<jats:title>Abstract</jats:title><jats:p>Gut microbiota is involved in immune modulation and immune checkpoint inhibitors (ICIs) efficacy. Single‐arm phase II CAVE‐mCRC and CAVE‐LUNG clinical trials investigated cetuximab + avelumab combination in <jats:italic>RAS</jats:italic> wild‐type (WT) metastatic colorectal cancer (mCRC) and chemo‐refractory nonsmall cell lung cancer (NSCLC) patients, respectively. A comprehensive gut microbiota genetic analysis was done in basal fecal samples of 14 patients from CAVE‐mCRC trial with circulating tumor DNA (ctDNA) <jats:italic>RAS/BRAF</jats:italic> WT and microsatellite stable (MSS) disease. Results were validated in a cohort of 10 patients from CAVE‐Lung trial. 16S rRNA sequencing revealed 23 027 bacteria species in basal fecal samples of 14 patients from CAVE‐mCRC trial. In five long‐term responding patients (progression‐free survival [PFS], 9‐24 months) significant increases in two butyrate‐producing bacteria, <jats:italic>Agathobacter M104/1</jats:italic> (<jats:italic>P</jats:italic> = .018) and <jats:italic>Blautia SR1/5</jats:italic> (<jats:italic>P</jats:italic> = .023) were found compared to nine patients with shorter PFS (2‐6 months). A significantly better PFS was also observed according to the presence or absence of these species in basal fecal samples. For <jats:italic>Agathobacter M104/1</jats:italic>, median PFS (mPFS) was 13.5 months (95% confidence interval [CI], 6.5‐20.5 months) vs 4.6 months (95% CI, 1.8‐7.4 months); <jats:italic>P</jats:italic> = .006. For <jats:italic>Blautia SR1/5</jats:italic>, mPFS was 5.9 months (95% CI, 2.2‐9.7 months) vs 3.6 months (95% CI, 3.3‐4.0 months); <jats:italic>P</jats:italic> = .021. Similarly, in CAVE‐Lung validation cohort, <jats:italic>Agathobacter M104/1</jats:italic> and <jats:italic>Blautia SR1/5</jats:italic> expression were associated with PFS according to their presence or absence in basal fecal samples. <jats:italic>Agathobacter</jats:italic> and <jats:italic>Blautia</jats:italic> species could be potential biomarkers of outcome in mCRC, and NSCLC patients treated with cetuximab + avelumab. These findings deserve further investigation.</jats:p>