One of the major limitations of tissue
One of the major limitations of tissue based biomarkers in lung cancer is that about 30% of all patients have inadequate tumor tissue for biomarker testing . Blood based TMB (bTMB) is a non-invasive biomarker with the potential to independently predict clinical benefit. Blood based TMB has been prospectively evaluated in the phase 2 B-F1RST trial and has shown its benefit as a predictive marker for front-line single agent atezolizumab in advanced NSCLC . Patients with a high (score ≥16) bTMB achieved a significantly higher ORR than patients with a low (score <16) bTMB (28.6% vs. 4.4%; P < 0.0002). Furthermore, bTMB high patients showed a non-significant trend for longer PFS (4.6 vs. 3.7 months, HR, 0.66; 90% CI 0.42–1.02) and OS (NR vs. 13.1 months, HR, 0.77; 90% CI, 0.41–1.43) compared to bTMB low patients. Results from the B-FAST trial, where patients with high bTMB are randomized to front-line atezolizumab or platinum-based ChT will shed more light on the predictive potential of bTMB .
Bringing all active agents to the front-line Talaporfin sodium (ME2906) the challenge of finding active subsequent treatments. To date, there is very little understanding of the mechanisms of immune-resistance at relapse. Salvage regimens like docetaxel +/- antiangiogenics, gemcitabine or vinorelbine show limited efficacy. Re-introducing a platinum-based ChT after a longer period of IO maintenance could to be a reasonable treatment approach. Combining IO with immune-stimulating cytokines to overcome immune resistance is part of ongoing research [48,49].
Author contribution Christoph Ackermann Fabrice Barlesi Raffaele Califano Martin Reck Luis Paz-Ares
Introduction Lung cancer (LC) is the most common cancer worldwide with an estimated 2+ million newly diagnosed cases annually . Despite the decreasing incidence of mortality, LC accounts for more than 1.2 million deaths annually, with an age-standardized 5-year net survival rate of only 10–20% . There are two main types of LC: small cell lung cancer (SCLC) and non-SCLC (NSCLC). NSCLC accounts for approximately 85% of all LC cases . Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are administered as the first-line treatment for patients with advanced EGFR mutation-positive NSCLC. The frequency of EGFR mutations in NSCLC is greater in Asian vs. Caucasian populations (up to 50–60% vs. ˜10%, respectively) [, , ]. Clinical trials comparing first-generation EGFR-TKIs (gefitinib and erlotinib) with platinum-based first-line chemotherapy in common EGFR mutation-positive NSCLC unequivocally showed that the use of EGFR-TKIs improved the primary endpoint of progression-free survival (PFS) as compared to chemotherapy (9.2–13.1 vs. 4.6–6.3 months, respectively) and were better tolerated [, , ]. However, none of the first-generation TKI trials reported a benefit in overall survival (OS). The lack of an OS benefit for first-generation TKIs was confirmed in a meta-analysis of six trials that compared PFS and OS in patients with exon 21 and exon 19 EGFR mutation-positive NSCLC . Additionally, some patients discontinued EGFR-TKI treatment because of the development of adverse events. Switching EGFR-TKI treatments because of adverse events is an effective option for patients with EGFR mutation-positive NSCLC . Afatinib is a second-generation EGFR-TKI with excellent therapeutic effects. Particularly, of the many EGFR-TKIs, the use of afatinib leads to acquired resistance to EGFR-TKIs due to minor mutations to alleles of EGFR . Afatinib showed an OS benefit in comparison with first-line chemotherapy in the LUX-Lung 3 and 6 trials . In a pre-specified subgroup analysis of exon 19 EGFR mutation-positive NSCLC patients, a significant and clinically relevant median OS benefit of 12.2 and 13 months (LUX-Lung 3 and 6, respectively) was demonstrated with the use of afatinib [14,15]. This benefit was observed in both trials and in both Caucasian and Asian populations, as well as in a Japanese subgroup, despite a cross-over rate from chemotherapy to TKI of 100% . Furthermore, Ezeife et al. reported the efficacy of afatinib rechallenge in heavily pretreated patients with advanced NSCLC . However, many cases require a dose reduction from the standard prescription dose of 40 mg/day [17,18]. Especially, many Japanese patients require dose reductions due to severe side effects . However, there are no reports about the cause of this inter-ethnic difference.