Linkage between Psychological Factors and Response to Immune Checkpoint Inhibitor Therapy: A Preliminary Study.

Substantial evidence has accumulated showing that psychological distress affects immune regulation, the response to cancer treatment, and survival. The effect of psychological parameters on the effectiveness of immune checkpoint inhibitor (ICI) treatment has not yet been studied. This preliminary study aimed to (a) examine the associations between psychological factors and responses to ICI treatment and (b) assess the associations between psychological factors and blood measures of sPD-1, sCTLA-4, and cytokines that may alter the effect of ICI treatment. The participants were 62 individuals with advanced cancer, aged 18 years or older, who were candidates for ICI treatment as a new line of treatment. The participants answered questionnaires and provided blood samples and medical data prior to the start of ICI treatment and 3 months after. Perceived health status was positively associated with better responses to ICI treatment. In the subsample of participants with biomarkers, worse health-related quality of life was associated with higher IL-6 and sCTLA-4; emotional distress and sleep difficulties were associated with higher sCTLA-4; and better perceived health was associated with lower IL-6 and TNFα. sPD-1 was not associated with psychological measures. This preliminary study found for the first time that some psychological measures could be linked to responses to cancer treatment, possibly via pro-inflammatory cytokines and sCTLA-4.

Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study.

PURPOSE: The treatment for unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT) followed by consolidation durvalumab. This study aimed to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field. METHODS AND MATERIALS: This investigation was a nonrandomized, open-label, single-arm, phase 2, prospective, proof-of-concept study. Eligible patients were classified as having treatment-naïve, nonoperable, stage III epidermal growth factor receptor-mutant NSCLC. Patients received 80 mg of oral osimertinib daily for 12 weeks before definitive radiation therapy (RT) and/or surgery. The response was assessed at weeks 6 and 12. For responders, sequential definitive RT and/or surgery were planned. Nonresponders were started on standard CRT. After RT ± surgery or CRT, patients were followed for 2 years without adjuvant therapy. The primary endpoint was the objective response rate (ORR), with September 20, 2022, set as the cut-off for data collection. Secondary endpoints were safety and the gross tumor volume (GTV), planned tumor volume (PTV), and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before versus after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumor-free DNA (ctDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT. RESULTS: Twenty-four patients were included (19 women; median age, 73 years; range, 51-82 years). Nineteen of 24 had never smoked, 20 of 24 had adenocarcinoma, 16 of 24 had exon 19 deletions, and 8 of 24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (1 dropped out and 2 were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response, 3 complete response, and 1 progressive disease). After induction osimertinib, 13 of 20 patients were definitively radiated, 3 of 20 underwent surgery, and 5 of 20 were excluded. Four patients were restaged as stage IV (contralateral ground-glass opacities responded to osimertinib), and 1 patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathologic complete response. The median GTV, PTV, and V20% before osimertinib treatment were 47.4 ± 76.9 cm3 (13.5-234.9), 227.0 ± 258.8 cm3 (77.8-929.2), and 27.1 ± 16.4% (6.2-60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm3 (2.99-137.7; -48 ± 20%; P = .02), 181.9 ±198.4 cm3 (54-718.1; -31 ± 20%; P = .01), and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; P = .04), respectively. PTV/GTV/V20% reduction was associated with tumor size and central location. The median follow-up time was 28.71 months (range, 0.4-45.1 months), and median disease-free survival was not reached (mean, 30.59; standard error, 3.94; 95% confidence interval, 22.86-38.31). ctDNA was detected in 5 patients; 4 of 5 were positive for ctDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were ctDNA negative at baseline became weakly positive after RT and then were negative at follow-up. No significant adverse events were reported during the osimertinib or radiation phases. CONCLUSIONS: Neoadjuvant osimertinib therapy is feasible in patients with stage III lung cancer NSCLC, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks before definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumor size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal-epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48-91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47-69), whereas it was 68% (95% CI, 50-82) in treatment-naïve and 50% (95% CI, 35-65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7-14.3), whereas it was 10.6 months (95% CI, 5.5-15.7) in first-line and 9.1 months (95% CI, 3.1-15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2-23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17-77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

Osimertinib in advanced EGFR-mutant lung adenocarcinoma with asymptomatic brain metastases: an open-label, 3-arm, phase II pilot study.

BACKGROUND: Osimertinib is selective for both epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported. METHODS: In this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naive (arm A = 20) or previously treated with an EGFR-TKI and Thr790Met positive (arm B = 18) or negative (arm C = 10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression-free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513. RESULTS: The iORRs were 84.2%, 66.7%, and 50% and the iDCRs were 94.7%, 94.4%, and 80% in arms A, B, and C, respectively. The median iPFS was 11.8 months (95% CI 7.7 to NA), 7.6 months (95% CI 5.3 to NA), and 6.3 months (95% CI 3.9 to NA) in arms A, B, and C, respectively. Following dose escalation, pooled iORR was 54% (arm A = 5, arm B = 4, arm C = 2). Adverse events were similar to those in previously published literature. CONCLUSION: Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and -negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

Long term follow-up of EGFR mutated NSCLC cases.

PURPOSE: A substantial fraction of all non-small cell lung cancers(NSCLC) carry a mutation in the EGFR gene for which an effective treatment with anti-tyrosine kinases(TKIs) is available. We studied the long term survival of these patients following the introduction of TKIs. EXPERIMENTAL DESIGN: All consecutive cases of NSCLC newly diagnosed with advanced disease were referred for free tumor EGFR mutation testing at Clalit's national personalized medicine laboratory. Mutations and deletions in target codons 18-21 of EGFR were sought using RT-PCR and fragment analysis. Comprehensive EMRs were used to collect full data on treatments and clinical status. RESULTS: A cohort of 3,062 advanced NSCLC cases, included 481(15.7%) somatic EGFR mutation carriers (17.5% of all adenocarcinomas, 26.7% of females with adenocarcinomas). TKIs treatment to EGFR mutation carriers was provided to 85% of all eligible. After a median follow up period of 15.9 months for EGFR mutated cases the hazard ratio for overall survival of EGFR-mutated NSCLC treated with TKIs was 0.55(0.49-0.63, p<0.0001) when compared with EGFR wild-type(WT) tumors under usual care. After adjusting for age, sex, ethnicity, smoking history and tumor histology, all of which had an independently significant effect on survival, the HR for TKI-treated, EGFR-mutated tumors, was 0.63 (0.55-0.71, p<0.0001). Treating EGFR-WT cases with TKIs yielded a high HR=1.32 (1.19-1.48). CONCLUSIONS: TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years. Squamous histology, smoking, male sex and Arab ethnicity were associated with higher NSCLC mortality hazard. Treating non-EGFR-mutated NSCLC with TKIs seems detrimental. Statement of Significance: • TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years but not much longer. • Treating non-EGFR-mutated NSCLC with TKIs seems detrimental and should probably be avoided. • Squamous histology of non-small cell lung cancer, smoking history, male sex and Arab ethnicity were associated with altogether higher NSCLC mortality hazard.

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases.

BACKGROUND: Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood-brain barrier compared with previous EGFR-TKIs, and thus, a 52% reduction in the risk of intracranial disease progression is seen when it is used as a first line of therapy compared with gefitinib and erlotinib. It is also efficient as second-line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report 11 patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either first- or second-line setting. METHODS: This is a subcohort analysis from a larger nonrandomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 mg to 160 mg in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) patients with intracranial progression in either first- (arm A) or second-line setting (arm B for T790M+ and C for T790M-). RESULTS: Eleven patients, 5 in arm A, 4 in arm B, and 2 in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4 ± 8.9 (6.6-30.7) months for arm A, 8.7 ± 1.8 (6.3-11.2) for arm B, and 14.5 ± 7.8 (6.7-22.3) for arm C. Intracranial response rate to dose escalation was 54% (6 of 11) with 2 of 11 having intracranial stability. Median iPFS was 4.3 ± 7.4 (0.7-25.5) months; 3.8 ± 6.4 (1.8-18.9), 5.6 ± 9.7 (0.7-25.5), and 7.0 ± 2.7 (4.3-9.6) for arms A/B/C, respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose-limiting symptoms. CONCLUSIONS: Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80 mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.