Predictive markers of response to immune checkpoint inhibitor rechallenge in metastatic non-small cell lung cancer.

Aim: The present study aims to evaluate the efficacy of rechallenge with immune checkpoint inhibitors (ICIs) compared to chemotherapy and the predictive role of clinical parameters in non-small cell lung cancer (NSCLC) patients who were rechallenged. Methods: The study included 113 metastatic NSCLC patients who had initially responded to ICIs and platinum-based chemotherapy, either in combination in the first line or sequentially in the first and second line, but later experienced disease progression. Of those patients, 52 later received ICI rechallenge and 61 were exposed to chemotherapy. Results: In the rechallenge cohort, the median age was 67 years, 38 patients were men (73.1%), 26 (50.0%) had squamous cell carcinoma. Patients who underwent ICI rechallenge had longer overall survival (OS) compared to those who received chemotherapy (12.9 months vs. 9.6 months, P = 0.008). Multivariate analysis for progression-free survival (PFS) and OS revealed that poor Eastern Cooperative Oncology Group Performance Status (ECOG PS; PFS: P = 0.013 and OS: P = 0.037), absence of objective response during initial ICI therapy (PFS: P = 0.014 and OS: P = 0.028), and baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P = 0.001 and OS: P = 0.003) were negative predictive factors of ICI rechallenge. The three parameters were included in a risk model named as the NEO score, which stratified patients who received ICI rechallenge into two predictive groups. Patients with ECOG PS 0-1, objective response during initial ICI treatment, and NLR < 3.8 (favorable group) had longer PFS (8.6 months vs. 3.0 months, P < 0.001) and OS (16.6 months vs. 5.5 months, P < 0.001) compared to those with absence of all three markers (poor group). There was no association between the NEO score and survival outcomes in patients who did not undergo rechallenge. Conclusions: ICI rechallenge showed a survival benefit, particularly in NSCLC patients with NLR < 3.8, good ECOG PS, and objective response.

Clinical predictors of response to single­agent immune checkpoint inhibitors in chemotherapy­pretreated non­small cell lung cancer.

Single-agent immune checkpoint inhibitors (ICIs) are the standard option for chemotherapy-pretreated metastatic non-small cell lung cancer (NSCLC), however only a subset of patients responds to this treatment. The present study aimed at the development of a tool for personalized prediction of the efficacy of ICIs. The study included 181 epidermal growth factor receptor/anaplastic lymphoma kinase-negative patients with metastatic NSCLC receiving single-agent ICI in the second or later line of therapy. For the comparison, a total of 63 metastatic patients with NSCLC treated by chemotherapy were also analyzed. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, never-smoking status and the baseline neutrophil-to-lymphocyte ratio (NLR) ≥4.3 were associated with reduced progression-free survival (PFS) and overall survival (OS) [ECOG PS: Hazard ratio (HR)=2.09; P=0.028 and HR=2.02; P=0.035, respectively; never-smoking: HR=3.53; P=0.007 and HR=1.80; P=0.004, respectively; NLR ≥4.3: HR=4.34; P<0.0001 and HR=4.89; P<0.0001 respectively]. Patients with an NLR <4.3, who had a favorable ECOG PS (0-1) and smoking history in the past, derived the utmost benefit from ICI [n=77; objective response rate (ORR)=35%; PFS and OS: 17.1 and 33.7 months, respectively]. The worst efficacy of ICI was observed in patients who had an NLR ≥4.3 coupled with poor ECOG PS and/or never-smoking status (n=38; ORR=8%; PFS=3.2 months and OS=7.2 months). The remaining patients belonged to the group with intermediate outcomes (n=66; ORR=17%; PFS and OS: 4.3 and 12.2 months, respectively). While combination of these factors was highly predictive for ICIs, it was not associated with outcomes of chemotherapy treatment. Easily available characteristics of the patients allow for highly accurate predictions of outcomes of single-agent ICI therapy in chemotherapy-pretreated NSCLC.

Inflammatory and autoimmune predictive markers of response to anti-PD-1/PD-L1 therapy in NSCLC and melanoma.

Immune checkpoint inhibitors (ICI) are a standard in cancer therapy, but few patients respond to the treatment. The aim of the present study was the determination of immunological markers for monitoring response to ICI. The present study included 74 patients receiving ICI in subsequent [group 1; non-small cell lung cancer (NSCLC)] and first-line setting (group 2; melanoma) and 30 patients with NSCLC receiving first-line chemotherapy. In groups 1 and 2 ß-2 microglobulin (B2-MG), neopterin (NPT), IL-6, IL-18, HLA-DRB1 and autoantibodies were assessed after two months of ICI, and before the start of next administration in group 3. In group 1 low level of B2-MG (P<0.0001), NPT (P<0.0001), IL-6 (P<0.0001), IL-18 (P=0.0003), HLA-DRB1*03 (P=0.016) and anti-TPO antibodies (P=0.016) were associated with response >six months. In group 2 high level of B2-MG (P=0.0001), NPT (P=0.0016), IL-6 (P=0.013) and IL-18 (P=0.032) were associated with early disease progression (

Efficacy of lorlatinib in lung carcinomas carrying distinct ALK translocation variants: The results of a single-center study.

BACKGROUND: Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use. METHODS: This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 (n = 5), 1 (n = 26) or none (n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program. RESULTS: Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared to the remaining patients (1.1 months vs. 23.7 months and 10.5 months vs. not reached, respectively; p < 0.0001 for both comparisons). ALK translocation variants were known for 28 patients; there was no statistical difference between patients with V.1 and V.3 rearrangements with regard to the OS or PFS. CONCLUSION: Use of lorlatinib results in excellent disease outcomes, however caution must be taken for patients experiencing no adverse effects from this drug.

Variability in lung cancer response to ALK inhibitors cannot be explained by the diversity of ALK fusion variants.

Multiple laboratory evidences indicate that distinct variants of ALK translocations differ in their biochemical properties and responsiveness to ALK tyrosine kinase inhibitors (TKIs). These data are supported by some clinical studies, which showed improved responses to crizotinib in non-small cell lung cancer (NSCLC) patients carrying particular variants of ALK translocation. We retrospectively considered 64 Russian patients with ALK-rearranged NSCLC, who were treated by crizotinib (n = 23), ceritinib (n = 39) or alectinib (n = 2). ALK fusion variants were genotyped by PCR. Median progression-free survival (PFS) approached to 18 and 21 months in subjects with "short" (v.3a/b, v.5a/b) vs. "long" (TAPE-domain containing) fusion variants (p = 0.783), respectively; similar data were obtained while comparing EML4/ALK variant 1 vs. other ALK translocations (19 and 21 months, respectively; p = 0.604). Objective response rates were also strikingly similar in the above groups ("short": 88%, "long": 77%, p = 0.479; variant 1: 76%, other translocations: 81%, p = 0.753). Furthermore, ALK variants did not influence the disease outcomes when patients treated by crizotinib and ceritinib were analyzed separately. Overall, PFS on ALK TKI did not depend on whether the drug was administered upfront or after chemotherapy. Ceritinib produced significantly longer PFS than crizotinib (p = 0.022). In conclusion, this study revealed that distinct ALK translocation variants render similar clinical responsiveness to ALK inhibitors.