seen in renal cell carcinoma, urothelial and head and neck cancers. Notably, grade 3 or 4 irAEs were associated with increased ORR but worse OS.
A positive association was noted between the development of irAEs and ORR, PFS, and OS in patients treated with ICIs, irrespective of disease site, type of ICI and irAE. Grade 3 or higher toxicities resulted in better ORR, but worse OS.
Small-cell lung cancer (SCLC) remains a disease with poor prognosis, particularly in extensive-stage SCLC (ES-SCLC). Current standard-of-care treatment includes chemotherapy with platinum agents and ...etoposide plus immunotherapy with atezolizumab or durvalumab, which has achieved a mean overall survival of 12–13 months in clinical trials. However, long-term survival in ES-SCLC, even with the addition of immunotherapy, continues to be rare. We present the case of a middle-aged male patient diagnosed with ES-SCLC who was treated with four cycles of induction chemotherapy (carboplatin and etoposide) and atezolizumab, starting maintenance atezolizumab every 21 days thereafter, and thoracic radiotherapy. After 9 months, he experienced mild disease progression and was rechallenged with six cycles of carboplatin and etoposide with continued atezolizumab. Subsequent imaging showed near-complete disease resolution which has been sustained since. He has continued on maintenance atezolizumab since diagnosis and has achieved 60 months overall survival and 44 months progression-free survival. Throughout treatment, he has maintained a high functional capacity and only experienced one immune-related adverse event. Our patient is representative of a small subset who are capable of achieving durable responses to immunotherapy and his case highlights the need for further research to elucidate the clinical and biological factors driving this response.
Antibody-Drug conjugates (ADCs) are a relatively new class of drugs with a promise to improve the outcomes in specific cancers. By delivering the cytotoxic agent to tumor cells expressing specific ...antigens, ADCs achieve a better therapeutic index and more potency. ADCs have been approved for several hematological and solid malignancies, including breast, urothelial and gastric carcinoma. Recently, trastuzumab deruxtecan (TDXd) was the first ADC approved for previously treated metastatic HER2-mutant non-small cell lung cancer (NSCLC). Many promising ADCs are in the pipeline for clinical development in non-small cell lung cancer, including sacituzumab govitecan, patritumab deruxtecan, datopotamab deruxtecan and tusamitamab ravtansine. There is a hope that these drugs would cater to the unmet need of specific patient populations, including patients with currently untargetable mutations. We hope these drugs, e.g., TROP2 targeted ADCs, will also give more options for therapy in NSCLC to improve outcomes for patients. In this comprehensive review, we will be discussing the recent evidence including targets, efficacy and the safety of newer ADC candidates in NSCLC. We will also briefly discuss the specific toxicities, novel biomarkers, overcoming resistance mechanisms, challenges and the way forward, as these new ADCs and combinations find a way into the clinical practice.
Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage ...NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.
Phosphoinositide 3-kinase (PI3K) inhibitors may overcome drug resistance and improve advanced breast cancer (ABC) outcomes. We conducted a systematic review and meta-analysis to assess the efficacy ...and safety of adding a PI3K inhibitor to the standard of care (SOC) treatment in ABC. The electronic databases Ovid, PubMed, Cochrane Central Register of Controlled Trials and Embase, were searched for relevant randomised trials. Pooled hazard ratios (HRs) for progression-free survival (PFS) and pooled risk ratios (RRs) for objective response rates (ORRs), disease control rates (DCRs) and toxicity were meta-analysed using the Mantel–Haenszel method and generic inverse variance. Five studies were included. In unselected patients, the addition of a PI3K inhibitor decreased the risk of progression by 21% (2329 participants, HR = 0.79; 95% confidence interval CI, 0.71–0.88). A marginal improvement in ORR (2329 participants, RR = 1.26; 95% CI, 1.01–1.57) and no improvement in DCR (2146 participants, RR = 1.05; 95% CI, 0.94–1.18) were achieved with a significant increase in toxicity of any grade (2386 participants, RR = 1.05; 95% CI, 1.03–1.06) and of grade III and higher (2386 participants, RR = 1.91; 95% CI, 1.76–2.08). A PFS benefit was seen in patients with and without PI3K pathway activation assessed on tumour and only in patients with an activated PI3K pathway when it was assessed from the plasma using circulating tumour DNA (ct-DNA) analysis. The addition of a PI3K inhibitor decreases the risk of progression in unselected ABC patients and particularly in patients with an activated PI3K pathway detected on ct-DNA analysis. However, their significant dose-limiting toxicity is a limiting factor. Selective PI3K inhibitors are being tested to assess whether these better-tolerated agents have a role in ABC treatment.
•Pan–phosphoinositide 3-kinase (PI3K) inhibitors decrease the risk of disease progression in breast cancer.•Pan-PI3K inhibitors significantly increase the risk of developing adverse events.•PI3K mutation on circulating tumour DNA is predictive of PI3K inhibitors activity.•Pan-PI3K inhibitors have limited clinical utility; validated biomarkers are needed.•Results from selective PI3K inhibitors trials are awaited.
We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact ...mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial-mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC.
Background: Neither paclitaxel plus trastuzumab (P-H) nor docetaxel-cyclophosphamide plus trastuzumab (TC-H) have been prospectively compared in HER2-positive early-stage breast cancer (EBC). A ...randomized trial was performed to assess the feasibility of a larger study. Methods: Lower-risk HER2-positive EBC patients were randomized to either P-H or TC-H treatment arms. The co-primary feasibility outcomes were: ≥75% patient acceptability rate, active trial participation of ≥50% of medical oncologists, ≥75% and ≥90% treatment completion, and receipt rate of planned cycles of chemotherapy, respectively. Secondary outcomes: Febrile neutropenia (FN) rate, treatment-related hospitalizations, health-related quality of life (HR-QoL) questionnaires. Analyses were performed by per protocol and intention-to-treat. Results: Between May 2019 and March 2021, 49 of 52 patients agreed to study participation (94% acceptability rate). Fifteen (65%) of 23 medical oncologists approached patients. Rates of FN were higher (8.3% vs. 0%) in the TC-H vs. P-H arm. Median (IQR) changes in scores from baseline in FACT-Taxane Trial Outcome Index at 24 weeks were −4 (−10, −1) vs. −6.5 (−15, −2) for TC-H and P-H arms, respectively. Conclusions: A randomized trial comparing P-H and TC-H was feasible. Expansion to a larger trial would be feasible to explore patient-reported outcomes of these adjuvant HER2 chemotherapy regimens.
One year of adjuvant trastuzumab is considered the standard treatment for patients with HER2 positive breast cancer. However, a shorter duration of trastuzumab may be associated with reduced costs ...and side effects. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant trastuzumab are not consistent and have not been systematically reviewed using a non-inferiority meta-analysis approach.
We conducted a systematic review and meta-analysis of randomized trials to assess whether a shorter duration of adjuvant trastuzumab was non-inferior to one year of treatment or not. The non-inferiority margin for the meta-analysis was pre-defined as the median of the margins of all the trials included. Data of 11,376 patients from 5 trials were analyzed. Non-inferiority margins in included studies varied from 1.15 to 1.53 with median of 1.29 for HR of DFS. A shorter duration of trastuzumab was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03–1.24) but inconclusive for OS (HR 1.14, 95%CI 1.00–1.30). In a subgroup analysis for DFS outcome, shorter therapy was non-inferior in patients with ER positive disease (HR 1.10, 95%CI 0.95–1.28) and those with sequential therapy (HR 0.97, 95%CI 0.75–1.27) and when the duration of treatment was 6 months (HR 1.09, 95%CI 0.98–1.22). Although a shorter duration of adjuvant trastuzumab was non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer based on our HR margin of 1.29, any benefit of a shorter duration comes at a loss of efficacy with an increase in absolute risk up to 3.9% for 5 year DFS. Whether the potential increased risk is clinically acceptable for the benefits of a shorter duration remains debatable.
•Shorter duration of adjuvant trastuzumab in HER2 positive breast cancer is attractive.•Inconsistent results seen from the PHARE and PERSEPHONE trials.•Meta-analysis suggests shorter duration of trastuzumab is non-inferior.•Highlights need for appropriately chosen and applied non-inferiority margin.
Abstract
Background
Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy.
...Methods
We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis.
Results
CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio HR: 2.44; 95% confidence interval CI: 1.41-4.24;
p
=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35;
p
=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;
p
=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51;
p
=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS (HR:2.02;95% Cl:1.16-3.51;
p
=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33;
p
=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34;
p
=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69;
p
<0.001).
Conclusion
The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.
PDF
