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  • CFTRinh-172 Fig shows a possible first


    Fig. 1 shows a possible first-line treatment algorithm for advanced non-squamous NSCLC. The KEYNOTE-189 trial provided solid data for pembrolizumab plus pemetrexed/(cis)carboplatin demonstrating a significant PFS and OS benefit over ChT with a HR of 0.49 and a benefit consistency across all PD-L1 subgroups. Despite the longest PFS of all reviewed trials (8.8 months) KEYNOTE-189 showed a lack of PFS benefit in the subgroup of PD-L1 negative patients. A QoL analysis in KEYNOTE-189 showed an improved tolerability and better control of symptoms compared to ChT alone, despite a slightly higher incidence of grade 3–5 AEs in the investigational arm [29]. The occurrence of 1.7% nephritis and 5.2% of acute kidney injuries CFTRinh-172 urging caution in patient monitoring and potentially requesting treatment modification especially looking at a pemetrexed maintenance therapy. The same ChT regimen, pemetrexed/(cis)carboplatin, combined with atezolizumab showed a significant PFS benefit over ChT in the IMpower-132 trial with an HR of 0.60 with a consistent beneficial trend, irrespective of PD-L1 expression, age, smoking status and ethnicity (Asian vs. non-Asian). OS data were not mature and not statistically significant at the interim analysis (13.6 vs. 18.1 months) suggesting atezolizumab plus platinum based ChT as an additional possible treatment regimen. The IMpower-150 regimen (atezolizumab plus bevacizumab plus carboplatin/paclitaxel) showed PFS and OS superiority over bevacizumab plus carboplatin/paclitaxel with an ORR of 63.5%. The regimen showed a consistent trend of benefit across all PD-L1 levels as well as in patients with and without liver metastases. The IMpower-130 regimen (atezolizumab plus nab-paclitaxel/carboplatin) showed clear superiority in PFS despite a 20% rate of Pemetrexed switch maintenance therapy in the control arm. The PFS benefit was consistent across all PD-L1 predefined subgroups. The OS benefit did not reach statistical significance in all three PD-L1 strata, possibly due to high (59.2%) crossover from ChT to IO on progression. The results of several ongoing combination studies (CheckMate-9LA: [nivolumab/ipilimumab plus ChT], POSEIDON: [durvalumab/tremelimumab plus ChT]) [30,31] investigating two and four drug regimens of PD-(L)1 plus CTLA-4 inhibition +/- ChT are eagerly awaited and will reveal further knowledge of efficacy and tolerability in this setting. For fit patients with advanced squamous NSCLC and a PD-L1 expression of <50% pembrolizumab plus carboplatin/(nab)-paclitaxel is the IO-based frontline treatment with the most convincing evidence as investigated in the KEYNOTE-407 trial. The regimen demonstrated a PFS advantage with a HR of 0.56, a substantial OS benefit with a 36% risk reduction for death and an absolute benefit of 4.6 months compared to ChT alone. Importantly, the OS benefit was consistent in all subgroups, regardless of PD-L1 expression. On the basis of the results of the IMpower-131 study, atezolizumab plus carboplatin/(nab)-paclitaxel may be considered as an alternative treatment option. The addition of atezolizumab to ChT showed a significant PFS benefit with an HR of 0.71, however, the beneficial effect did not translate into a significant OS prolongation. In the subgroup with a PD-L1 expression of 1–49%, the treatment showed a detrimental effect with an unfavourable HR of 1.34, which is not fully understood. The results from KEYNOTE-407 and IMpower-131 study sound a note of caution that different CPIs might not be easily interchangeable. Furthermore, the individual development of anti-drug-antibodies (ADA) against CPI might explain variable outcomes and toxicity profiles by choosing different CPI. ADA might be able to alternate CPI’s pharmacokinetic in neutralizing the drug or enhance drug clearance. The issue with measuring ADA is the big difference in assay sensitivity which might influence the variable degrees of measured ADA prevalence for different CPI [32]. Similarly to non-squamous NSCLC patients, there might be a role for a front-line combination of ipilimumab plus nivolumab in the subset of squamous NSCLC patients with a high TMB (≥10 mut/Mb) as investigated in the CheckMate-227 study. These data are biologically plausible, however at the moment they remain preliminary and not robust enough (small patient number, secondary analysis) to draw definite conclusions or to give advisory suggestions. Fig. 2 shows a potential treatment algorithm for advanced squamous cell NSCLC patients.