Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes ...immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
•Coexisting alterations in KEAP1, PBRM1, SMARCA4 and STK11 define a subset of lung adenocarcinoma unresponsive to immunotherapy.•Tumors harboring co-mutations had inferior survival outcomes compared with both single-mutant and wild-type tumors.•Tumors with co-occurring alterations are misclassified as immunoresponsive by tumor mutational burden.•An immunologically cold phenotype characterizes lung adenocarcinoma with coexisting mutations.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+).
We ...conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design.
Five trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36–0.58, P < 0.0001 and overall response rate (ORR) (HR 2.08, 95% CI 1.75–2.46, P < 0.0001) over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials.
In EGFR-M+ patients, first-line TKI increase both PFS and ORR by ∼25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation.
In the last few years, non-small cell lung cancer (NSCLC) treatment has totally revolutionized by the improvement in molecular diagnostics and the introduction of targeted therapies, becoming the ...standard of care in patients with actionable alterations. Mostly, genomic mutations are mutually exclusive although some cases of co-occurring actionable alterations could be discovered, especially with the recent introduction of genomic sequencing by next generation sequencing (NGS). Few data are available in the treatment of these particular cases. The co-occurring RAS G12C mutation seems to be a poor prognostic factor in patients with ALK rearranged NSCLC. We report two cases of women with diagnosis of advanced adenocarcinoma oncogene addicted with ALK rearrangement and KRAS G12C mutation. In both cases the PD-L1 status was high (> 50 %). Although both received Alectinib as ALK inhibitor, the lesion rapidly progressed. The patients had benefit only by treatments with chemotherapy, while anti PD-1/PD-L1 axis inhibitors seemed to be inefficient. Precise diagnostic techniques allow the detection of concomitant driver alterations; therefore, oncologists should consider these rare double mutations in NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver alterations and the relevant treatment paradigm
We assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by ...intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer.
This was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%.
Between October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases.
FOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.
Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting ...80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted.
The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan–Meier method.
Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with ‘major’ uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer ‘minor’ mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy.
The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon–common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
•Largest dataset of NSCLC with uncommon EGFR alterations treated with osimertinib.•Best outcomes with compound uncommon–common EGFR mutations and with G719X, L861X, or S768I.•Heterogeneous activity with rarer mutations; no response with alterations at E709 residue.•Confirmed activity in the central nervous system, with intracranial ORR of 58%.•Amplification of EGFR or MET, TP53 mutations, and EGFR E709K are putative mechanisms of resistance.
Background. Irinotecan is a selective inhibitor of topoisomerase I, an enzyme part of the replication and transcription system of DNA. Irinotecan is employed, with different modalities, in the ...treatment of metastatic colorectal cancer, and recently it has been officially approved in association with fluorouracil (FU) and leucovorin (LV) as a first-line option in metastatic colorectal cancer.
Results. One of the problems linked to the administration of this drug is the high intestinal toxicity, which constitutes its dose limiting toxicity (DLT). In routine practice, loperamide is employed as symptomatic drug for the treatment of CPT-11-induced diarrhoea, but is not completely adequate to control the problem. The role of the intestinal bacterial microflora in the pathogenesis of CPT-11-induced intestinal toxicity has been recently discovered. The active metabolite of CPT-11, SN38, is generated from CPT-11 by sieric carboxylesterase, and subsequently conjugated to SN38-G by hepatic UDP–glucuronyltransferase. SN38-G is the inactive metabolite of CPT-11 and is excreted into the small intestine, from which it is eliminated in the faeces. Some studies have shown the ability of intestinal bacterial β-glucoronidases to transform SN38-G into SN38, causing direct damage to the intestinal mucosa. Thus, alternative strategies such as intestinal alkalinization and anti-cyclooxygenase 2 (COX-2) therapy have been explored.
Conclusions. In this review, we will illustrate the mechanisms which cause the CPT-11-induced diarrhoea and the potential measures available to prevent it.
Background: The aim of this study was to characterize the factors associated with chemotherapy-induced amenorrhea (CIA) and to examine whether the phase of the menstrual cycle at chemotherapy start ...could affect the rate of CIA in premenopausal women with early breast cancer. Methods: CIA was defined as the cessation of menses for at least 3 months during or after chemotherapy. Menstrual phase was defined as days 1–6, follicular phase as days 7–14, luteal phase as days 15–20 and premenstrual phase as days 21–28. Univariate and multivariate predictors of CIA were examined. Results: Among 111 premenopausal women, univariate analysis showed a higher incidence of CIA in patients treated in the follicular phase rather than in other menstrual cycle phases (67.6% compared with 45.5%; P=0.03). The rate of CIA increased with age: 65.2% and 45.8% in patients aged >42 and ≤42 years, respectively (P=0.05). Upon multivariate analysis these differences remained statistically significant and duration of chemotherapy of more than six cycles correlated significantly with the incidence of CIA (P=0.03). Conclusions: The major implication of this analysis is that the timing of treatment within the menstrual cycle may potentially modulate the onset of CIA. This work and its future confirmation using prospective randomized trials would be useful in predicting the likelihood of CIA and in counseling breast cancer patients, especially those with a good prognosis who benefit less from chemical castration.
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