Good bacteria help fight cancer: Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32

Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Purpose: Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. Methods: We identified patients who were PD-(L)1–naïve with advanced non–small-cell lung cancer from two institutions—Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center—who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti–PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Results: Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001). Conclusion: Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non–small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.

Immunotherapy, principally represented by programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, has been approved worldwide as treatment for advanced non–small cell lung cancer (NSCLC) and has been hailed as an important addition to the treatment armamentarium for this population. In an unselected previously treated NSCLC population, response rates with single-agent immune checkpoint inhibitors (ICIs) range between 14% and 20%, with median overall survival (OS) of 10 to 12 months.^1-5 However, when this population is stratified by specific biomarkers, notably positive PD-L1 expression by immunohistochemical analysis, these outcomes improved, reaching up to 30% response with a median OS of 20 months,^3,5 in contrast to patients with negative or weak PD-L1 expression (1%-49% positive tumor cells, accounting for approximately 67% of the population) for whom response rates between 8% and 19% have been reported with median OS slightly below 10 months.⁶ However, even within the PD-L1–positive stratum, the benefit with immunotherapy is not seen for the entire population, making the identification of biomarkers for patients likely to respond to ICI therapy a critical step in selecting the candidate population.

In the era of immuno-oncology, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have demonstrated a clear survival benefit as a single agent or in combination compared with standard chemotherapy in both treatment-naive patients^1-4 and patients previously treated^5-8 for advanced non–small cell lung cancer (NSCLC). However, progression rates reported with single-agent PD-1/PD-L1 inhibitors are in some cases equal to or higher than with conventional treatment, ranging from 33% to 44% in pretreated patients with NSCLC.^5-7 Recently, an acceleration of tumor growth during immunotherapy, defined as hyperprogressive disease (HPD), was reported in 9% of advanced cancers⁹ and in 29% of patients with head and neck cancer¹⁰ treated with PD-1/PD-L1 inhibitors.