Summary
Background
Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody–drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab.
Methods
In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0–1, and who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined a s 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.
Findings
Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4–5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4–5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1–5·2] vs 4·5 months [4·1–5·8]; hazard ratio 1·22 [0·85–1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).
Interpretation
Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.
Funding
Bayer Healthcare Pharmaceuticals.
Introduction
Before the approval of ipilimumab and nivolumab as a first-line combination immunotherapy in October, 2020, pemetrexed and platinum-based chemotherapy was the only first-line treatment for malignant pleural mesothelioma.1–4 In the second-line setting, median progression-free survival was 3·6 months with pemetrexed plus best supportive care versus 1·5 months with best supportive care alone in a population of pemetrexed-naive patients with malignant pleural mesothelioma.5 Following chemotherapy, only nivolumab has shown improved survival in a randomised phase 3 trial;6 current relapse treatment options are based on phase 2 clinical trials.7
The American Society of Clinical Oncology guidelines include vinorelbine chemotherapy as an option for patients with malignant pleural mesothelioma who have progressed after first-line treatment.8 In a phase 2 study of patients with relapsed disease, vinorelbine yielded an objective response rate of 16% and an overall survival of 9·6 months.9 In the phase 2 VIM study, median progression-free survival was 4·2 months with vinorelbine plus active supportive care versus 2·8 months with active supportive care alone.10 The prognosis of malignant pleural mesothelioma in the second-line setting is often poor due to limited therapeutic options. Therefore, development of novel therapies is of paramount importance.4,11
Mesothelin is a tumour differentiation antigen that is highly expressed in several cancers, including mesotheliomas, and pancreatic, ovarian, and lung adenocarcinomas.12 In normal tissue, its expression is limited to mesothelial cells lining the pleura, peritoneum, and pericardium.12,13 Anetumab ravtansine (also known as BAY 94–9343) is an antibody–drug conjugate comprising a fully human IgG1 anti-mesothelin antibody conjugated to the maytansine derivative tubulin inhibitor DM4 via a reducible disulphide linker.13 When released in tumour cells, DM4 disrupts microtubule polymerisation, resulting in cell cycle arrest and apoptosis.14 Preclinically, anetumab ravtansine was highly cytotoxic in mesothelin-expressing mesothelioma, pancreatic, colon, and ovarian cancer cell lines.13 In vivo, anetumab ravtansine had robust antitumour activity in mesothelin-expressing mesothelioma, pancreatic, and ovarian cancer patient-derived xenografts.13
Anetumab ravtansine showed promising antitumour activity in a phase 1 trial of various mesothelin-expressing solid tumour types, including malignant pleural mesothelioma.15 The maximum tolerated dose for anetumab ravtansine was identified to be 6·5 mg/kg once every 3 weeks or 2·2 mg/kg once every week. The objective response rate was 31% in patients with mesothelioma receiving anetumab ravtansine 6·5 mg/kg once every 3 weeks. Mesothelin expression was assessed in these patients, with high expression defined as 2+ or 3+ membrane staining intensity on at least 30% of viable tumour cells. Patients who achieved an objective response had at least 60% of tumour cells expressing mesothelin at 2+ and 3+ staining intensities. Anetumab ravtansine was well tolerated; the most common treatment-emergent adverse events were fatigue, nausea, diarrhoea, and anorexia.15
There are currently no validated predictive biomarkers of sensitivity or resistance to spindle poisons.16 BAP1 is the most commonly mutated tumour suppressor in mesothelioma.17 One retrospective analysis of patients treated with vinorelbine implicated BAP1 as a possible predictor of drug resistance.18
We aimed to examine the efficacy and safety of anetumab ravtansine as a single agent in comparison with vinorelbine in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab.19
Methods
Study design and participants
This study was an open-label, randomised, active-controlled, phase 2 trial, conducted across 76 hospitals in 14 countries (appendix pp 38–41) that has now been completed.
Eligible patients aged 18 years and older had histologically confirmed unresectable locally advanced or metastatic malignant pleural mesothelioma and had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab based on modified Response Evaluation Criteria in Solid Tumors for malignant pleural mesothelioma (mRECIST). The last dose of previous therapy must have been at least 28 days before the start of study treatment. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least 3 months. Patients were required to have mesothelin over expression, defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry. Exclusion criteria included inadequate hematological, hepatic, or renal function; known HIV infection; active or ongoing infection; and brain metastases or meningeal tumours or other metastases in the central nervous system. Patients with recent history of other malignancies were also ineligible, except for those with adequately treated non-melanoma skin cancer, cervical cancer in situ, and superficial bladder cancer at the time of diagnosis. A full list of eligibility criteria can be found in the protocol (appendix).
The study protocol and amendments were approved by each study site’s Independent Ethics Committee or Institutional Review Board (appendix). The trial adhered to the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent.
Randomisation and masking
Patients were randomly assigned (2:1) to receive anetumab ravtansine or vinorelbine using an interactive voice and web response system provided by the sponsor. We used permuted-block randomisation stratified by time to progression on first-line treatment (<6 vs ≥6 months), with no masking to treatment allocation.
Procedures
Patients were scheduled to receive anetumab ravtansine (6·5 mg/kg once every 3 weeks) via intravenous infusion for 1 h on day 1 of each 21-day cycle, or vinorelbine (30 mg/m2 once every week) via intravenous injection for 6–10 min. The dosing and scheduling were based on the prescribing information for vinorelbine.20 Patients continued treatment until protocol-defined progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. After treatment, all patients attended a 30-day safety follow-up visit, and patients without disease progression entered active follow-up. Permitted dose modifications of anetumab ravtansine or vinorelbine due to haematological or non-haematological toxicities can be found in the protocol (appendix).
Patient demographics and some characteristics (disease stage [unresectable, locally advanced or metastatic relapsed malignant pleural mesothelioma confirmed by histology] and mesothelin expression) were obtained during a prescreening phase. Further disease characteristics and relevant medical history were collected during screening.
Radiographic assessments (ie, CT and MRI scans) were done at screening, during treatment (every 6 weeks during the first 6 months after the start of study treatment, every 9 weeks until the end of year 2, and every 12 weeks thereafter), and active follow-up until disease progression or study completion. Progression was assessed according to blinded central radiology review and conducted in real time with the results provided to investigators before the next dosing decision. Disease and survival status were assessed during long-term follow-up every 3 months until data maturation for the final overall survival analysis was reached, death, loss to follow-up, withdrawal of consent, or study completion.
Patient-reported outcomes were assessed at screening, on day 1 of cycle 2 and every cycle thereafter, at the safety follow-up visit, and during the active follow-up period with the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) and MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma (MDASI-MPM).
Safety data were collected at each visit (except during long-term follow-up, which was defined as the period following centrally confirmed radiological progression, or withdrawal of consent to active follow-up, when no safety data were collected). Except for corneal epitheliopathy, which was assessed using an internally developed Bayer system, treatment-emergent adverse events were classified by the investigator by type (using the Medical Dictionary for Regulatory Activities criteria versions 20.0 and 20.1) and severity (using the Common Terminology Criteria for Adverse Events version 4.03). To assess the predictive relationship of mesothelin expression and soluble mesothelin-related peptides with clinical activity, mesothelin expression was assessed prospectively using Ventana mesothelin (SP74) immunohistochemistry assay (Roche Diagnostics, Tucson, AZ, USA) using archival tumour tissue at the prescreening stage of the study. Soluble mesothelin-related peptides expression was determined by enzyme-linked immunosorbent assay (MESOMARK, Fujirebio Diagnostics, Malvern, PA, USA) using plasma samples collected pre-dose at day 1 of cycle 1. To identify additional predictive biomarkers of response or resistance to anetumab ravtansine, plasma samples were collected from 47 patients with malignant pleural mesothelioma treated with anetumab ravtansine, and underwent next-generation sequencing using a customised PlasmaSELECT targeted panel of 67 well-characterised cancer-associated genes specifically designed for malignant pleural mesothelioma (Personal Genome Diagnostics, Baltimore, MD, USA; appendix p 26).
Outcomes
The primary endpoint was progression-free survival, defined as time from randomisation to centrally confirmed evidence of disease progression according to modified Response Evaluation Criteria in Solid Tumors for malignant pleural mesothelioma (mRECIST)21 or death.
The secondary endpoint overall survival was the first prespecified endpoint in the family-wise error rate gatekeeping hierarchy. Overall survival was defined as time from randomisation to death from any cause. Additional key prespecified secondary efficacy endpoints in the gatekeeping hierarchy order were patient-reported outcomes, which included time to worsening of symptoms, time to worsening of pain, symptom improvement rate, and pain improvement rate, assessed using the LCSS-Meso and MDASI-MPM questionnaires. Other secondary endpoints were objective response rate (defined as the proportion of patients achieving a complete response or partial response per mRECIST), disease control rate (defined as the proportion of patients achieving a complete response, partial response, or stable disease), duration of response (defined as time from documentation of tumour response to disease progression or death without documented progression), durable response rate (defined as the number of patients with a duration of response >180 days divided by the total number of randomised patients), and safety.
Pharmacokinetics, immunogenicity, and biomarkers (mesothelin expression, soluble mesothelin-related peptide expression, and next-generation sequencing per PlasmaSELECT target gene panel) were also assessed as prespecified other additional endpoints.
Statistical analysis
The study had two prespecified analyses. Progression-free survival and most efficacy endpoints matured at the time of the primary progression-free survival analysis on May 31, 2017. Final overall survival, duration of response, and durable response rate matured subsequently on April 6, 2018. Safety was assessed at baseline and continuously throughout the study and during follow-up; the safety analysis was based on the April 6, 2018, data cutoff. In addition, the protocol was amended after the primary analysis to provide for continued collection of overall survival data beyond maturation of the final overall survival analysis. This exploratory overall survival analysis was performed following completion of the study in July 2, 2019.
Baseline characteristics, extent of exposure, and safety data were assessed using summary statistics.
Progression-free survival was assessed using a single-stage, single-sided formal hypothesis test with null hypotheses: progression-free survival under treatment with anetumab ravtansine is not superior to vinorelbine, versus the alternative hypothesis: anetumab ravtansine is superior. A modified treatment policy strategy was used for intercurrent events, censoring for missing assessments but not change of therapy. The sample size calculation assumed a true median progression-free survival of 3·6 months under vinorelbine treatment (estimated using best reported outcomes from previous studies at the time of the study),5,22 constant hazards, and a 2:1 treatment to comparator randomisation. Target accrual was 210 randomly assigned patients. A one-sided log-rank test with a significance level of 0·0125 and 90% power to detect a 100% prolongation of progression-free survival (hazard ratio [HR] 0·5) required 117 progression-free survival events.
The study was formally powered for the secondary endpoint overall survival and was assessed using a formal two-stage group sequential hypothesis testing procedure with an interim analysis at the time of the primary progression-free survival analysis. The null hypothesis stated that overall survival with anetumab ravtansine is not superior to vinorelbine versus the alternative hypothesis that it was superior. A treatment policy strategy was used. The sample size calculation assumed true median overall survival of 9·6 months under vinorelbine treatment, constant hazards, and 2:1 randomisation with 210 patients. The group sequential design with one-sided log-rank tests with an overall family-wise error rate of 0·025 and 80% power to detect a 60% prolongation of overall survival (HR 0·63) required 159 overall survival events using a Lan-DeMets alpha spending function with O’Brien-Fleming superiority boundary. 87 overall survival events were observed at the time of the primary progression-free survival analysis cutoff (interim overall survival). With 159 nominal total events required for final overall survival, the calculated interim α was 0·00245, and the adjusted final α was 0·02421. The log-rank tests used the same stratification factors as progression-free survival.
Efficacy was assessed in the intent-to-treat population, including all randomly assigned patients. Safety was evaluated in the safety population, comprising all randomly assigned patients who received any amount of any study drug. An independent data monitoring committee was established for this study to ensure ongoing safety of patients.
An independent patient-reported outcome review board developed a composite symptom score and determined thresholds for improvement and worsening of pain or symptoms. This scoring system and determined thresholds was based on analyses of blinded, pooled data from this study and was conducted according to procedures prespecified in the protocol, statistical analysis plan, and blinded patient-reported outcome review charter. Time to worsening of symptoms and pain were tested with a one-sided log-rank test, and symptom and pain improvement rates with a one-sided Cochran–Mantel–Haenszel test, all with the same stratification factor as progression-free survival and a significance level of 0·025.
Kaplan–Meier curves were constructed for progression-free survival, overall survival, duration of response, and times to worsening of symptoms and pain with two-sided 95% CIs; the HR was calculated with a Cox-proportional hazards model. For the descriptive analyses of objective response rate, disease control rate, durable response rate, best change in tumour size in target lesions from baseline, and symptom and pain improvement rates, rates with 95% exact binomial CIs were calculated.
Based on primary analysis data, post-hoc subgroup analyses of progression-free survival and overall survival were performed on the stratified intent-to-treat population and are represented by four tumour mesothelin expression quartiles (mesothelin 1–mesothelin 4) and four soluble mesothelin-related peptides expression quartiles (SMRP1–SMRP4; appendix pp 1–2). Survival curves of these subgroups were generated using Kaplan–Meier method. Sensitivity analyses of progression-free survival based on predefined subgroups were also conducted; subgroups were age, sex, race, ethnicity, previous bevacizumab therapy, ECOG performance status, MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM) scores (composite symptom and pain), slit lamp exam Bayer grade, and time to progression on first-line treatment per case report form (appendix p 42). Results of cell-free DNA biomarker analysis were also analysed post-hoc. Statistical analyses were done using SAS version 9.2. A p value of less than 0·05 was considered statistically significant. This study is registered with ClinicalTrials.gov, NCT02610140.
Role of the funding source
The study was designed by Bayer in consultation with HLK and DAF. The sponsor was responsible for the collection of the data. Bayer employees also participated in the conduct of the study and were involved in the analysis and interpretation of the data. All authors contributed to writing and reviewing the report, and collectively made decisions regarding content.
Results
Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled. 547 patients provided samples for mesothelin expression analysis by immunohistochemistry, of which 425 (78%) samples were determined to be mesothelin-positive per study inclusion criteria. After full screening for study eligibility, 248 patients were enrolled and included in the intention-to-treat population (figure 1). 166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine. Three (2%) of 166 patients randomly assigned to anetumab ravtansine, and ten (12%) of 82 patients randomly assigned to vinorelbine discontinued from the study before first treatment. Patient disposition at final progression-free survival and overall survival analyses is shown in the appendix (p 3).
Figure 1: Trial profile.
ITT=intention-to-treat. *547 patients provided mesothelin expression samples, of whom 537 received a mesothelin expression result.
Demographics and baseline characteristics, including time to progression on first-line systemic anticancer therapy, were generally balanced between the treatment groups (table 1). Disease histology was mainly epithelioid across enrolled patients. Data on systemic anticancer therapy received by patients in each treatment group during follow-up are shown in the appendix (pp 4–7).
Table 1:
Baseline characteristics of the intention-to-treat population
| Anetumab ravtansine (n=166) | Vinorelbine (n=82) | |
|---|---|---|
|
| ||
| Median age, years | 67 (61–72) | 66 (60–72) |
| Sex | ||
| Male | 122 (73%) | 62 (76%) |
| Female | 44 (27%) | 20 (24%) |
| Race | ||
| White | 157 (95%) | 75 (92%) |
| Black or African American | 3 (2%) | 0 |
| Asian | 2 (1%) | 1 (1%) |
| Not reported | 4 (2%) | 6 (7%) |
| Ethnicity | ||
| Not Hispanic or Latino | 157 (95%) | 71 (87%) |
| Hispanic or Latino | 4 (2%) | 4 (5%) |
| Not reported | 5 (3%) | 7 (9%) |
| Median baseline weight, kg | 74 (63–85) | 76 (66–87) |
| Eastern Cooperative Oncology Group performance status | ||
| 0 | 61 (37%) | 29 (35%) |
| 1 | 105 (63%) | 53 (65%) |
| Histology | ||
| Epithelioid | 159 (96%) | 79 (96%) |
| Biphasic | 7 (4%) | 2 (2%) |
| Missing | 0 | 1 (1%) |
| Stage at study entry (TNM classification) | ||
| I | 0 | 1 (1%) |
| IA | 1 (1%) | 1 (1%) |
| II | 6 (4%) | 7 (9%) |
| III | 58 (35%) | 25 (30%) |
| IV | 101 (61%) | 48 (59%) |
| Median time from initial diagnosis, months | 13.6 (9.4–20.9) | 14.2 (9.3–22.8) |
| Median time since most recent progression, months | 2.1 (1.4–27) | 1.9 (14.3–0) |
| Time to progression on first-line treatment*, months | ||
| <6 | 65 (39%) | 30 (37%) |
| ≥6 | 101 (61%) | 52 (63%) |
Data are n (%) or median (IQR).
Per case report form.
At the primary progression-free survival analysis (data cutoff May 31, 2017), 105 (63%) of 166 patients treated with anetumab ravtansine versus 43 (52%) of 82 patients treated with vinorelbine had disease progression or died. With a median follow-up of 4·0 months (IQR 1·4–5·5) in the anetumab ravtansine group and 3·9 months (1·4–5·4) in the vinorelbine group, progression-free survival with anetumab ravtansine was not superior to that with vinorelbine (median 4·3 months [95% CI 4·1–5·2] vs 4·5 months [4·1–5·8]; HR 1·22 [0·85–1·74]; log-rank p=0·86; figure 2). Subgroup analyses did not show any significant differences between the treatment groups regarding the progression-free survival endpoint (appendix p 27). Anetumab ravtansine was not superior to vinorelbine in patient-reported outcome endpoints (appendix p 8).
Figure 2: Kaplan–Meier estimates of progression-free survival.
At data cutoff on May 31, 2017, 27 (16%) patients were still receiving anetumab ravtansine and ten (12%) patients were still receiving vinorelbine.
With longer follow-up, at the time of the final efficacy analyses (data cutoff April 6, 2018), 113 (68%) of 166 patients treated with anetumab ravtansine versus 48 (59%) of 82 patients treated with vinorelbine had died. With a median follow-up of 8·6 months (IQR 4·3–15·3) in the anetumab ravtansine group and 8·7 months (3·5–14·3) in the vinorelbine group, overall survival with anetumab ravtansine was not superior to that with vinorelbine (median 9·5 months [95% CI 8·3–12·3] vs 11·6 months [8·6–13·1]; HR 1·07 [0·76–1·51]; log-rank p=0·66; figure 3). In an exploratory analysis for overall survival done at the end of the study (data cutoff July 2, 2019), 127 (77%) of 166 patients treated with anetumab ravtansine versus 59 (72%) of 82 patients treated with vinorelbine had died. Median overall survival in July, 2019, was unchanged from the final a nalysis (April, 2018) with a slightly lower HR of 0·98 (95% CI 0·72–1·34; appendix p 28).
Figure 3: Kaplan–Meier estimates of overall survival.
At the time of the final overall survival analysis (data cutoff April 6, 2018), nine (5%) patients were still receiving anetumab ravtansine and one (1%) patient was still receiving vinorelbine.
Descriptive analyses of all prespecified secondary efficacy endpoints including objective response rate, disease control rate, duration of response and durable response rate were completed and based on final data cutoff (April 6, 2018). Objective response rate and disease control rate appeared to be similar between treatment groups (table 2). No complete responses were reported in either treatment group. The proportion of patients with best responses of partial response, stable disease, and progressive disease appeared similar between treatment groups (table 2, figure 4). Duration of response and durable response rate appeared similar between the treatment groups. Median duration of response was 7·4 months (95% CI 6·0–not estimable) in the anetumab ravtansine group and 6·7 months (3·0–10·3) in the vinorelbine group. Durable response rate was 7·2% (95% CI 3·8–12·3; 12 of 166 patients) in the anetumab ravtansine group and 4·9% (1·3–12·0; four of 82 patients) in the vinorelbine group. Treatment duration in the intention-to-treat population is shown in figure 4.
Table 2:
Treatment responses
| Anetumab ravtansine (n=166) | Vinorelbine (n=82) | |
|---|---|---|
|
| ||
| Best overall response | ||
| Complete response | 0 (0%, 0.0–2.2) | 0 (0%, 0.0–4.4) |
| Partial response | 16 (9.6%, 5.6–15.2) | 6 (7.3%, 2.7–15.2) |
| Stable disease | 106 (63.9%, 56.0–71.2) | 50 (61.0%, 49.6–71.6) |
| Progressive disease | 24 (14.5%, 9.5–20.7) | 9 (11.0%, 5.1–19.8) |
| Not estimable | 0 (0%, 0.0–2.2) | 0 (0%, 0.0–4.4) |
| Not available | 20 (12.0%, 7.5–18.0) | 17 (20.7%, 12.6–31.1) |
| Objective response rate* | 16 (9.6%, 5.6–15.2) | 6 (7.3%, 2.7–15.2) |
| Disease-control rate† | 122 (73.5%, 66.1–80.0) | 56 (68.3%, 57.1–78.1) |
Data are n (%, 95% CI). At the time of secondary data cutoff (April 6, 2018), nine (5%) patients were still receiving anetumab ravtansine and one (1%) patient was still receiving vinorelbine. Three (2%) patients in the anetumab ravtansine group and ten (12%) patients in the vinorelbine group never received study treatment. Responses were categorised according to the modified Response Evaluation Criteria in Solid Tumors.
Patients with a complete response or partial response.
Patients with a complete response, partial response, or stable disease.
Figure 4: Antitumour activity in intention-to-treat population.
(A) Best change in tumour size in target lesions from baseline and (B) treatment duration in patients with malignant pleural mesothelioma. The distribution of best overall response did not change from the April 6, 2018, to July 2, 2019, data cutoff. At the time of updated analysis (July 2, 2019) no patients were being treated with either anetumab ravtansine or vinorelbine. Dashed horizontal lines indicate cutoff for partial response (–30%) and progressive disease (+20%) according to mRECIST.
Median mesothelin expression was 75% (IQR 50–90) of tumour cells with 2+ or 3+ membrane staining intensity (appendix p 1). Baseline plasma soluble mesothelin-related peptide levels were determined in 225 patients, and the median baseline plasma soluble mesothelin-related peptide level was 4·5 nmol/L (IQR 2·10–11·20; appendix p 2), which is higher than the common diagnostic threshold of soluble mesothelin-related peptides in malignant pleural mesothelioma (2·0 nmol/L).8
In a post-hoc subgroup analysis, patients treated with anetumab ravtansine in mesothelin expression quartiles 2–4 showed longer progression-free survival than patients in quartile 1 (appendix p 30). However, similar results were not observed for patients treated with vinorelbine. A similar analysis showed that patients treated with anetumab ravtansine also showed longer overall survival in quartiles 2–4 than patients in the first quartile (appendix p 35). No differences in overall survival between mesothelin expression quartiles were observed for patients treated with vinorelbine.
Analysis of progression-free survival by soluble mesothelin-related peptides expression quartiles found no association between soluble mesothelin-related peptide levels and progression-free survival in either treatment group (appendix p 21, pp 31–34). In the subgroup analysis of overall survival in soluble mesothelin-related peptides expression quartiles, overall survival was longer in quartile 1 than in quartiles 2–4 in both treatment groups although the difference did not reach statistical significance to predict overall survival efficacy in the anetumab ravtansine group (appendix p 35).
Consistent with previously reported results,15 the immunogenicity and pharmacokinetics of anetumab ravtansine were dose-proportional and exposures were similar between cycles (data not shown).
Plasma samples collected from patients treated with anetumab ravtansine underwent cell-free DNA isolation and next-generation sequencing using a PlasmaSELECT assay (appendix p 26). Circulating tumour DNA next-generation sequencing outputs were generated for 47 patients (14 with progressive disease, 19 with stable disease, and 14 with a partial response), mostly with stage 3 or 4 disease (43 [91%] of 47 patients). The overall median cell-free DNA concentration was 12·9 ng/mL (IQR 9–20·6 ng/mL; appendix p 24).
Analysis of the clinical activity and mutation profile of plasma samples from 47 patients treated with anetumab ravtansine showed that 24 (51%) of 47 patients with best responses of partial response (n=8), stable disease (n=8), and progressive disease (n=8) had 47 somatic mutations (appendix p 37). 23 (49%) of 47 patients with best responses of partial response (n=6), stable disease (n=11), and progressive disease (n=6) had no detectable somatic mutations. Somatic mutations unique to patients with a partial response as best response were DDX51 and EZH2 (appendix p 37). In patients with progressive disease as best response, unique mutations were AR, BRCA2, CCND3, CDK4, MET, and POLE. BAP1 was the most frequently mutated gene; the mutation rate was 29% in patients with progressive disease as best response (four of 14 patients) versus 5% in patients with stable disease (one of 19 patients) and 0% in patients with a partial response.
To understand the nature of the observed somatic mutations, we analysed the exon sequence data in all 11 somatic mutations detected in eight patients with confirmed partial response. The somatic mutation types were substitution, deletion, and missense mutations leading to deleterious aminoacid sequence alterations (appendix p 25). Except for BAP1, which was more prevalent in non-responders, no significant correlation could be established between clinical activity and genomic alterations data in the anetumab ravtansine group. Hence, further circulating tumour DNA analysis from patients in the vinorelbine group was not done.
The safety population comprised 163 patients treated with anetumab ravtansine and 72 patients treated with vinorelbine (table 3; a full list of all grade 3–5 adverse events in shown in the appendix, pp 13–20). Grade 3 or 4 treatment-emergent adverse events were observed in 78 (48%) of 163 patients in the anetumab ravtansine group and 53 (74%) of 72 patients in the vinorelbine group. The most common grade 3 or worse events were neutropenia (one [1%] of 163 patients in the anetumab ravtansine group vs 28 [39%] of 72 patients in the vinorelbine group), pneumonia (seven [4%] vs five [ 7%]), n eutrophil c ount decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Treatment-emergent deaths occurred in ten (6%) of 163 patients treated with anetumab ravtansine (pneumonia [n=3], sepsis [n=2], dyspnoea [n=2], atrial fibrillation [ n=1], g eneral p hysical h ealth d eterioration [n=1], hepatic failure [n=1], mesothelioma [n=1], and renal failure [n=1]; one patient had 3 events [hepatic failure, renal failure, and sepsis]) and one (1%) patient treated with vinorelbine (pneumonia). One of the two patients in the anetumab ravtansine group who developed sepsis leading to death was considered to be study drug related. None of the patients in the vinorelbine group were considered to have died due to a study drug-related treatment-emergent adverse event.
Table 3:
Treatment-emergent adverse events (by Medical Dictionary for Regulatory Activities preferred term) occurring in at least 10% of patients receiving anetumab ravtansine or vinorelbine
| Anetumab ravtansine (n=163) |
Vinorelbine (n=72) |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| Grade 1–2 | Grade 3 | Grade 4 | Grade 5 | Grade 1–2 | Grade 3 | Grade 4 | Grade 5 | ||
|
| |||||||||
| Anaemia | 12 (7%) | 3 (2%) | 0 | 0 | 15 (21%) | 5 (7%) | 0 | 0 | |
| Neutropenia | 3 (2%) | 0 | 1 (1%) | 0 | 9 (13%) | 16 (22%) | 12 (17%) | 0 | |
| Corneal disorder | 61 (37%) | 4 (2%) | 0 | 0 | 0 | 0 | 0 | 0 | |
| Dry eye | 22 (13%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Abdominal pain | 18 (11%) | 3 (2%) | 0 | 0 | 8 (11%) | 2 (3%) | 0 | 0 | |
| Constipation | 28 (17%) | 1 (1%) | 0 | 0 | 34 (47%) | 1 (1%) | 0 | 0 | |
| Diarrhoea | 52 (32%) | 4 (2%) | 0 | 0 | 14 (19%) | 1 (1%) | 0 | 0 | |
| Nausea | 68 (42%) | 0 | 0 | 0 | 24 (33%) | 0 | 0 | 0 | |
| Vomiting | 34 (21%) | 0 | 0 | 0 | 5 (7%) | 0 | 0 | 0 | |
| Asthenia | 26 (16%) | 7 (4%) | 0 | 0 | 15 (21%) | 1 (1%) | 0 | 0 | |
| Chest pain | 24 (15%) | 3 (2%) | 1 (1%) | 0 | 12 (17%) | 1 (1%) | 0 | 0 | |
| Fatigue | 53 (33%) | 7 (4%) | 0 | 0 | 18 (25%) | 4 (6%) | 0 | 0 | |
| Pyrexia | 23 (14%) | 1 (1%) | 0 | 0 | 13 (18%) | 1 (1%) | 0 | 0 | |
| Infusion-related reaction | 10 (6%) | 8 (5%) | 0 | 0 | 4 (6%) | 0 | 0 | 0 | |
| ALT increased | 11 (7%) | 9 (6%) | 0 | 0 | 5 (7%) | 1 (1%) | 0 | 0 | |
| AST increased | 18 (11%) | 3 (2%) | 0 | 0 | 3 (4%) | 1 (1%) | 0 | 0 | |
| Neutrophil count decreased | 1 (1%) | 2 (1%) | 0 | 0 | 6 (8%) | 9 (13%) | 3 (4%) | 0 | |
| Weight decreased | 16 (10%) | 1 (1%) | 0 | 0 | 8 (11%) | 0 | 0 | 0 | |
| White blood cell count decreased | 1 (1%) | 1 (1%) | 0 | 0 | 4 (6%) | 5 (7%) | 0 | 0 | |
| Decreased appetite | 54 (33%) | 3 (2%) | 0 | 0 | 15 (21%) | 2 (3%) | 0 | 0 | |
| Arthralgia | 19 (12%) | 0 | 0 | 0 | 3 (4%) | 0 | 0 | 0 | |
| Back pain | 10 (6%) | 1 (1%) | 0 | 0 | 8 (11%) | 1 (1%) | 0 | 0 | |
| Myalgia | 22 (13%) | 7 (4%) | 0 | 0 | 5 (7%) | 0 | 0 | 0 | |
| Neuropathy peripheral | 20 (12%) | 7 (4%) | 0 | 0 | 5 (7%) | 0 | 0 | 0 | |
| Peripheral sensory neuropathy | 16 (10%) | 4 (2%) | 0 | 0 | 0 | 0 | 0 | 0 | |
| Insomnia | 11 (7%) | 0 | 0 | 0 | 10 (14%) | 0 | 0 | 0 | |
| Cough | 21 (13%) | 0 | 0 | 0 | 10 (14%) | 1 (1%) | 0 | 0 | |
| Dyspnoea | 23 (14%) | 7 (4%) | 0 | 2 (1%) | 19 (26%) | 3 (4%) | 0 | 0 | |
Data are n (%). The data cut-off for safety analysis was April 6, 2018. Three (2%) patients in the anetumab ravtansine group and ten (12%) patients in the vinorelbine group never received study treatment and are not included here. ALT=alanine aminotransferase. AST=aspartate aminotransferase.
Serious treatment-emergent adverse events considered to be drug-related occurred in 12 (7%) of 163 patients in the anetumab ravtansine group and 11 (15%) of 72 patients in the vinorelbine group. The most common were infusion-related reactions for anetumab ravtansine (two [1%] of 163 patients), and for vinorelbine were neutropenia (two [3%] of 72 patients) and pneumonia (two [3%] of 72 patients). Treatment-emergent adverse events resulting in dose modifications occurred less frequently in the anetumab ravtansine group than the vinorelbine group (75 [46%] of 163 patients vs 58 [81%] of 72 patients). 37 (23%) of 163 patients in the anetumab ravtansine group and 37 (51%) of 72 patients in the vinorelbine group had dose reductions. Discontinuation due to treatment-emergent adverse events occurred more frequently in the anetumab ravtansine group than the vinorelbine group (45 [28%] of 163 patients vs 13 [18%] of 72 patients). All treatment-emergent adverse events leading to permanent treatment discontinuation are shown in the appendix (pp 9–12).
Discussion
To our knowledge, this is the first prospective, randomised, phase 2 study in patients with relapsed malignant pleural mesothelioma, which includes analyses stratified by mesothelin expression, and is the first clinical trial in malignant pleural mesothelioma to include analysis of plasma cell-free DNA by next-generation sequencing. Malignant pleural mesothelioma was selected as the first indication for anetumab ravtansine primarily due to high levels of mesothelin expression.12
The results of this study indicate that anetumab ravtansine was not superior to vinorelbine in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin who have progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab. Patients who had received previous treatment with immuno therapy drugs were not enrolled into the study. As this global phase 2 study had a registration-intent, an active-controlled vinorelbine treatment group was recommended by regulatory authorities. Vinorelbine is one of the recommended second-line therapies in the American Society of Clinical Oncology guidelines after first-line systemic treatment of malignant pleural mesothelioma.8 Progression-free survival was similar between anetumab ravtansine and vinorelbine (median 4·3 months vs 4·5 months). Furthermore, progression-free survival outcomes in both treatment groups were similar to median progression-free survival for vinorelbine plus active supportive care in the VIM study (4·2 months).10
As reported previously, MDASI-MPM is a reliable instrument for assessing the severity of symptoms of patients with malignant pleural mesothelioma.23 The results of our patient-reported outcomes analysis showed that anetumab ravtavsine was not superior to vinorelbine for these endpoints. Moreover, it was not superior in a prespecified secondary endpoint of median overall survival.
Consistent with previous results,15 median baseline plasma soluble mesothelin-related peptide level observed in this study (4·5 nmol/L [IQR 2·10–11·20]) was higher than the common diagnostic threshold (2·0 nmol/L) for malignant pleural mesothelioma.8 Although overall mesothelin expression levels were not associated with patients’ response to treatment, patients in the anetumab ravtansine group expressing higher levels of mesothelin (51–100%) had longer progression-free survival and overall survival than patients with lower mesothelin expression (30–50%). This effect was not observed in patients in the vinorelbine-treated group. This finding suggests that high mesothelin expression levels are not prognostic per se in malignant pleural mesothelioma but rather associated with anetumab ravtansine treatment, with differential expression of mesothelin potentially contributing to differing overall survival outcomes. By contrast, patients with higher baseline soluble mesothelin-related peptide levels did not have longer overall survival with anetumab ravtansine versus vinorelbine; higher baseline soluble mesothelin-related peptide levels were associated with shorter overall survival in both treatment groups. These findings suggest that tumours potentially shedding more soluble mesothelin-related peptides could be larger or more aggressive, since high soluble mesothelin-related peptide levels have previously been identified as a negative prognostic factor in patients with malignant pleural mesothelioma.24 However, the interpretation of data could be complicated by tumour heterogeneity, variety in tumour load, degree of soluble mesothelin-related peptides shedding, and immunohistochemistry results derived from a single lesion.
With appropriate management, anetumab ravtansine had a tolerable treatment-emergent adverse event profile. Although the incidence of treatment-emergent deaths was slightly increased with anetumab ravtansine versus vinorelbine (6% [ten patients] vs 1% [one patient]), only one event (sepsis) was considered to be related to anetumab ravtansine. Moreover, the anetumab ravtansine group had a lower occurrence of grade 3–4 treatment-emergent adverse events, and fewer treatment-emergent adverse events leading to dose modifications, suggesting that overall, anetumab ravtansine could potentially be more tolerable than vinorelbine.
Comprehensive genomic analysis has previously been done using malignant pleural mesothelioma tumour samples.17,25 The non-invasive liquid biopsy methods allow more direct and sensitive detection of tumour-associated genetic alterations in the plasma of patients with cancer.26 A previous study investigated genetic alterations in malignant pleural mesothelioma by analysing cell-free DNA using whole exome sequencing and detected limited numbers of mutations.27 However, until now, a comprehensive analysis of cell-free DNA by next-generation sequencing in phase 2/3 studies of patients with malignant pleural mesothelioma with well defined characteristics had not been done.
Our data suggest that cell-free DNA next-generation sequencing of plasma samples is feasible in malignant pleural mesothelioma. In patients with no confirmed partial response (non-responders) somatic mutations in BAP1 were detected. Somatic mutations in BRCA1 were also detected, mainly in non-responders. BRCA1 expression is regulated by BAP1, and BRCA1 is thought to regulate the spindle assembly checkpoint.16,28 A 2020 study provided insight into how BAP1 and BRCA1 mutations might confer resistance to anetumab ravtansine.16 By contrast with mesothelioma-derived wild-type BAP1 cell lines, BAP1 mutant cell lines appeared to have a defective spindle assembly checkpoint, continuing cell cycle progression following treatment with anetumab ravtansine.16 Although cell-free DNA analysis was not performed for vinorelbine-treated patients in this study, loss of BRCA1 has previously been established as a mediator of resistance to vinorelbine in patients with malignant pleural mesothelioma.29 A retrospective analysis also showed that BAP1 expression could correlate with response to vinorelbine through microtubule formation inhibition in mesothelioma,18 suggesting that BAP1 inactivation potentially confers resistance to vinorelbine. As the mechanisms of both anetumab ravtansine and vinorelbine involve microtubule inhibition,14,29 it is plausible that both drugs share common resistance mechanisms, which could underlie the similar clinical activity observed across treatment groups.
To our knowledge, this is one of the first and largest studies to date showing that plasma cell-free DNA can be detected and analysed in patients with relapsed malignant pleural mesothelioma. The mutations detected in this study are consistent with previously reported genomic alterations in malignant pleural mesothelioma tumour samples.17,25 However, somatic mutations were only detected in 51% of patients using a custom gene panel. Potential reasons for this low number of somatic mutations could be low mutational burden in malignant pleural mesothelioma and shedding only small quantities of cell-free DNA into the blood.17 Supporting this finding, cell-free DNA was only detectable in the plasma of 36% of patients with malignant pleural mesothelioma in a cohort study.30
In summary, although this phase 2 study showed no superiority of anetumab ravtansine over vinorelbine, post-hoc subgroup analyses suggested that mesothelin expression was associated with clinical activity. BAP1 somatic mutations were observed in patients with resistance to treatment with anetumab ravtansine. Although we did detailed genomic analysis of patient samples, we do not have a thorough understanding of why the study was negative and the further mechanisms of resistance to anetumab ravtansine are yet to be elucidated. Considering the number of mesothelin-expressing non-responders observed in the study, the identification and understanding of optimal biomarkers will be important for predicting sensitivity to anetumab ravtansine treatment in future malignant pleural mesothelioma studies.
Supplementary Material
Research in context.
Evidence before this study
We searched PubMed and abstracts from major oncology congresses from inception to Oct 13, 2021, for all clinical studies, in English, evaluating mesothelin-targeted therapeutics in patients with relapsed malignant pleural mesothelioma, primarily focusing on phase 2/3 trials of second-line treatment using search terms that included but were not limited to “mesothelioma” OR “mesothelin” OR “antimesothelin”. Mesothelin is a cell-surface glycoprotein with limited expression in normal human cells but high expression in many cancers, particularly in malignant pleural mesothelioma, and promotes cancer cell proliferation, local invasion, and metastasis, suggesting it could be a target for therapeutic intervention. There is no US Food and Drug Administration-approved standard of care for patients with malignant pleural mesothelioma who have progressed following platinum-pemetrexed-based therapy. Vinorelbine is recommended in the US American Society of Clinical Oncology guidelines as a second-line treatment option. In 2021, vinorelbine in combination with active supportive care showed significantly improved progression-free survival versus active supportive care alone in the phase 2 VIM trial. In 2021, after ARCS-M was completed, the phase 3 trial CONFIRM comparing nivolumab versus placebo was the first study ever to show improvement in both progression-free survival and overall survival in patients with relapsed malignant pleural mesothelioma. Phase 1 data have shown promising antitumour activity of anetumab ravtansine, a mesothelin-targeting antibody–drug conjugate, in patients with malignant pleural mesothelioma, warranting further investigation in phase 2 studies. BAP1 mutations correlated with shorter overall survival in vinorelbine-treated patients in a retrospective study and correlated with defective spindle assembly checkpoints following treatment with anetumab ravtansine in vitro.
Added value of this study
To our knowledge, this is the first clinical trial in relapsed malignant pleural mesothelioma including analysis of patients stratified by mesothelin expression and plasma cell-free DNA by next-generation sequencing to identify biomarkers of response or resistance to anetumab ravtansine. In this study, anetumab ravtansine was not superior to vinorelbine in terms of progression-free survival or overall survival in the second-line treatment setting for patients with mesothelin-expressing malignant pleural mesothelioma. Anetumab ravtansine had a manageable safety profile. A post-hoc analysis showed that BAP1 mutations were observed in patients who did not respond to anetumab ravtansine, potentially supporting the notion that BAP1 mutations confer resistance to spindle poisons.
Implications of all the available evidence
Further studies are warranted to define active treatments for patients with relapsed malignant pleural mesothelioma. Posthoc analyses suggested that plasma soluble mesothelin-related peptide and tissue mesothelin levels were associated with survival times in patients treated with anetumab ravtansine. Therefore, stratified therapy for malignant pleural mesothelioma might be feasible.
Acknowledgments
This study was funded by Bayer Healthcare Pharmaceuticals. We would like to thank the patients, their families, and all investigators involved in this study. We would also like to thank Andreas Schlicker and Georg Beckmann of Bayer AG (Berlin, Germany), and Steve Almond, Hamdi Chouikha, Hong Zheng, Cornelia Fulgenzi, Kiran Tottempudi, and Mary Koularmanis, all of Bayer Healthcare Pharmaceuticals (Whippany, NJ, USA) for their contributions to this study. Medical writing support was provided by Francesca Murphy, and editorial support was provided by Travis Taylor, both of Scion (London, UK) supported by Bayer Healthcare Pharmaceuticals.
Footnotes
Declarations of interests
HLK reports grants paid to the University of Chicago to support clinical trials for Aduro, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Harpoon, Inhibrx, MacroGenics, Merck, Polaris, Seattle Genetics, and Vivace; consulting fees from Bristol Myers Squibb, Deciphera, Inventiva, Novocure, and Seattle Genetics; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events for AstraZeneca; support for attending meetings, travel, or both from AstraZeneca and Inventiva; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Inventiva, and Seattle Genetics; and leadership or fiduciary role on board of directors for the International Mesothelioma Interest Group. SN reports personal payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Pfizer, Pharmamar, Roche, and Takeda; and personal fees for participation on a data safety monitoring board or advisory board from AstraZeneca, Bayer, Daiichi Sanko, Eli Lilly, Pfizer, Roche, Sanofi, and Takeda. AB reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Eli-Lilly, Pfizer, Roche, and Takeda; and support for attending meetings, travel, or both for Boehringer Ingelheim, Merck Sharp and Dohme, and Roche. GLC reports personal consulting fees for their advisory role for Novocure and Zai Lab; personal speaker engagements for Astellas, AstraZeneca, Merck Sharp and Dohme, Novocure, and Zai Lab; and support for attending meetings, travel, or both for Astellas, Novocure, and Merck Sharp and Dohme. JGJVA reports consulting fees for the advisory boards for Amphera, Bayer, Bristol Myers Squibb, Eli-Lilly, and Merck Sharp and Dohme; patents issued on allogenic tumour cell lysate and on combination immuno-oncology, owned by Erasmus MC Cancer Centre; participation on a data safety monitoring board or advisory board for Biocad; unpaid leadership role for the International Association for the Study of Lung Cancer; and stock or stock options for Amphera. JSp reports clinical trial reimbursement to Guy’s & St Thomas’ NHS Foundation Trust from Bayer, BergenBio, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, IO Biotech, Lytix, Seattle Genetics, and Starpharma; consulting fees paid to King’s College London from Apobec, AVACTA, Bristol Myers Squibb, IO Biotech, and Seattle Genetics; support for attending meetings, travel, or both from Amgen and Janssen; participation on a data safety monitoring board or advisory board for AstraZeneca and Merck; and stock or stock options (co-founder) for Epsilogen. PT reports fees for a symposium presentation from AstraZeneca; and a conference registration fee from AstraZeneca. KN reports personal fees for advisory boards from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Belgium, and Roche Belgium; personal fees for lectures from Roche Belgium; and support for attending meetings, travel, or both from AstraZeneca, Merck Sharpe and Dohme, and Pfizer. AG reports payment to Newcastle upon Tyne Hospitals NHS Foundation Trust for the care of patients on a study from Bayer (support for this manuscript). JAB reports institutional payment to the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital for support of investigator-initiated study from Merck Sharp and Dohme, consulting fees paid to the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital from Bristol Myers Squibb, and payment to the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital for participation on a data safety monitoring board or advisory board for Roche. AS reports consulting fees from ArQule and Sanofi; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Abbvie, Amgen, ArQule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Eli-Lilly, Gilead, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda; and participation on a data safety monitoring board or advisory board for Bayer, Bristol Myers Squibb, Eisai, Gilead, Merck Sharp and Dohme, Pfizer, and Servier. SC reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Merck Sharp and Dohme Oncology, and Pfizer; and support for attending meetings, travel, or both from Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Merck Sharp and Dohme Oncology, and Pfizer. JPVM reports consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Pfizer, and Roche; payment and reimbursement of expenses for services and consultancy from Amgen; registration fees from AstraZeneca, Merck Sharp and Dohme Belgium, Bristol Myers Squibb, GlaxoSmithKline, and Roche; and travel and accommodation support from AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme Belgium, and Roche. AKN reports personal fees for consulting for clinical trials, quality of life research, and tumour measurement from Bayer (support for this manuscript); grants or contracts to institution from AstraZeneca and Douglas Pharmaceuticals; consulting fees from Atara Biotherapeutics (personal), Pharmabcine (institutional), and Seagen (personal); personal payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Bristol Myers Squibb; travel support from AstraZeneca; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb (personal). GBJ reports personal grants or contracts from Adaptimmune, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Elelixis, Genentech, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, MedImmune, Merck, Novartis, Regeneron, Repertoire Immune Medicines, Roche, Tmunity Therapeutics, Torque, Verastem, and Xcovery; personal consulting fees for AbbVie, Adicet, Amgen, Ariad, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, Genentech, Gilead, Instil Bio, Janssen, Lilly, Maverick Therapeutics, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Viogin Biotech, and Xcovery; participation on a data safety monitoring board or advisory board for Maverick Therapeutics and Virogin Biotech (personal); and stock or stock options for Virogin Biotech. GBJ also has an immediate family member employed by Johnson and Johnson and Janssen. JSi is an employee of Bayer Healthcare Pharmaceuticals with ownership of stock; and reports unpaid leadership roles for the American Statistical Association, International Society for Clinical Biostatistics, and the Pharmaceutical Industry Working Group on Estimands in Oncology. LK is an external employee of Bayer Healthcare Pharmaceuticals. KK is an employee of Bayer AG Pharma with ownership of stock. AOW is an employee of Bayer AG Pharma. BHC and CE are employees of Bayer Healthcare Pharmaceuticals. RH reports institutional support for the conduct of this study via a Cooperative Research and Development Agreement (CRADA) between Bayer and the Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. He also has a CRADA with TCR2 for conduct of clinical studies unrelated to this manuscript. DAF reports grants from Astex Therapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp and Dohme; personal fees from Aldeyra, Atara, Bristol Myers Squibb, Inventiva, Lab21, Roche, RS Oncology, and Targovax; and non-financial support from Bristol Myers Squibb, Clovis, Eli-Lilly, and Roche. All other authors declare no competing interests.
Contributor Information
Hedy L Kindler, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
Silvia Novello, Department of Oncology, University of Turin, Orbassano, Turin, Italy.
Alessandra Bearz, Department of Medical Oncology and Immune-Related Cancers, CRO-IRCCS Centro di Riferimento Oncologico di Aviano, Aviano, Italy.
Giovanni L Ceresoli, Department of Medical Oncology, Oncology Unit, Cliniche Humanitas Gavazzeni, Bergamo, Italy.
Joachim G J V Aerts, Department of Pulmonary Medicine, Erasmus MC Cancer Centre, Rotterdam, Netherlands.
James Spicer, Comprehensive Cancer Centre, King’s College London, London, UK.
Paul Taylor, Department of Medical Oncology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
Kristiaan Nackaerts, Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, Universitair Ziekenhuis Leuven, KU Leuven, Leuven, Belgium.
Alastair Greystoke, Department of Medical Oncology, Northern Centre for Cancer Care, Newcastle upon Tyne, UK.
Ross Jennens, Epworth Cancer Services Clinical Institute, Epworth Healthcare, Richmond, VIC, Australia.
Luana Calabrò, Department of Oncology, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy.
Jacobus A Burgers, Department of Thoracic Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
Armando Santoro, Humanitas University, Milan, Italy; Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Milan, Italy.
Susana Cedrés, Department of Medical Oncology, University Hospital Vall d’Hebron, Barcelona, Spain.
Piotr Serwatowski, Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Santiago Ponce, Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Jan P Van Meerbeeck, Department of Thoracic Oncology, Antwerp University and University Hospital and European Reference Network for Rare or Low Prevalence Complex Disease (ERN-LUNG), Antwerp, Belgium.
Anna K Nowak, Medical School, University of Western Australia, Perth, WA, Australia; National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Perth, WA, Australia.
George Blumenschein, Jr, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jonathan M Siegel, Clinical Statistics Oncology, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
Linda Kasten, Statistics, Syneos Health Clinical Solutions, Morrisville, NC, USA.
Karl Köchert, Biomarker and Data Insights, Bayer AG Pharma, Berlin, Germany.
Annette O Walter, Translational Medicine Oncology, Bayer AG Pharma, Berlin, Germany.
Barrett H Childs, Oncology Development, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
Cem Elbi, Global Clinical Development, Oncology, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
Raffit Hassan, Department of Thoracic and GI Malignancies, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Dean A Fennell, Leicester Cancer Research Centre, University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, UK.
Data sharing
Availability of data underlying this study will be determined according to Bayer’s commitment to the EFPIA/PhRMA (principles for responsible clinical trial data sharing), which pertains to scope, timepoint, and process of data access. As such, Bayer commits to sharing, upon request from qualified scientific and medical researchers, patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the USA and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after Jan 1, 2014. Interested researchers can use Clinical Study Data Request to request access to anonymised patient-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsors section of the portal. Data access will be granted to anonymised patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.
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