Circulating tumor DNA (ctDNA) is an approved noninvasive biomarker to test for the presence of EGFR mutations at diagnosis or recurrence of lung cancer. However, studies evaluating ctDNA as a noninvasive “real-time” biomarker to provide prognostic and predictive information in treatment monitoring have given inconsistent results, mainly due to methodological differences. We have recently validated a next-generation sequencing (NGS) approach to detect ctDNA. Using this new approach, we evaluated the clinical usefulness of ctDNA monitoring in a prospective observational series of patients with non-small cell lung cancer (NSCLC). We recruited 124 patients with newly diagnosed advanced NSCLC for ctDNA monitoring. The primary objective was to analyze the prognostic value of baseline ctDNA on overall survival. ctDNA was assessed by ultra-deep targeted NGS using our dedicated variant caller algorithm. Common mutations were validated by digital PCR. Out of the 109 patients with at least one follow-up marker mutation, plasma samples were contributive at baseline (n = 105), at first evaluation (n = 85), and at tumor progression (n = 66). We found that the presence of ctDNA at baseline was an independent marker of poor prognosis, with a median overall survival of 13.6 versus 21.5 mo (adjusted hazard ratio [HR] 1.82, 95% CI 1.01–3.55, p = 0.045) and a median progression-free survival of 4.9 versus 10.4 mo (adjusted HR 2.14, 95% CI 1.30–3.67, p = 0.002). It was also related to the presence of bone and liver metastasis. At first evaluation (E1) after treatment initiation, residual ctDNA was an early predictor of treatment benefit as judged by best radiological response and progression-free survival. Finally, negative ctDNA at E1 was associated with overall survival independently of Response Evaluation Criteria in Solid Tumors (RECIST) (HR 3.27, 95% CI 1.66–6.40, p < 0.001). Study population heterogeneity, over-representation of EGFR-mutated patients, and heterogeneous treatment types might limit the conclusions of this study, which require future validation in independent populations. In this study of patients with newly diagnosed NSCLC, we found that ctDNA detection using targeted NGS was associated with poor prognosis. The heterogeneity of lung cancer molecular alterations, particularly at time of progression, impairs the ability of individual gene testing to accurately detect ctDNA in unselected patients. Further investigations are needed to evaluate the clinical impact of earlier evaluation times at 1 or 2 wk. Supporting clinical decisions, such as early treatment switching based on ctDNA positivity at first evaluation, will require dedicated interventional studies.

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

Standard treatment of high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor is intravesical instillation with Bacillus Calmette-Guérin (BCG) (induction and maintenance regimens); however, BCG therapy still fails in 30%-40% of patients. Prior studies suggest that programmed death-ligand 1 (PD-L1) expression and alterations in immune infiltration might be associated with BCG failure. The ALBAN trial is an international, 1 : 1 randomized, open-label phase III trial comparing the combination of atezolizumab (an anti-PD-L1 antibody) and BCG (arm B) versus BCG alone (arm A) for BCG-naive patients with high-risk NMIBC. The primary endpoint was investigator-assessed event-free survival (EFS). Key secondary endpoints included high-grade recurrence-free survival, complete response rate, and duration of response in patients with carcinoma in situ disease, as well as overall survival. In total, 255 patients were randomly assigned to arm A and 262 to arm B. The trial did not meet its primary endpoint; there was no significant difference in EFS between arms, with a hazard ratio of 0.98 (95% confidence interval 0.71-1.36, P = 0.9106). EFS results were consistent across all prespecified subgroups. The safety profile of the treatment combination was consistent with that of the individual agents but showed higher rates of treatment-related adverse events (TRAEs) and grade ≥3 TRAEs than BCG alone. This phase III trial in BCG-naive patients with high-risk NMIBC did not demonstrate an EFS benefit from the addition of atezolizumab to 1-year BCG therapy, in contrast to positive EFS results reported with another PD-(L)1 agent, suggesting that any benefit from checkpoint-BCG therapy may be context- and agent-specific rather than a class effect. Future research should focus on biomarker-driven patient selection and optimization of the timing, duration, and route of checkpoint delivery relative to BCG.

Background As the population ages and cancer therapies improve, there is an increased call for elderly cancer patients to be admitted to the intensive care unit (ICU). This study aimed to assess short-term survival and prognostic factors in critically ill patients with solid tumors aged ≥65 years. Methods We conducted a retrospective study. The primary endpoint was ICU mortality. Resumption of anticancer therapy in patients who survived the ICU stay and 90-day mortality were secondary endpoints. All patients aged ≥65 years admitted to the ICU of Georges Pompidou Hospital (Paris, France) between 2009 and 2014 were eligible. Results Of 2327 eligible elderly patients (EP), 262 (75.0 ± 6.7 years) with solid tumors were analyzed. These patients were extremely critically ill (SAPS 2 61.9 ± 22.5), and 60.3% had metastatic disease. Gastrointestinal, lung and genitourinary cancers were the most common types of tumors. Mechanical ventilation was required in 51.5% of patients, inotropes in 48.1% and dialysis in 12.6%. Most patients (66.7%) were admitted for reasons unrelated to cancer, including sepsis (30.5%), acute respiratory failure (28.2%) and neurological problems (8.0%). ICU mortality in patients with cancer was 33.6 versus 32.6% among patients without cancer (p = 0.75). Among the cancer EP, the 90-day mortality was 51.9% (n = 136). In multivariate analysis, increased SAPS 2 score and primary tumor site were associated with 90-day death, whereas previous anticancer therapies and poor performance status were not. Among survivor patients from ICU with anti-tumoral treatment indication, 77 (52.7%) had resumption of anticancer treatment. Conclusions Elderly solid tumor patients admitted to the ICU had a mortality rate similar to EP without cancer. Prognostic factors for 90-day mortality were more related to severity of clinical status at admission than the presence or stage of cancer, suggesting that early admission of EP with cancer to the ICU is appropriate.

Introduction: Sunitinib is a multi-target, anti-angiogenic tyrosine kinase inhibitor and a key molecule in the treatment of metastatic renal cell carcinoma (mRCC). Since it first demonstrated its efficacy ten years ago, overall survival of mRCC has more than doubled, in part due to sunitinib. In most recent years, progress has been made in the comprehension of its mechanism of action and resistance. Areas Covered: In this article, clinical trials involving sunitinib in kidney cancer have been reviewed, defining its different indications in metastatic and localized RCC. The rationale of sunitinib’s efficacy, preclinical trials, past-clinical trials and ongoing clinical trials are summarized. Dose and scheme base are discussed, as the recommended dosage is frequently not well tolerated. Combination therapies appear to be toxic. Novel immunotherapies are changing the landscape of mRCC treatment and challenging sunitinib. Special attention has been paid towards cancer cell biology and immunity involved in treatment response. Expert Commentary: Sunitinib’s place in the therapeutic arsenal is being redefined with the arrival of major challengers. Dosage and scheduling of sunitinib remains a major challenge.