Daily Respiratory Research Analysis
Three studies stand out today: a preplanned phase 3 analysis shows serum VEGF-A can identify metastatic NSCLC patients who benefit from adding bevacizumab to chemo-immunotherapy; a nationwide Rwandan study demonstrates that Xpert MTB/RIF Ultra yields a high rate of false rifampicin resistance in very low bacillary-load samples, calling for confirmatory testing; and a multicenter single-arm trial (CRES) reports strong 3-year survival with S-1+cisplatin chemoradiation followed by surgery for super
Summary
Three studies stand out today: a preplanned phase 3 analysis shows serum VEGF-A can identify metastatic NSCLC patients who benefit from adding bevacizumab to chemo-immunotherapy; a nationwide Rwandan study demonstrates that Xpert MTB/RIF Ultra yields a high rate of false rifampicin resistance in very low bacillary-load samples, calling for confirmatory testing; and a multicenter single-arm trial (CRES) reports strong 3-year survival with S-1+cisplatin chemoradiation followed by surgery for superior sulcus lung cancer.
Research Themes
- Biomarker-guided precision therapy in lung cancer
- Diagnostic stewardship for drug-resistant tuberculosis
- Optimization of trimodality treatment for superior sulcus lung cancer
Selected Articles
1. Serum VEGF-A as a biomarker for the addition of bevacizumab to chemo-immunotherapy in metastatic NSCLC.
In a preplanned biomarker analysis within a phase 3 trial (APPLE), baseline serum VEGF-A (and isoforms) measured by ELISA identified metastatic nonsquamous NSCLC patients who derived significant PFS benefit from adding bevacizumab to atezolizumab plus platinum chemotherapy. The work supports serum VEGF-A as a practical predictive biomarker for tailoring anti-VEGF use with chemo-immunotherapy.
Impact: Provides a clinically actionable biomarker to personalize bevacizumab use with chemo-immunotherapy in metastatic NSCLC, potentially improving outcomes and minimizing toxicity/costs.
Clinical Implications: Consider baseline serum VEGF-A testing to guide adding bevacizumab to atezolizumab plus platinum chemotherapy; patients with low VEGF-A appear to gain PFS benefit. Validation and cutoff standardization are needed before routine adoption.
Key Findings
- Baseline low serum VEGF-A identified patients with significant PFS benefit from adding bevacizumab to atezolizumab + platinum chemotherapy.
- VEGF-A and its isoforms can be quantified via ELISA, enabling practical implementation.
- Preplanned analysis within a phase 3 RCT supports VEGF-A as a predictive (not merely prognostic) biomarker for anti-VEGF add-on.
Methodological Strengths
- Preplanned biomarker analysis embedded in a phase 3 randomized trial
- Standardized ELISA measurements at baseline with clinically relevant endpoint (PFS)
Limitations
- Biomarker groups were not randomized; potential residual confounding
- Findings derived from a single trial dataset without external validation or prespecified universal cutoffs
Future Directions: Conduct prospective biomarker-enriched or biomarker-stratified RCTs, define and validate universal VEGF-A/isoform cutoffs, and assess cost-effectiveness and OS benefit.
Anti-vascular endothelial growth factor (VEGF) agents in combination with immunotherapies have improved outcomes for cancer patients, but predictive biomarkers have not been elucidated. We report here a preplanned analysis in the previously reported APPLE study, a phase 3 trial evaluating the efficacy of the bevacizumab in combination with atezolizumab, plus platinum chemotherapy in metastatic, nonsquamous non-small cell lung cancer (NSCLC). We investigated the correlation of serum VEGF-A and its isoforms at baseline with treatment response by using an enzyme-linked immunosorbent assay. We reveal that the addition of bevacizumab significantly improves the progression-free survival in patients with the low VEGF-A level. Our results demonstrate that measuring serum VEGF-A or its isoforms may identify NSCLC patients who are likely to benefit from the addition of bevacizumab to immunotherapy. These assays are easy to measure and have significant potential for further clinical development.
2. Paucibacillary Tuberculosis Drives the Low Positive Predictive Value of Xpert MTB/RIF Ultra for Rifampicin Resistance Detection in Low-Prevalence Settings.
In Rwanda, only 32% of Xpert Ultra RR-TB calls were confirmed on repeat testing; among samples with very low bacillary load, 89% of RR calls were false, yielding substantial overtreatment. Programs should confirm RR-TB detected at very low bacillary load (e.g., via repeat Ultra, rpoB sequencing, or pDST) and adjust algorithms accordingly.
Impact: Directly informs global TB diagnostic algorithms to prevent unnecessary RR-TB treatment when Ultra indicates resistance at very low bacillary load.
Clinical Implications: When Ultra reports rifampicin resistance with very low bacillary load, require confirmatory testing before initiating RR-TB regimens. Implement repeat Ultra and, where feasible, rpoB sequencing and pDST to improve PPV.
Key Findings
- Only 32% (41/129) of initial Ultra RR-TB calls were concordant on repeat Ultra testing.
- Among 'very low' bacillary load samples, 89% had false RR results (risk ratio 8.20; 95% CI 3.56–18.85).
- Overall, 53% (54/101) of patients with reference testing received unnecessary RR-TB treatment due to false resistance calls.
Methodological Strengths
- Nationwide real-world cohort with repeat Ultra plus rpoB sequencing and phenotypic DST as reference
- Quantified effect of bacillary load categories on false resistance risk
Limitations
- Reference testing was not available for all unconfirmed cases, introducing potential verification bias
- Single-country setting may limit generalizability to other epidemiologic contexts
Future Directions: Develop and validate diagnostic algorithms that incorporate bacillary load thresholds to trigger confirmatory testing; assess cost-effectiveness and patient outcomes of revised workflows.
BACKGROUND: Xpert MTB/RIF Ultra (Ultra) aimed to improve the specificity in identifying rifampicin-resistant tuberculosis (RR-TB), compared to Xpert MTB/RIF. METHODS: In a nationwide study in Rwanda, patients diagnosed with RR-TB by Ultra between December 2021 and January 2024 underwent repeat Ultra testing, complemented by rpoB gene sequencing and phenotypic drug-susceptibility testing (pDST), serving as reference tests. RESULTS: Of 129 patients initially diagnosed with RR-TB by Ultra, only 41 (32%) had concordant rifampicin results upon repeat Ultra testing. The remaining 88 patients (68%) had unconfirmed resistance on repeat Ultra. Reference testing was available for 40 (98%) of 41 confirmed cases, all verified as true RR-TB. Among 88 unconfirmed cases, reference testing was available for 61 (69%), with 7 (11%) confirmed as true RR-TB, whereas 54 (89%) were found to have rifampicin-susceptible TB. Notably, 89% of 55 patients with very low bacillary loads on their initial Ultra had false RR-TB results, a significantly higher risk of false resistance compared to other bacillary load categories combined (risk ratio: 8.20; 95% confidence interval [CI]: 3.56-18.85; P < .001). Consequently, 53% (54/101) of initial RR patients with available reference testing received unnecessary RR-TB treatment. CONCLUSIONS: Ultra represents a valuable tool for rapid RR-TB detection; however, in low prevalence settings its low positive predictive value for RR detection is largely driven by samples with very low bacillary loads. As programs expand active case-finding and early detection of asymptomatic disease, the proportion of TB detected with very low bacillary load will increase. Diagnostic algorithms require adjustments to prevent unnecessary RR-TB treatment.
3. CRES
In the multicenter single-arm CRES trial for superior sulcus NSCLC, induction S-1+cisplatin with concurrent 66 Gy radiotherapy followed by surgery achieved ORR 42%, pCR 33%, and 3-year OS/PFS of 73.2%/53.3%. Local control was excellent, with relapse dominated by distant metastases, supporting this trimodality approach as a potential standard.
Impact: Provides confirmatory multicenter data supporting a specific induction CRT regimen (S-1+cisplatin, 66 Gy) plus surgery for superior sulcus NSCLC with high 3-year survival.
Clinical Implications: For fit patients with superior sulcus NSCLC, consider induction S-1+cisplatin with concurrent 66 Gy radiotherapy followed by surgery. Vigilance for distant relapse is warranted, suggesting a role for optimized systemic therapy and surveillance.
Key Findings
- Objective response rate 42% and pathological complete response rate 33% after S-1+cisplatin CRT followed by surgery.
- Three-year overall survival 73.2% and progression-free survival 53.3%.
- Relapses were predominantly distant metastases; treatment-related deaths occurred in two during induction (pneumonia) and one postoperative (cardiac arrest).
Methodological Strengths
- Multicenter confirmatory design with standardized radical-dose radiotherapy (66 Gy)
- Use of hard clinical endpoints including pCR, OS, and PFS
Limitations
- Single-arm design without randomized comparator limits causal inference
- Generalizability beyond participating centers and populations requires caution
Future Directions: Compare this regimen against other induction CRT backbones in randomized trials; evaluate systemic therapy intensification or consolidation to reduce distant relapse.
PURPOSE: This multicenter single-arm confirmatory trial (CRES METHODS: Patients received induction therapy comprising three cycles of S-1 + cisplatin with concurrent radiotherapy (66 Gy in 33 fractions) followed by surgery. S-1 was administered orally at 40 mg/m RESULTS: Sixty-one patients with a superior sulcus non-small cell lung cancer received induction therapy. Radiological tumor invasion sites were the chest wall (n = 57), subclavian artery (n = 18), and subclavian vein (n = 10). Forty-nine patients underwent a lobectomy and combined resection of the involved structures. The objective and pathological complete response rates were 42 % (95 % confidence interval: 29-54 %) and 33 % (95 % confidence interval: 20-46 %), respectively. The 3-year overall survival and progression-free survival rates were 73.2 % (95 % confidence interval: 60.1-82.7 %) and 53.3 % (95 % confidence interval: 40.0-65.0 %), respectively. The patterns of first tumor relapse were locoregional only in one, distant metastasis only in 18, and both in four patients. Two pneumonia cases during induction therapy and one cardiac-arrest case on postoperative day 3 resulted in death. CONCLUSIONS: Induction therapy using S-1 + cisplatin and concurrent radical-dose radiotherapy followed by surgery maximized local control and improved overall survival without impairing safety, potentially representing a new standard treatment.