The study investigated the safety, efficacy, and pharmacokinetics of alflutinib (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily) in 130 patients with EGFR T790M positive advanced NSCLC, which progressed following first- or second-generation EGFR tyrosine kinase inhibitor therapy. Seventy-nine patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. The overall objective response rate in dose-expansion (40–240 mg) was 76.7% (70.6% in patients with central nervous system metastases). Possible treatment-related adverse events (AEs) were reported in 79% of all patients, with treatment-related grade 3 or higher AEs in 8%. No clear dose-response relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. In summary, alflutinib was clinically effective with acceptable toxicity profile in study patient population, warranting further studies to confirm the results.
To improve characterization of transitional mesothelioma (TM) subtypes [epithelioid (EM), biphasic (BM) or sarcomatoid (SM)], randomly selected 49 representative digitalized sections from surgical biopsies were analyzed by 16 pathologists on morphological, immunohistochemical, and molecular aspects. Comprehensive integrated transcriptomic analysis and unsupervised deep learning algorithm were applied in the study. The panelists recorded 784 diagnoses, with the presence of a TM component in 51% of the cases. The lesion was classified as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 was less frequent in TM versus EM and BM while p16 homozygous deletion was higher in TM versus BM and SM (73%, 63% and 46%, respectively). TM was closer to SM than to EM based on RNA sequencing unsupervised clustering analysis. TM identification could achieve a 94% accuracy using deep learning analysis. To conclude, the findings suggest that TM pattern in non-epithelioid mesothelioma should be classified at minimum as a subgroup of SM type.
The authors assessed the use of RNA next-generation sequencing (NGS) in identifying gene fusions and exon-skipping events in patients with no driver mutation detected by DNA NGS. A cohort of stage IV NSCLC cases from both in-house and referral hospitals consisting 38.5% cytology samples and 61.5% microdissected histology samples were analyzed. Molecular profiles were compared between a parallel workup of DNA NGS and RNA NGS (cohort 1, n = 198) and a sequential workup of DNA NGS followed by RNA NGS (cohort 2, n = 192). The results demonstrated that sequential workup is the most efficient approach in detecting mutation and fusion in smoking-associated NSCLC because it drastically reduced the number of unnecessary diagnostic steps and the accompanying costs, as additional RNA NGS was necessary in only 53% of all cases. The parallel workup is recommended for never-smokers, whose tumors were enriched for fusions and exon-skipping events, because the workup has a shorter median turnaround time (9 days versus 15 days) and RNA NGS has a much higher yield. Combination of DNA NGS and RNA NGS was shown to be feasible on small tissue samples including for cytology tests, can drastically reduce the complexity and cost of molecular workup, and also provides flexibility in the constantly evolving landscape of actionable targets in NSCLC.
Several COVID-19 cases present with mild upper respiratory symptoms or are asymptomatic, leading to undetected transmission of the SARS-CoV-2 virus. There is an urgent need to assess body site-specific virus replication and infectivity. In this study, the authors analyzed virulence and infectivity of nine hospitalized COVID-19 cases. There were no discernible differences in oro- versus naso-pharyngeal viral loads. The average viral load from swabs until day 5 from symptom onset was 6.78 x 105 copies/swab. After day 5, swabs had an average viral load of 3.44 x 105 copies/swab and a 39.93% detection rate. The last positive swab was seen on day 28 from symptom onset. Average viral load in sputum was 7.00 x 106 copies/ml. While the authors successfully isolated live virus during the first week of symptoms (16.66% in swabs, 83.33% in sputum), no live virus isolates were obtained from samples taken after day 8 despite concomitant high viral loads. All urine and serum samples tested negative for SARS-CoV-2 RNA, and virus isolation from stool samples was unsuccessful regardless of viral RNA concentration in stool samples. The authors also conducted RT-PCR to identify viral subgenomic messenger RNA to assess actively infected cells and found evidence of active viral replication in throat swabs during the first 5 days after symptom onset and up to 10 days in sputum. On sequencing full viral genomes from all patients, they discovered separate genotypes in throat swabs and sputum suggesting independent virus replication in the throat instead of passive shedding from the lung. The decline in RNA concentrations was slower in sputum samples than swabs. Seroconversion as detected by IgM and IgG immunofluorescence was seen in 50% patients by day 7 and in all patients by day 14. Strikingly, no viruses were isolated after day 7 but viral detection outlasted symptom duration. In conclusion, this study shows that viral shedding can continue even after symptom resolution and seroconversion, and that adequate surveillance and isolation procedures must be kept in place for recovering patients.
Reference: Wölfel, R. et al. Virological assessment of hospitalized patients with COVID-2019. Nature https://doi.org/10.1038/s41586-020-2196-x (2020).
Although radiographic screening has shown to reduce cancer related mortality, only a minority of eligible adults get screened. This may be overcome by readily available blood-based screening. In this study, Chabon et al describe a sequencing methodology called cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze circulating tumor DNA (ctDNA) to facilitate screening. They genotyped tumor tissue, plasma cfDNA and leukocyte DNA from early stage NSCLC patients, low-risk controls and risk-matched controls using a 255 gene targeted sequencing panel. They identified a strong association between pre-treatment ctDNA levels and clinical outcomes. They discovered that most somatic mutations in the cfDNA of lung cancer patients and risk-matched controls reflect clonal hematopoiesis and are non-recurrent. They also developed a machine-learning method called ‘lung cancer likelihood in plasma’ (Lung-CLiP) to discriminate early-stage lung cancer patients from risk matched controls. The integration of single nucleotide variants (SNVs) and genome-wide copy number alterations (CNAs) from plasma cfDNA and matched leukocyte DNA, with machine-learning models helps provide a ‘Lung-CLiP score’ that estimates the likelihood of lung-cancer derived cfDNA in a blood sample. Lung-CLiP scores correlated well with tumor-informed ctDNA levels (Spearman r = 0.59; p=0.00011) and achieved similar performance as tumor-informed ctDNA analysis. The performance of Lung-CLiP was prospectively validated in 46 early-stage NSCLC patients and risk-matched controls that were enrolled at an independent institution. In conclusion, the authors propose that integrating Lung-CLiP with low dose CT scan could further improve performance and increase screening rates.
Reference: Chabon, J.J., Hamilton, E.G., Kurtz, D.M. et al. Integrating genomic features for non-invasive early lung cancer detection. Nature 580, 245–251 (2020).
Recently various studies have evaluated the use of oral anticoagulant for cancer-related venous thromboembolism. Rivaroxaban and edoxaban have been approved for this indication although their use is limited by increase in risk of bleeding. In this trial (Caravaggio trial), investigators tried to evaluate the efficacy and safety of apixaban for the treatment of cancer-associated venous thromboembolism. Over 26 months period, 1170 patients were recruited from 119 centers. All patients had symptomatic or incidentally detected proximal lower limb deep venous thrombus or pulmonary artery thrombus with active cancer diagnosed in the past six months. Patients were randomized to two group in 1:1 ratio. The control group was given daily dalteparin subcutaneous injection, whereas the intervention arm received oral apixaban. The primary outcome was confirmed recurrent venous thromboembolism, whereas clinically significant overt bleeding was the primary safety outcome. Of the 1170 patients, randomized 1155 patients were included in the modified intention-to-treat analysis. Among results, it was observed that recurrent venous thromboembolism was diagnosed in 5.6% of the patients in the apixaban group and 7.9% of the patients in Dalteparin group (p<0.0001, for non-inferiority). At the same time, major bleeding was noted in 3.8% of the apixaban group and 4% in the dalteparin group. Sites of bleeding did not differ among the two groups. The incidence of clinically relevant non-major bleeding was non-significantly higher in the apixaban group as compared to the dalteparin group (9.0% versus 6.0%). Death rates were similar in the two groups. Combined assessment of the primary endpoints (recurrent venous thromboembolism and/or significant bleeding) was also similar in both groups. It was concluded that apixaban is non-inferior to subcutaneous dalteparin for the treatment of recurrent venous thromboembolism associated with cancer. This trial adds to the evidence that oral anticoagulants have similar efficacy and safety profile for the treatment of cancer-associated venous thromboembolism as that of parenteral anticoagulants.
Reference: Agnelli G, Becattini C, Meyer G, Munoz A, Huisman MV, Connors JM, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. The New England journal of medicine. 2020. https://doi.org/10.1056/NEJMoa1915103.
Radiotherapy is one of the cornerstones for the management of locally advanced non-small cell lung cancer (NSCLC). The efficacy and safety of radiotherapy is derived from the precision of its delivery, which is further dependent on the selection of target volume. In this study, Nestle et al. tried to evaluate 18F-FDG PET-based treatment planning versus standard treatment in patients with locally advanced NSCLC. It was an open-label, multicenter, randomized controlled trial where subjects with stage II or III NSCLC, were recruited from various centers. Patients were randomized into two groups, one was the conventional target group, and other was 18F-FDG PET-based target group. In 18F-FDG PET-based target group, gross tumor volume was expanded into all directions by 2 mm, and all PET-positive or histopathologically proven mediastinal lymph nodes were included. Whereas in the conventional target group, the gross tumor volume was expanded up to 3 cm to include tumor-associated atelectasis. In addition, mediastinal lymph nodes with size > 1 cm were also included for irradiation. The primary outcome was time to loco-regional progression, and secondary endpoints were time to out-of-field progression and time to in-field progression. Out of 205 patients who were randomly assigned to the two groups, 171 were included in the per-protocol analysis. Over a period of 6.8 weeks, an escalated dose of 60 to 74 Gy was prescribed. In results, it was found that mean escalated dose of total radiotherapy was significantly higher in the 18F-FDG PET-based target group, whereas gross tumor volume was also higher in the same group. Cumulative incidence of loco-regional progression of tumor was higher in the conventional target group as compared to the 18F-FDG PET-based target group, as per per-protocol analysis (HR 0.57 (95% CI 0.30-1.06). Progression-free survival and overall survival were similar in the two groups. Similarly, the risk for out-of-field recurrence was similar in the two groups. Overall treatment-related toxicities were generally mild to moderate and similar in the two groups. Secondary endpoints were similar in the two groups. Authors concluded that imaging-based reduction in target volumes is feasible and non-inferior to conventional target volume planned. Further, quality assured 18F-FDG PET-based target volume reduction might lead to improved local control without any increased toxicity.
Reference: Nestle U, Schimek-Jasch T, Kremp S, Schaefer-Schuler A, Mix M, Kusters A, et al. Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomized, controlled trial. The Lancet Oncology. 2020;21(4):581-92.
On March 27, 2020, the US Food and Drug Administration (FDA) approved durvalumab in combination with etoposide- and platinum-based chemotherapy for first-line treatment of extensive stage small cell lung cancer. This combination was studied in the phase 3 randomized, multicenter, active-controlled, open-label CASPIAN trial (NCT03043872). Patients were randomized to receive chemotherapy alone or chemotherapy plus durvalumab or chemotherapy plus durvalumab plus tremelimumab. The primary endpoint of the study was overall survival. Median overall survival with durvalumab plus chemotherapy was 13 months compared with 10.3 months for chemotherapy alone (hazard ratio 0.73; 95% CI: 0.59, 0.91; p=0.0047). Median progression free survival was 5.1 months in the durvalumab plus chemotherapy on and 5.4 months in the chemotherapy alone. Overall response rate was 68% in the durvalumab plus chemotherapy arm and 58% in the chemotherapy alone. Results from the durvalumab and tremelimumab plus chemotherapy arm are awaited. The recommended durvalumab dose is 1500 mg every 3 weeks with a platinum agent and etoposide followed by 1500 mg every 4 weeks as a single agent.
On April 3, 2020, the National Institute of Health and Care Excellence (NICE) of the United Kingdom released guidelines on the use of lorlatinib in previously treated advanced ALK-positive NSCLC. Lorlatinib is recommended as an option for treating ALK-positive advanced NSCLC in adults whose disease has progressed after alectinib or ceritinib as the first ALK TKI or after crizotinib and at least one other ALK TKI. While lorlatinib has not been directly compared to other drugs, the committee based its recommendation on indirect comparisons between lorlatinib and chemotherapy. Clinical evidence supporting this approval came from the single-arm phase I/II trial of lorlatinib in ALK-positive metastatic NSCLC. Pooled results of 139 patients from cohorts EXP-3B, EXP-4, EXP-5 were used for this authorization. The results showed an overall response rate of 40.3% (95% CI: 32.1, 48.9), median PFS of 6.9 months (95% CI: 5.4,8,2) and median OS of 20.4 months (95% CI: 5.4, 8.2) with lorlatinib. Indirect comparisons were uncertain but suggest that lorlatinib results in longer progression free survival than platinum doublet chemotherapy or quadruplet therapy with atezolizumab, bevacizumab, carboplatin and paclitaxel. The committee acknowledged that more than 50% of patients with ALK-positive NSCLC develop brain metastases and that lorlatinib’s intracranial activity may improve quality of life and survival for these patients. Lorlatinib meets NICE’s criteria to be considered a life-extending treatment at the end of life.
Recently a study published in Thorax Journal, revealed that a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) increases the risk of having lung cancer as high as smoking. In this study 338,548 Korean citizens who had undergone at least one health checkup over a period from 2002 to 2013, were included. Over a follow up of more than 2.3 million patient years it was found that 1834 participants developed lung cancer with an incidence rate of 4.9 per 1000 person years among COPD patients. The calculated hazard ratio was 2.67 among never-smokers who had COPD whereas the hazard ratio for smokers without COPD was 1.97. It was also reflected among smokers-with-COPD group where the hazard ratio was exponentially high (6.19). In spite of having technical limitation, researcher were able to conclude that COPD, in itself, is a strong and independent predictor of developing lung cancer. This study can have significant future implications as COPD increases the morbidity of lung cancer and restricts the use of treatment modalities like surgery. Early screening and diagnosis of lung cancer especially among COPD patients, irrespective of smoking status, may add to survival advantage.
Park HY, Kang D, Shin SH, Yoo K-H, Rhee CK, Suh GY, et al. Chronic obstructive pulmonary disease and lung cancer incidence in never smokers: a cohort study. Thorax. 2020:thoraxjnl-2019-213732.