Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Predictors of response and survival in a large cohort of 319 Waldenström macroglobulinemia patients treated with ibrutinib monotherapy

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (OR 0.2, 95% CI 0.1-0.5; p<0.001) and deep response (OR 0.3, 95% CI 0.2-0.6; p=0.001). CXCR4 mutations (HR 2.0, 95% CI 1.2-3.4; p=0.01) and platelet count 100 K/uL or less (HR 2.5, 95% CI 1.3-4.9; p=0.007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these two factors. The median PFS for patients with zero, one and two risk factors were not reached, 5 years and 3 years (p<0.001). Patients with two risk factors had HR 2.2 (95% CI 1.3-3.8; p=0.004) compared with one factor, and patients with one factor had HR 2.3 (95% CI 1.1-5.1; p=0.03) compared with zero factors. Age 65 years or older was the only factor associated with overall survival (HR 3.2, 95% CI 1.4-7.0; p=0.005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

Sex-Based Clinical Outcome in Advanced NSCLC Patients Undergoing PD-1/PD-L1 Inhibitor Therapy—A Retrospective Bi-Centric Cohort Study

Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n = 228) or ICI-CHT combination treatment (n = 80) for advanced NSCLC. Kaplan–Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10–3.29, p = 0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00–1.11, p = 0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32–3.15, p = 0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03–1.14, p = 0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41–11.2, p = 0.009) significant for PFS; and ECOG ≥ 2 (HR 5.58, 95%CI: 1.88–16.5, p = 0.002) and CRP (HR 1.19, 95%CI: 1.06–1.32, p = 0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, while ECOG ≥ 2 had a significant interaction with OS (HR 1.90, 95%CI 1.04–3.46, p = 0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02–1.16, p = 0.007) and OS (HR 1.11, 95%CI: 1.03–1.19, p = 0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.

Clinical and Functional Predictors of Response to a Comprehensive Pulmonary Rehabilitation in Severe Post-COVID-19 Patients

Background: Pulmonary rehabilitation (PR) following severe and very severe COVID-19 infection is known to be effective, according to typical assessments. However, not all patients benefit from PR to the same extent. This analysis aimed to identify the impact of different factors on PR outcomes in post-COVID-19 patients. Methods: This prospective observational study included 184 post-COVID-19 patients. The achievement of the predicted reference walking distance (6 min walking distance (6-MWD)) served as a parameter with which to identify responders and non-responders to PR. Several parameters (e.g., Functional Independent Measurement (FIM); pulmonary function testing (Forced Vital Capacity, FVC); 6MWD) were assessed in order to estimate their impact on PR success. Logistic regression models and classification and regression trees were used for multivariate analysis. Results: A total of 94 patients (51%) reached their reference 6MWD by the end of PR. FVC (0.95 (0.93–0.97)), 6MWD at admission (0.99 (0.99–1.00)), and FIM motoric (0.96 (0.93–0.99)) correlated with the risk not reaching the reference distance. The most important variable was the 6MWD at admission. Classification and regression tree identified 6MWD ≥ 130 m at admission and FVC predicted of >83% as the strongest predictor for reaching predicted 6-MWD. Conclusion: Post-COVID-19 patients with lower 6MWD, lower motoric FIM scores and lower FVC at admission have a high risk of not reaching their target values of physical performance despite intensive rehabilitation. As well as identifying them, it is of utmost importance to develop optimal PR concepts for these patients.