Targeted Oncology最新文献

The treatment landscape for patients with advanced urothelial carcinoma continues to evolve. Enfortumab vedotin plus pembrolizumab has received Food and Drug Administration approval based on recent phase 3 trial data showing superior efficacy compared with first-line platinum-based chemotherapy; however, its distinct toxicity profile may make it less suitable for some patients, and availability in some countries may be limited by cost considerations. Consequently, platinum-based chemotherapy is expected to remain an important first-line treatment option. Choice of platinum regimen (cisplatin- or carboplatin-based) is informed by assessment of clinical characteristics, including performance status, kidney function, and presence of peripheral neuropathy or heart failure. For patients without disease progression after completing platinum-based chemotherapy, avelumab first-line maintenance treatment is recommended by international guidelines. For patients who have disease progression, pembrolizumab is the preferred approach. Additionally, following results from a recent phase 3 trial, nivolumab plus cisplatin-based chemotherapy has also received Food and Drug Administration approval and is an additional first-line treatment option for cisplatin-eligible patients. Later-line options for patients with advanced urothelial carcinoma, depending on prior treatment, may include enfortumab vedotin, erdafitinib (for patients with FGFR2/3 mutations or fusions/rearrangements), sacituzumab govitecan, and platinum rechallenge. For the small proportion of patients ineligible for any platinum-based chemotherapy (i.e., unsuitable for cisplatin or carboplatin), immune checkpoint inhibitor monotherapy with pembrolizumab or atezolizumab is a first-line treatment option, although approved agents vary between countries. In summary, this podcast discusses recent developments in the treatment landscape for advanced urothelial carcinoma, eligibility for platinum-based chemotherapy, potential first-line treatment options, and treatment sequencing. Supplementary file1 (MP4 246907 KB).

Background

The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC).

Objective

The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting.

Patients and Methods

The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis.

Results

Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50–0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47–0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil–lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab.

Conclusion

In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Futibatinib (LYTGOBI^®) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor receptor (FGFR)1-4. It is approved in the EU, Japan and the USA for the treatment of adults with locally advanced or metastatic cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy. In the phase II part (FOENIX-CCA2) of a multinational phase I/II study in this patient population, monotherapy with futibatinib 20 mg once daily was associated with clinically meaningful and durable responses, sustained health-related quality of life (HR-QOL), and a manageable safety profile with supportive care and as-needed dose modifications. Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.

Kristen Rat Sarcoma viral oncogene (KRAS) mutations are one of the most common oncogenic drivers found in 12-14% of non-small cell lung cancer (NSCLC) and 4% of colorectal cancer tumors. Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations. In preclinical studies, divarasib was 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib. While sotorasib met its primary endpoint in the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed. Adagrasib has demonstrated clinical benefit in the phase I/II KRYSTAL-1 study setting, however, 44.8% of patients reported grade 3 or higher toxicities. Divarasib has been studied in a phase I dose expansion cohort with promising efficacy [objective response (ORR) 53.4% and PFS 13.1 months]. Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.

Background: Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients.

Objective: This multicenter retrospective study aimed to investigate the efficacy and safety of second-line treatment regimens in older patients with advanced or recurrent non-small cell lung cancer (NSCLC).

Patients and methods: We retrospectively analyzed 145 patients aged ≥ 70 years with advanced or recurrent NSCLC treated with second-line chemotherapy after platinum-based therapy between April 1, 2016, and March 31, 2021. Patients were subdivided into the DTX + RAM (n = 38) and single-agent (n = 107) groups.

Results: The median time to treatment failure was 6.3 months (95% confidence interval [CI] 3.6-9.6) in the DTX + RAM group and 2.3 months (95% CI 1.7-3.0) in the single-agent group (p < 0.01). The median overall survival was 15.9 months (95% CI 12.3-Not Achieved) in the DTX + RAM group and 9.4 months (95% CI 6.9-15.1) in the single-agent group (p = 0.01). Grade ≥ 3 adverse events frequency was not significantly different between the two groups, except for edema. Patients in the DTX + RAM group who did not discontinue treatment owing to adverse events exhibited the most favorable prognosis.

Conclusions: These findings suggest that the DTX + RAM combination is an effective second-line therapy for older patients with advanced or recurrent NSCLC, offering favorable efficacy without treatment discontinuation owing to adverse events.

Background: Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV.

Objective: To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (^EEDVs_Mit) in children with recurrent / refractory solid or CNS tumours expressing EGFR.

Patients and methods: Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent ^EEDVs_Mit. Thirty-seven patients' tumours were screened for EGFR expression. ^EEDVs_Mit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 10^{8 E}EDVs_Mit per dose and escalated to 5 × 10^{9 E}EDVs_Mit per dose.

Results: EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, ^EEDVs_Mit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response.

Conclusions: EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response.

Clinicaltrials:

Gov identifier: NCT02687386.

Background: Palbociclib in combination with endocrine therapy is approved for treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In addition to clinical trials, several real-world studies have evaluated the effectiveness of palbociclib. With increased life expectancy in the general population, breast cancer in older women is also expected to increase.

Objective: The aim was to systematically review evidence from both clinical trials and real-world studies for palbociclib treatment outcomes in older patients with HR+/HER2- advanced/metastatic breast cancer (a/mBC). Older patients are often underrepresented in clinical trials, and real-world evidence (RWE) will enrich the analysis of palbociclib outcomes in this subgroup of patients.

Design: A systematic literature search in PubMed, EMBASE, and Cochrane Library through May 4, 2023, yielded 2355 unique articles. A total of 52 articles (13 and 39 articles reporting results from seven randomized controlled trials [RCTs] and 37 RWE studies, respectively) were included based on study eligibility criteria.

Results: All RCTs used age cutoffs of ≥ 65 years to define older population (n = 722; 437 received palbociclib); all RWE studies, except one with an age cutoff of > 60 years, had age cutoffs of ≥ 65 years or higher to define older population (n = 9840; 7408 received palbociclib). Overall, in studies that compared efficacy (progression-free survival [seven RCTs, 20 RWE studies], overall survival [four RCTs, 11 RWE studies], tumor response [three RWE studies], and clinical benefit rate [one RCT, two RWE studies]) and safety outcomes (three RCTs, three RWE studies) between older and younger patients, palbociclib showed similar benefits, regardless of age. Results from two RCTs and two RWE studies showed that global quality of life (QoL) was maintained in older patients receiving palbociclib. Overall, palbociclib dose modifications (two RWE studies), dose reductions (one RCT, seven RWE studies), and treatment discontinuation rates (three RCTs, three RWE studies) were higher in older patients compared with younger patients; however, these differences did not appear to adversely impact efficacy outcomes.

Conclusions: In this systematic review, data from RCTs showed that palbociclib was effective, well tolerated, and maintained QoL in older patients with HR+/HER2- a/mBC. Palbociclib treatment in older patients in real-world settings was associated with similar clinical benefit as in RCTs.

Prospero registration: CRD42023444195.

Background: Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice.

Objective: We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods: We assessed clinical priority of AEs reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) by attributing a score to each AE disproportionally reported with ADCs. Four criteria were assessed: clinical relevance, reporting rate, reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators).

Results: We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia, and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N = 8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; and pulmonary embolism with T-DM1 (N = 31, median onset 109 days, 52% with reported metastasis).

Conclusion: The heterogeneous spectrum of post-marketing toxicities for ADCs used in breast cancer, as emerging from the FAERS, is largely in line with preapproval evidence. Although causality cannot be proved, we call for increased awareness by oncologists on potential serious unexpected reactions, including early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1.