Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

The value of disease-free survival (DFS) and osimertinib in adjuvant non-small-cell lung cancer (NSCLC): an international Delphi consensus report.

BACKGROUND: Rates of disease recurrence and death following surgery remain high in early-stage non-small-cell lung cancer (NSCLC), despite adjuvant treatment and curative intent. Recently, osimertinib showed overwhelming evidence for disease-free survival (DFS), as demonstrated by an overall reduction in the risk of disease recurrence or death in the adjuvant setting of 80% versus control in the ADAURA study (stage IB-IIIA; hazard ratio 0.20; 99.12% confidence interval 0.14-0.30; P < 0.001). However, due to the early unblinding of ADAURA and lack of mature overall survival data, there is a need to qualitatively confirm consensus on the clinical and patient relevance of DFS. MATERIALS AND METHODS: We conducted a modified Delphi panel study consisting of two rounds of surveys, followed by a consensus meeting. An international panel of experts in the field of NSCLC and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (n = 13) was asked to rate agreement and comment on a list of pre-defined statements covering key consensus gaps. Statements were eliminated or updated between surveys, depending on the level of agreement. A final list of agreed-upon statements was drafted in the consensus meeting. RESULTS: Consensus was reached on 32 qualitative statements, with topics including unmet needs in early-stage NSCLC, the value of DFS, and the value of osimertinib. Crucially, DFS was agreed to be a clinically and patient-relevant endpoint in adjuvant NSCLC. The relevance of DFS was found to relate to the ability of an adjuvant therapy, such as osimertinib, to keep patients in the clinically valuable curative intent setting, while preventing the burden associated with distant and locoregional recurrence, and progressive disease. CONCLUSIONS: Addressing the need for measures that reflect clinical benefit is essential to continue improving outcomes for NSCLC patients. To that end, this work provides a qualitative framework for clinicians to consider the clinical and patient relevance of DFS in adjuvant NSCLC and the benefit demonstrated in ADAURA thus far.

Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer.

BACKGROUND: The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies. PATIENTS AND METHODS: Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy. RESULTS: 21 patients were enrolled (06/2010-02/2015). Median age: 62y (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%); IV 5(24%). Median GTV 64 cm3 (range 1-224 cm3). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia. CONCLUSION: We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.

First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions.

Small-cell lung cancer (SCLC) is an aggressive and rapidly growing disease with poor prognosis. Despite intense efforts to improve clinical outcomes, platinum/etoposide chemotherapy has remained the most effective regimen for first-line extensive disease SCLC for decades. The addition of immune checkpoint inhibitors, and specifically programmed death-ligand 1 inhibitors, to standard platinum/etoposide, significantly improves survival and represents a promising advance in this field. However, identification of a predictive biomarker to refine patient selection is an area of unmet need. Further understanding of tumour immunity and mechanism of resistance is required to design novel strategies that improve survival. In this review, we describe recent developments and future directions on first-line immune checkpoint blockade for extensive disease-SCLC.

Choice of second-line systemic therapy in stage IV small cell lung cancer (SCLC) - A decision-making analysis amongst European lung cancer experts.

OBJECTIVES: Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. MATERIAL AND METHODS: The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. RESULTS: The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3-6 months since the end of first-line therapy. CONCLUSION: Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in.

Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts.

BACKGROUND: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. METHODS: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. RESULTS AND CONCLUSION: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial.

BACKGROUND: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen. PATIENTS AND METHODS: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13. RESULTS: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. CONCLUSIONS: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. CLINICAL TRIALS NUMBER: NCT02763579.

Immune checkpoint blockade for non-small cell lung cancer: What is the role in the special populations?

In recent years, non-small cell lung cancer (NSCLC) entered in a new era of anticancer treatments with the success of checkpoint inhibitors (CPIs). These are now part of daily practice from locally advanced to metastatic NSCLC. However, the registration phase III trials are highly selective and not fully representative of the patients seen in real-world clinical practice. This is particularly obvious for older and frail patients, which represent the majority of NSCLC cases worldwide. The median age of the patients enrolled in clinical trials is 10 years younger than what is seen in clinic and patients with performance status (PS) ≥2 were excluded from registration studies. No strong conclusions can be drawn from the available trials where older and frail patients have been excluded. The majority of data on efficacy according to age are derived from underpowered subgroup analysis and there are no age-specific safety data published. Current data suggest that older patients may derive a similar benefit with no increased toxicity when compared with younger patients. However, the recent development of immunotherapychemotherapy combinations and the potential higher incidence of toxicity, raise additional concerns for these populations where adequate patient selection is paramount. CPI is not recommended for patients with PS 3-4 and should be considered with caution for those with PS 2. The evidence for patients with pre-existing autoimmune disease (AID), organ transplant or chronic viral infections (such us viral hepatitis B and C or human immunodeficiency virus) is less clear and low level. Although CPI are potentially safe in selected patients with AID with minimal activity and well-controlled chronic viral infections, patients with solid organ transplant face a significant risk of graft loss and death. Therefore, a decision to treat these groups of patients should always be discussed at a multidisciplinary level.

Professional burnout in European young oncologists: results of the European Society for Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey.

BACKGROUND: Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists ≤40 (YOs). METHODS: A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/lifestyle factors. Statistical analyses were carried out to identify factors associated with burnout. RESULTS: Total of 737 surveys (all ages) were collected from 41 European countries. Countries were divided into six regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). Seventy-one percent of YOs showed evidence of burnout (burnout subdomains: depersonalization 50%; emotional exhaustion 45; low accomplishment 35%). Twenty-two percent requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (P < 0.0001). Burnout was highest in central European (84%) and lowest in Northern Europe (52%). Depersonalization scores were higher in men compared with women (60% versus 45% P = 0.0001) and low accomplishment was highest in the 26-30 age group (P < 0.01). In multivariable linear regression analyses, European region, work/life balance, access to support services, living alone and inadequate vacation time remained independent burnout factors (P < 0.05). CONCLUSIONS: This is the largest burnout survey in European Young Oncologists. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance, access to support services and adequate vacation time may reduce burnout levels. Raising awareness, support and interventional research are needed.

The effect of human-mattress interface's temperature on perceived thermal comfort.

In recent years, methods that allow for an objective evaluation of perceived comfort, in terms of postural, physiological, cognitive and environmental comfort, have received a great deal of attention from researchers. This paper focuses on one of the factors that influences physiological comfort perception: the temperature difference between users and the objects with which they interact. The first aim is to create a measuring system that does not affect the perceived comfort during the temperatures' acquisition. The main aim is to evaluate how the temperature at the human-mattress interface can affect the level of perceived comfort. A foam mattress has been used for testing in order to take into account the entire back part of the human body. The temperature at the interface was registered by fourteen 100 Ohm Platinum RTDs (Resistance Temperature Detectors) placed on the mattress under the trunk, the shoulders, the buttocks, the legs, the thighs, the arms and the forearms of the test subject. 29 subjects participated in a comfort test in a humidity controlled environment. The test protocol involved: dress-code, anthropometric-based positioning on mattress, environment temperature measuring and an acclimatization time before the test. At the end of each test, each of the test subject's thermal sensations and the level of comfort perception were evaluated using the ASHRAE (American Society of Heating, Refrigerating and Air-Conditioning Engineers) scale. The data analyses concerned, in the first instance, correlations between the temperature at the interface and comfort levels of the different parts of the body. Then the same analyses were performed independently of the body parts being considered. The results demonstrated that there was no strong correlation among the studied variables and that the total increase of temperature at interface is associated with a reduction in comfort.

Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinum-based chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings.

Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.

INTRODUCTION: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. PATIENTS AND METHODS: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. RESULTS: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. CONCLUSIONS: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.

Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage Non-Small Cell Lung Cancer (NSCLC): a European survey conducted by the European Society for Medical Oncology (ESMO) young oncologists committee.

BACKGROUND: Early stage Non-Small Cell Lung Cancer (NSCLC) is potentially curable with surgery. ESMO guidelines recommend cisplatin-based adjuvant chemotherapy (CT) for completely resected stage II-III NSCLC. There is limited evidence for the use of adjuvant CT and/or radiotherapy (RT) in incompletely resected (R1) early stage NSCLC. MATERIALS AND METHODS: A European survey of thoracic oncologists was conducted to evaluate use of adjuvant CT and RT for R1-resected NSCLC and to identify factors influencing treatment decisions. Demographics and information on clinical stage, regimens, cycles planned, radiotherapy sites, multidisciplinary management and discussion about inconclusive evidence with the patient were collected. Univariate and multivariate analyses were performed. RESULTS: 768 surveys were collected from 41 European countries. 82.9% of participants were medical oncologists; 49.3% ESMO members; 37.1% based in University Hospitals; 32.6% practicing oncology for over 15 years and 81.4% active in research. 91.4% of participants prescribed adjuvant CT and mostly cisplatin/vinorelbine (81.2%) or cisplatin/gemcitabine (42.9%). 85% discussed limited clinical evidence with the patient. In the univariate analysis, a statistically significant association with CT prescription was found for medical oncology specialty (p<0.001), ESMO membership (p<0.001), activity in clinical research (p=0.002) and increased frequency of ESMO guidelines consultation (p for trend <0.001). 48.3% of participants prescribed adjuvant RT and its prescription were associated with radiation oncology specialty (p<0.001), not being an ESMO member (p<0.001), years practicing specialty (p for trend=0.001), workload of lung cancer patients (p for trend=0.027) and decreased frequency in consulting ESMO guidelines (p<0.001). In the multivariate analysis, medical oncology and radiation oncology were the best discriminator for prescription of adjuvant CT and RT, respectively. CONCLUSION: This survey demonstrates that adjuvant CT and RT are commonly used in clinical practice for R1-resected NSCLC despite limited evidence. Prospective trials are necessary to clarify optimal management in this setting.

The current and future role of the medical oncologist in the professional care for cancer patients: a position paper by the European Society for Medical Oncology (ESMO).

The number of cancer patients in Europe is rising and significant advances in basic and applied cancer research are making the provision of optimal care more challenging. The concept of cancer as a systemic, highly heterogeneous and complex disease has increased the awareness that quality cancer care should be provided by a multidisciplinary team (MDT) of highly qualified healthcare professionals. Cancer patients also have the right to benefit from medical progress by receiving optimal treatment from adequately trained and highly skilled medical professionals. Built on the highest standards of professional training and continuing medical education, medical oncology is recognised as an independent medical specialty in many European countries. Medical oncology is a core member of the MDT and offers cancer patients a comprehensive and systemic approach to treatment and care, while ensuring evidence-based, safe and cost-effective use of cancer drugs and preserving the quality of life of cancer patients through the entire 'cancer journey'. Medical oncologists are also engaged in clinical and translational research to promote innovation and new therapies and they contribute to cancer diagnosis, prevention and research, making a difference for patients in a dynamic, stimulating professional environment. Medical oncologists play an important role in shaping the future of healthcare through innovation and are also actively involved at the political level to ensure a maximum contribution of the profession to Society and to tackle future challenges. This position paper summarises the multifarious and vital contributions of medical oncology and medical oncologists to today's and tomorrow's professional cancer care.

A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.

BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.