CONFERENCE UPDATE: WCLC 2020
Lung cancer in the evolving field of precision medicine
According to Dr. David Gandara, University of California Davis, Comprehensive Cancer Center, United States, the requisites for implementing precision medicine are: i) the ability to profile tumors for biomarkers, ii) having drugs against these biomarker targets, and iii) having clinical trial designs that characterize the drug activity.
Currently, precision medicine is not perceived as universally successful. Apart from BRCA gene testing for breast cancer, only a few cancer-related genes have diagnostic or prognostic values.1 However, non-small cell lung cancer (NSCLC) is an exception that is found to have genomicallydefined histologic subsets, including adenocarcinoma and squamous cell carcinoma, through next-generation sequencing (NGS).2 As such, the National Comprehensive Cancer Network (NCCN) NSCLC Guidelines Panel now strongly recommends broader molecular profiling to identify rare NSCLC driver mutations for which effective drugs may already be available, and encourages patients to participate in clinical trials for best disease management.3 Particularly for advanced NSCLC, testing for 8 oncogene drivers is recommended as these drivers can be targeted by the currently available medications.3
In addition to driver mutations, NSCLC biomarker studies have evolved from testing clinical-histologic factors to single genes, then multiplex molecules, and finally high throughput NGS of the entire genomes, exomes or transcriptomes for drug selection.2 Compared with other high throughput tumor profiling methods such as hotspot panels or exclusionary sequential testing, NGS testing is more cost-effective with a faster turnaround time.4 However, NGS of tumor biopsy is not always feasible due to tissue availability and adequacy. In these cases, plasma circulating tumor DNA (ctDNA) genotyping in parallel might be useful for treatment selection.
Apart from tumor genotyping, immune phenotyping through biomarker measurement also helps assess the potential benefit of receiving checkpoint immunotherapy. An example of an effective, predictive biomarker is the programmed death ligand-1 (PD-L1), its high expression (specifically 50% or greater), indicates a survival benefit from receiving immune checkpoint single or combination therapy. Nevertheless, Dr. Gandara pointed out that PD-L1 is an incomplete biomarker, and that patients with no PD-L1 expression may still experience survival benefit from checkpoint immunotherapy.
On the other hand, tumor mutational burden (TMB) is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. However, the lack of harmonization in panel-based TMB quantification, adequate methods to convert TMB estimates across different panels and robust predictive cut-offs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice.5 Other biomarkers associated with checkpoint immunotherapy efficacy in NSCLC also include gene expression signature and tumor infiltration lymphocytes. However, these biomarkers are quantified continuously, but not discreetly, and the combination of these biomarkers is only useful for adding predictive value.
While successful tumor profiling has to be complemented by robust clinical trial design, which is challenging or infeasible.6 As many mutations are rare, occurring in only 5-15% of patients, a large number of patients have to be screened at multiple centres to accrue sufficient participants, and they have to wait for several weeks with a small chance of participating in the study at the end.6 To address these unmet needs, biomarker-driven master protocols were conceived to investigate multiple therapies matched to biomarkers within a single clinical trial infrastructure aiming to accelerate the drug testing and approval process.6
The S1400 Lung-MAP Master Protocol is one such study that included a screening component for NGS and a clinical trial component with biomarker-driven substudies or non-match substudies for patients who were ineligible.6 Combining data from the substudies, 7% of patients responded to targeted therapy, 16.8% responded to anti-PD-1 or anti- PD-L1 therapy for immunotherapy-naïve disease and 5.4% responded to docetaxel in the second-line therapy setting.6 From the results, the Lung-MAP study demonstrated that a biomarker-driven master protocol is feasible in an aggressive disease setting and can serve as an infrastructure to efficiently evaluate the activity of targeted therapies in rare disease populations.6 Through rapid evaluation, all targets evaluated by Lung-MAP, with the exception of MET, have received regulatory approval for drugs in class.6 While Lung-MAP has yet to identify new treatment biomarkers, it has prevented prolonged evaluation of ineffective drug targets that are already identified in lung cancer.6
In conclusion, cancer patients, especially those with NSCLC, should receive broad molecular profiling to identify oncogene driver mutations and select the best treatment option. When applying precision medicine to NSCLC, Dr. Gandara added, “We now have commercially available NGS-based testing that is both specific and sensitive…that enables community oncologists to [obtain results] in a timely fashion.”
Confirmed OS benefits of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA NSCLC patients: The ADAURA trial
The ADAURA trial was a randomized, double-blind, placebo-controlled, phase 3 study that evaluated the survival benefits of adjuvant osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in the treatment of patients with completely resected EGFR-mutated stage IB-IIIA non-small cell lung cancer (NSCLC).1 A total of 682 adult patients with completely resected stage IB, II, IIIA NSCLC were recruited and randomized 1:1 to receive either osimertinib 80mg daily or placebo for 3 years until disease recurrence or treatment completion.1 The primary endpoint of the ADAURA trial was disease-free survival (DFS) in stage II-IIIA patients.1 Overall survival (OS) is one of the key secondary endpoints of the ADAURA trial.1
Sotorasib demonstrates consistent clinical benefits in KRAS G12C-mutation advanced NSCLC regardless of genomic co-alterations: Subgroup analysis of CodeBreaK 200
The CodeBreaK 200 trial was the first randomized, phase 3 trial that compared the efficacy between sotorasib and docetaxel in patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-mutated advanced non-small cell lung cancer (NSCLC).1 A cohort of 345 adults with locally a
Multidisciplinary MTB-guided treatment improves survival outcomes of patients with heavily pretreated advanced solid tumors
A recent study, conducted by the Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong (HKUMed) and the Division of Clinical Pathology & Molecular Pathology, Hong Kong Sanatorium & Hospital (HKSH), has shown that patients with heavily pretreated advanced solid tumors and who had undergone treatment guided by the multidisciplinary molecular tumor board (MTB) exhibited a significantly longer overall survival (OS) than those who were treated with non-MTB-guided therapy.1
Adjuvant osimertinib and multidisciplinary-team approach in early-stage NSCLC management: A local case sharing
Non-small cell lung cancer (NSCLC) accounts for 85%of all types of lung cancer and is the most common cancer in Hong Kong with a total of 5,575 cases in 2019.1,2 Approximately 30% of NSCLC patients are diagnosed as early stage, and surgical resection is the preferred treatment option for possibly co
NIVO + chemo improves EFS in patients with resectable IB-IIIA NSCLC: the phase 3 CheckMate 816 trial
Improving long-term survival in patients with resectable non-small cell lung cancer (NSCLC) is still essential, despite advancements in the adjuvant therapies.1 The CheckMate 816 trial previously demonstrated a significant improvement in the pathologic complete response (pCR) with neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) compared with chemo alone in patients with resectable NSCLC, and maintained a good tolerability profile.1 As a result, this regimen has currently gained approval from the United States for the treatment of adult patients with resectable NSCLC.1
The potential new first-line mNSCLC treatment regardless of PD-L1: Durvalumab + tremelimumab + chemotherapy improved survival
Over the past decades, treatment options in advanced non-small cell lung cancer (NSCLC) patients without oncogenic drivers have been limited to cytotoxic chemotherapies with poor survival outcomes.1 Although patients’ overall survival (OS) has been prolonged with the current standard of care (SoC) (i.e. pembrolizumab with or without chemotherapy) in recent years, the clinical outcomes are still suboptimal.2,3 Dual immunotherapy, which brought substantial survival improvements across multiple malignancies such as advanced melanoma, sheds light on the further advance of metastatic NSCLC (without driver mutations) management.4 The combination of nivolumab (NIVO) and ipilimumab (IPI) with or without chemotherapy has demonstrated superior survival benefits in these patients, leading to the regulatory approval from the United States (US) Food and Drug Administration (FDA).5,6 More recently, the efficacy of durvalumab and tremelimumab plus chemotherapy (D + T + CT) in treatment-naïve metastatic NSCLC patients has also been evaluated in the POSEIDON trial.7 In a webinar organized by the Hong Kong Precision Oncology Society, Dr. Melissa L. Johnson presented the encouraging data from POSEIDON and discussed the latest advances of immunotherapy in metastatic NSCLC. Dr. Au, Siu-Kie Joseph also shared his expert insights on the new POSEIDON data and discussed their impacts on the local clinical practice in an interview with Omnihealth Practice.
DFS improvement with atezolizumab versus BSC after adjuvant chemotherapy: Phase 3 IMpower010 trial
Adjuvant chemotherapy is a standard of care after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC).1 The phase 3 IMpower010 trial aimed to evaluate adjuvant atezolizumab (anti-programmed death-ligand 1 (PD-L1)] versus best supportive care (BSC) after adjuvant platinum-based chemotherapy in patients with completely resected NSCLC, at the disease-free survival (DFS) interim analysis.2 The study randomized 1,005 people with a ratio of 1:1 to receive adjuvant atezolizumab (1,200mg every 21 days; for 16 cycles or 1 year) or BSC following surgical resection (4-12 weeks prior) and up to 4 cycles of adjuvant cisplatin-based chemotherapy.2 The possible impact on DFS and types of surgery therapies prior to adjuvant atezolizumab were also examined. DFS was presented by disease stage and nodal status (NO vs. N1 vs. N2).3
Monitoring biomarkers in non-small cell lung cancer patients treated with immune checkpoint inhibitors
The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the approach to advanced non-small cell lung cancer (NSCLC) by offering durable disease control with less side effects than traditional chemotherapy.1 However, as most patients do not benefit from ICIs, it is important to ide
A next generation ALK inhibitor: Clinical findings of brigatinib against crizotinib in ALK+ NSCLC from ALTA-1L
The potent and orally available anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, had successfully demonstrated activity and efficacy against non-small cell lung cancer (NSCLC) in patients who are refractory or could not tolerate crizotinib.1,2