Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade

Abstract

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

Keywords: BRAF mutation; T-cell receptor; colorectal cancer; immune checkpoint blockade; metastasis; microsatellite-stable; oxaliplatin.

Figure 1.

(a) Duration of study participation and efficacy assessment for the per-protocol BRAF-mutant population (experimental group (E), n = 3; control group (C), n = 6). Dynamics of plasma BRAF V600E DNA over the study treatment in (b) two experimental-group subjects and (c) three control-group subjects.

Figure 2.

Left framed panel: The primary tumor site; baseline endoscopy and biopsy (top), endoscopy and biopsy at radiologic complete response (bottom). Right framed panel: The metastatic disease; the primary tumor (encircled) and multiple liver metastases at baseline (top), the ascending colon and liver at radiologic complete response (bottom). Further details are displayed in Supplementary Figures S3 and S5.

Figure 3.

T-cell receptor (TCR) repertoire in sequential liver metastases. TCR sequencing was done on a baseline biopsy sample from one of multiple liver metastases, three samples from the two resected liver metastases that relapsed after the radiologic complete response, and two samples from the resected end-stage liver metastases. (a) T-cell fractions in the repertoire of each sample, stratified by sampling time. The mean number of TCR sequences detected was 22,185 at baseline, 82,263 at the first liver resection, and 7,252 at the second. (b) Repertoire clonality of each sample, stratified by sampling time. The clonality index is defined as 10 minus the area under the curve of the evenness profile, with higher values signifying more monoclonal repertoires. (c) Hill diversity profile and (d) Hill evenness profile for each repertoire, presented by mean (solid line) with 95% confidence interval (shaded area). The left part of the diversity curve (α = 0) represents the number of unique clones present in the repertoire. The further and more rapidly each curve declines at increasing α values, the more uneven is the clonal frequency distribution (more monoclonal repertoires). The evenness profiles represent the diversity profiles normalized by clonal richness in the repertoire.