Editor’s Note: What follows is a summary of data presented during the Presidential Plenary at the 2023 World Conference on Lung Cancer. In the coming weeks, look for more in-depth coverage and analysis of the science from #WCLC23, including a look at the potential implications of MARS2, FLAURA2, and other potentially practice-changing studies.
Is it time to retire the concept of resectable mesothelioma?
The first direct comparison of pleurectomy decortication plus chemotherapy versus chemotherapy alone found that surgery increases the risk of death in the first 42 months by 28% (p=0.03). Adding surgery to chemotherapy also increases serious adverse events and decreases both median survival and quality of life, the data show.
“Stopping surgery would increase survival by 28% for our patients,” said Eric Lim, MB ChB, MD, consultant thoracic surgeon, The Royal Brompton Hospital, and Professor of Thoracic Surgery, Imperial College London, London.
Dr. Lim presented the results of Mesothelioma and Radical Surgery 2 (MARS 2), the first randomized trial to compare surgery plus chemotherapy to chemotherapy alone, on Monday, September 11, during the Presidential Plenary at the 2023 World Conference on Lung Cancer. The session can be viewed on-demand by registered WCLC attendees through December 31.
Mesothelioma is one of the most aggressive thoracic malignancies with a median survival of 9 to 12 months after diagnosis, Dr. Lim said. Global guidelines and consensus statements recommend surgery as an option in selected patients to remove all visible disease and improve survival in addition to chemotherapy.
Researchers in the UK randomized 169 patients to surgery plus chemotherapy and 166 patients to chemotherapy alone. All but one accruing center had been designated as expertise centers for mesothelioma surgery in the country. There was no difference in long term survival between the two groups, but the surgery group showed increased mortality during the first 42 months as well as increased treatment costs.
Surgery led to a 3.36-fold increased risk for serious adverse events (p<0.001) and reduced quality of life scores in global health, physical functioning, social functioning, and role functioning, according to the data. Surgery patients reported worse positive symptom scores including pain, dyspnea, insomnia, loss of appetite, and financial difficulties.
“Patients’ global quality of life was reduced following surgery in all measures at a higher cost compared to chemotherapy alone,” Dr. Lim said. “Classifying this disease as unresectable from the outset would increase access to more effective systemic treatments to improve survival for patients with other stages of disease.”
However, discussant Paula A. Ugalde, MD, Associate Thoracic Surgeon at Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, argued it is too early to retire the concept of resectable mesothelioma.
“The primary outcome of the study was overall survival and there was clearly no difference in survival between the two arms,” Dr. Uglade said.
Dr. Ugalde also questioned multiple aspects of the study design and its execution, including the staging of patients using only a chest CT scan. This may have been suboptimal, she said, as mediastinal staging with PET-CT scans or MRI may better identify patients suitable for this procedure.
Dr. Uglade also questioned the validity of R distinction assuming that in pleurectomy / decortication all resections are a priori, not radical.
Strong Results for Lung Cancer Screening Based on Family History
Initial data from the first national lung cancer screening program based on family history as a risk factor showed strong results. The Taiwan Early Detection Program for Lung Cancer showed a cancer detection rate of 1.4% based on a family history of lung cancer and 0.6% based on individual smoking history. Of the lung cancers detected based on family history, 89.4% were stage 0-1 compared to 71.2% of lung cancers detected based on individual smoking history.
“This early detection program is a significant step forward in the fight against lung cancer,” said Chi-Yen Huang, MD, PhD, of the Taiwan Ministry of Health and Welfare Health Promotion Administration, Taipei, Taiwan. “Expanding screening to those who have a family history of lung cancer but have never smoked offers hope for saving lives through early detection and improved treatment outcomes.”
The early detection program evolved from TALENT, the Taiwan Lung Cancer Screening for Never-Smoker Trial. TALENT demonstrated a lung cancer detection rate 1.6 times higher in those with a family history of lung cancer compared to heavy smokers.
The national early detection program targets 2 populations: non-smokers with a family history of lung cancer, including women aged 45–74 years and men aged 50–74 years; and smokers aged 50–74 with at least 30 pack-years who agree to quit smoking or have quit within the past 15 years.
A total of 49,808 individuals were screened during the first year of the program with 531 lung cancers detected, an overall detection rate of 1.1%. A total of 85.1% were stage 0-1.
“This is the first ever national screening program to invite relatives of people with lung cancer to be screened,” Dr. Huang said. “Our initial results suggest it will be a great help in detecting more lung cancers at an earlier stage if we can expand screening to more family members of those with lung cancer.”
Modified Classification System for Pulmonary Adenocarcinomas May Improve Diagnostic Accuracy
According to another study presented during the session, a modified approach to classifying adenocarcinomas that mimics real world conditions improves reproducibility and could improve diagnosis.
A case control study that included elastin and cytokeratin 7 staining to help identify tissue artifacts induced by surgery and pathology-processing changes showed improved agreement among 42 pathologists across 13 countries in identifying adenocarcinoma in situ compared to the standard World Health Organization (WHO) classification system.
“Our findings suggest that the modified adenocarcinoma classification significantly enhances reproducibility and aligns better with the clinical reality,” said Erik Thunnissen, MD, PhD, Amsterdam University Medical Center, Amsterdam. “These results open new avenues for refining our understanding of these cancers and improving patient care.”
The study grew out of the IASLC Pathology Committee’s finding that accurately assigning invasion status based on the WHO classification of pulmonary adenocarcinomas is challenging. Dr. Thunnissen and colleagues used 70 resected adenocarcinomas < 3 cm to establish a baseline using the WHO criteria to assess invasion and scored the same cases using modified criteria over three rounds of assessments.
The baseline kappa value was 0.27, showing poor consistency and reproducibility. After an hour of tutoring for the modified criteria, kappa values increased to 0.45. A third round after feedback showed a kappa of 0.62, indicating improved consistency and reproducibility.
Comparison of biopsies with patient outcomes showed 100% concurrence between a “no-invasion” consensus recurrence-free survival for patients. A diagnosis of adenocarcinoma in situ after resection using the modified criteria suggests a cure. A WHO criteria classification of invasive disease would leave the same patient with the anxiety of potential recurrence.
“Adenocarcinoma in situ is underdiagnosed,” Dr. Thunnissen said. “These findings could enable a more confident diagnosis and treatment decision for patients with pulmonary adenocarcinomas.”
Osimertinib + Chemotherapy Superior to Osimertinib Monotherapy
Interim results of the FLAURA2 trial comparing osimertinib plus chemotherapy to osimertinib monotherapy as first line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC) show clear benefits for combination therapy.
According to the data presented during the plenary, patients in the combination arm sustained a median progression free survival of 25.5 months versus 16.7 months for osimertinib alone per investigator and 29.4 months versus. 19.9 months per blinded independent central review (BICR) with a hazard ratio of 0.62 for both (p<0.0001 per investigator, p=0.0002 per BICR).
Overall survival data are immature and follow up is ongoing.
“These findings mark a significant advancement in the management of advanced EGFR-mutated NSCLC,” said presenter Pasi A. Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. Dr. Jänne is also the David M. Livingston, MD Chair and Director of the Belfer Center for Applied Cancer Science at Dana-Farber.
“FLAURA2 supports osimertinib combined with platinum-pemetrexed chemotherapy as a new and promising first-line treatment option, poised to make a profound impact on patient outcomes in this challenging disease setting.”
EGFR tyrosine kinase inhibitors (EGFR-TKI) are standard of care first line treatment for EGFR-mutated advanced NSCLC. But most patients eventually experience disease progression. CNS metastases and L858R mutations are associated with poor prognosis. Osimertinib is a third generation EGFR-TKI that is both CNS-active and active against mutated EGFR.
FLAURA2 was an open-label study that randomized 276 patients to osimertinib plus platinum-pemetrexed and 275 patients to osimertinib alone across 21 counties during the COVID pandemic.
Though all subgroups benefited from the combination therapy, patients with CNS metastases had a more pronounced benefit with the combination treatment, with a median PFS of 24.9 months versus 13.8 months respectively (HR=0.47) with CNS metastases and 27.6 months versus 21.0 months without (HR=0.75). Results were similar by EGFR mutation at baseline, HR=0.60 for Ex19del and HR=0.63 for L858R.
Safety profiles were as expected for both groups, Dr. Jänne reported, and manageable with standard medical practice. Common adverse events included anemia, diarrhea, and nausea. There were no common Grade 4 AEs in the monotherapy arm and all Grade 4 AEs in the combination arm were hematological toxicities known to be associated with chemotherapy.
An excellent trial, said discussant Yi-Long Wu, MD, PhD, Professor of Oncology at Guangdong Lung Cancer Institute, Guangdong, China. Though he said it is difficult to draw clinically useful conclusions so long as overall survival data remain immature.
“Should FLAURA2 become the standard of care for first-line treatment of EGFR-mutant advanced NSCLC?” he asked. “Not yet. We are still waiting for overall survival results. But TKI-chemotherapy may be an option for first-line treatment, and it should be an option for patients with brain metastases or exon 21 mutation in the first-line setting. We need a combination in the first-line setting, but we need a combination with more efficacy, less toxicity, and greater convenience for patients.”
