In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor ...targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown.
We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival.
The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval CI, 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.
Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not ...been previously studied.
Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).
At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.
Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell ...lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs.
We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting.
Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 50%) or docetaxel (n=174 50%). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4–20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months 95% CI 4·3–7·8 vs 4·5 months 3·0–5·7; hazard ratio 0·66 0·51–0·86; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 33% vs n=61 40%) and serious treatment-related adverse events compared with docetaxel (n=18 11% vs n=34 23%). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 12%), alanine aminotransferase increase (n=13 8%), and aspartate aminotransferase increase (n=9 5%). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 9%), fatigue (n=9 6%), and febrile neutropenia (n=8 5%).
Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.
Amgen.
Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, ...notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described.
Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays.
After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs.
RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.
Lorlatinib is a novel, highly potent, brain‐penetrant, third‐generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad‐spectrum potency against most known resistance mutations that can ...develop during treatment with crizotinib and second‐generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid‐lowering agent. Prescription of supportive therapy should also consider the potential for drug‐drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK‐positive metastatic non‐small cell lung cancer previously treated with a second‐generation ALK TKI.
Implications for Practice
Despite the advancement of second‐generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK‐positive non‐small cell lung cancer. Lorlatinib is a potent, brain‐penetrant, third‐generation, macrocyclic ALK/ROS1 TKI, with broad‐spectrum potency against most known resistance mutations that can develop during treatment with existing first‐ and second‐generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
摘要
劳拉替尼是一种新型、高效、具有脑渗透作用的第三代 ALK/ROS1 酪氨酸激酶抑制剂 (TKI)，对克唑替尼和第二代 ALK TKI 治疗期间可能发生的大多数已知耐药突变具有广谱效力。295 名患者每日服用一次 100 mg 推荐剂量的劳拉替尼，在此基础上确立了劳拉替尼的安全谱。劳拉替尼相关不良事件的严重程度主要为轻度至中度，最常报告的不良事件是高胆固醇血症 (82.4%)、高甘油三酯血症 (60.7%)、水肿 (51.2%)、周围神经病变 (43.7%) 和中枢神经系统影响 (39.7%)。由于因不良事件引起的永久停药的发生率较低，因此可通过调整剂量和/或标准支持性药物疗法来有效管理上述不良事件。大多数患者 (81.0%) 服用至少一种降脂药。支持疗法的处方还应考虑劳拉替尼通过特定 CYP450 酶的参与发生药物相互作用的可能性。本文总结了劳拉替尼 I 期研究者的临床经验，并通过对临床研究方案和数据库的讨论和回顾，就报告的罗拉替尼主要不良事件(包括高脂血症、中枢神经系统影响、体重增加、水肿、周围神经病变和胃肠影响)的管理提供了专家共识意见。总体而言，根据美国食品药品监督管理局最新的批准，我们认为，凭处方每天服用一次 100 mg 的劳拉替尼对治疗 ALK 阳性转移性非小细胞肺癌患者(之前接受过第二代 ALK TKI 治疗)具有出色的安全性。
实践意义:尽管第二代间变性淋巴瘤激酶 (ALK) 酪氨酸激酶抑制剂 (TKI) 取得了发展，但中枢神经系统转移出现耐药性和进展仍是 ALK 阳性非小细胞肺癌面临的重要临床问题。劳拉替尼是一种高效、具有脑渗透作用的第三代大环 ALK/ROS1 TKI，对现有第一代和第二代 ALK TKI 治疗期间可能发生的大多数已知耐药突变具有广谱效力。本文为报告的劳拉替尼主要不良反应的临床管理提供了
建议。
This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most ...common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines.
To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC.
We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021.
We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC.
Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib' with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement.
Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement. ALK inhibitor versus chemotherapy Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment. ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence). ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period. ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy. Next-generation ALK inhibitor versus crizotinib Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases. Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib. Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib. Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting.
Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal.
Aim
Decreased cancer incidence and reported changes to clinical management indicate that the COVID‐19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a ...flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation.
Methods
A model was developed and made publicly available to estimate population‐level health economic outcomes by extrapolating and weighing stage‐specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3‐ and 6‐month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma).
Results
Using a conservative once‐off 3‐month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6‐month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years.
Conclusions
The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate individual patient data on shifts in stage of disease during and after the COVID‐19 pandemic are critical for further analyses.
Presentation and application of a framework to estimate the long‐term impact of delayed cancer diagnoses and treatment due to the COVID‐19 pandemic. Over the next 5 years, nearly 90 excess deaths and $12 million excess healthcare costs for 4 common cancers in Australia were estimated based on conservative assumptions.
Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer.
Patients were randomly ...assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed.
Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio HR, 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively).
Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
•All patients with KRASG12C mutant NSCLC were active or ex-smokers.•33 % KRAS mutant versus 40 % KRAS wildtype NSCLC developed brain metastases (p = 0.17).•40 % KRASG12C versus 41 % other KRAS mutant ...NSCLC developed brain metastases (p = 0.74)•Overall survival was similar between KRAS mutant and KRAS wildtype NSCLC (p = 0.54).•Overall survival was similar between KRASG12C and other KRAS mutant NSCLC (p = 0.39).
KRAS mutations are found in 20–30 % of non-small cell lung cancers (NSCLC) and were traditionally considered undruggable. KRASG12C mutation confers sensitivity to KRASG12C covalent inhibitors, however its prognostic impact remains unclear. This study assesses the frequency, clinical features, prevalence of brain metastases and outcomes in KRASG12C NSCLC in a real-world setting.
Patients enrolled in the prospective Thoracic Malignancies Cohort (TMC) between July 2012 to October 2019 with recurrent/metastatic non-squamous NSCLC, available KRAS results, and without EGFR/ALK/ROS1 gene aberrations, were selected. Data was extracted from TMC and patient records. Clinicopathologic features, treatment and overall survival (OS) was compared for KRAS wildtype (KRASWT) and KRAS mutated (KRASmut); and KRASG12C and other (KRASother) mutations.
Of 1386 NSCLC patients, 1040 were excluded: non-metastatic/recurrent (526); unknown KRAS status (356); ALK/EGFR/ROS1 positive (154); duplicate (4). Of 346 patients analysed, 144 (42 %) were KRASmut, of whom 65 (45 %) were KRASG12C. All patients with KRASG12C were active or ex-smokers, compared to 92 % of KRASother and 83 % of KRASWT. The prevalence of brain metastases during follow-up was similar between KRASmut and KRASWT (33 % vs 40 %, p = 0.17), and KRASG12C and KRASother (40 % vs 41 %, p = 0.74). The proportion of patients receiving one or multiple lines of systemic therapy was comparable. OS was similar between KRASmut and KRASWT (p = 0.54), and KRASG12C and KRASother (p = 0.39).
Patients with KRASmut and KRASWT, and KRASG12C and KRASother NSCLC have comparable clinical features, treatment and survival. While not prognostic, KRASG12C may be an important predictive biomarker as promising KRASG12C covalent inhibitors continue to be developed.
We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, ...paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors.
Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity.
Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response.
This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned.
Australian New Zealand Clinical Trials Registry ACTRN12609000672257.
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