Summary authored by Oluwadunni Emiloju, MDDS, MS

CAR T-Cell Therapy for Hematologic Malignancies: Toxicities, Efficacy, and Opportunities

Oluwadunni Emiloju, MDDS, MS

BRAF V600E mutation results in constitutive RAF kinase activity and downstream signaling in the MAPK pathway via MEK and ERK, resulting in cancer proliferation and survival.  About 10% of patients with metastatic colorectal cancer (mCRC) harbor BRAF V600E mutation1,2.  In some instances, BRAF V600E mutation coexists with deficient mismatch repair (dMMR), which is usually sporadic in nature3.  Prior to the approval of front-line immune checkpoint blockade for dMMRmCRC, BRAF V600E mutant mCRC had poorer survival compared to wild type BRAF mCRC(median, 10.4 months vs 34.7 months, P < .001)4.  Targeted therapy with BRAF inhibitors such as dabrafenib, vemurafenib, encorafenib in combination with MEK inhibitors such as binimetinib, trametinib have demonstrated remarkable clinical benefit in BRAFV600E mutant melanoma, and non-small-cell lung cancer5,6 but not in mCRC.  Vemurafenib monotherapy resulted in a dismal objective response rate (ORR) of 5% in a phase II trial with 21 BRAFV600E mutant mCRC patients7, while dabrafenib +trametinib (D+T) resulted in ORR of 12% including 1 complete response among 43 BRAFV600E mutant mCRC patients8.

The disparate response between BRAF V600E mutant mCRC and other solid tumors prompted further investigation.  Following the phase 2 study of D +T in mCRC, pharmacodynamic studies using pre-and during-treatment biopsies showed a mean decrease in phosphorylated-ERK (p-ERK) of 47% with D +T among mCRC, compared with a decrease of 75% with dabrafenib monotherapy in BRAF mutated melanoma.  Incomplete blockade of the MAPK pathway was hypothesized as being responsible for the reduced efficacy of this therapeutic strategy among mCRC patients. MAPK inhibition was however a valid target but a strategy for more complete inhibition was necessary8. In vitro testing revealed a cytostatic response of BRAFV600E mutant CRC cell lines compared with a cytotoxic response in melanoma cells to vemurafenib, and this correlated with sustained suppression of p-ERK in the melanoma cells in contrast to transient p-ERK suppression in the CRC cells. ERK reactivation in the CRC cell lines was mediated through EGFR activation and signaling through other components of the MAPK pathway including RAS and CRAF9. In addition, through an RNA-i genetic screening of the human kinome, EGFR knockdown in colon cancer cells was synergistic with vemurafenib which was subsequently explained by the fact that BRAFV600E inhibition resulted in feedback EGFR activation10.  These preclinical findings led to early phase clinical trials combining BRAFV600E with EGFR inhibitors11; or BRAFi + EGFRi + MEKi12 with an improved response rate of 21% among patients treated with the triplet regimen12 .  This led to a larger phase 3 randomized study which compared BRAFi + EGFRi + MEKi vs BRAFi + EGFRi vs EGFRi + chemotherapy (control).  The two intervention arms resulted in significantly longer overall survival compared with control (9 vs 5.4; 8.4 vs 5.4 months) resulting in FDA approval of BRAFi + EGFRi in the second-line treatment of BRAFV600E mutant mCRC13.  

In the aforementioned phase 2 study12, noninvasive monitoring with serial cell-free DNA analysis showed that upon disease progression on the triplet regimen, NRAS and KRAs mutations were the principal drivers of resistance in 48% of patients.  The emergence of these resistant mutations also coincided with a rebound in the BRAF V600E levels12. Furthermore, the coexistence of dMMR with BRAF mutations in mCRC was associated with a more favorable response to BRAF inhibition12, and cross talk between genomics (BRAF mutation) and immunology (dMMR and immune response) has led to further research whereby immune checkpoint blockade with anti PD1 antibodies in combination with BRAF inhibition are being investigated in early phase trials14,15.

This story of targeting BRAF V600E in mCRC beautifully illustrates that translating basic science research into the clinic in the form of clinically useful therapeutics, and using clinical observations along with correlative studies to inform the design and direction of future lab research is an iterative process: an initial failure may be the necessary first step to future success in translational oncology.These principles can be applied to other disease areas in Oncology, and this underscores the need for consistently incorporating correlative science into clinical trials.

References

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14.Tian J, Chen JH, Chao SX, et al. Combined PD-1, BRAF and MEK inhibition in BRAF(V600E) colorectal cancer: a phase 2 trial. Nat Med. 2023;29(2):458-466.

15.Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer. Journal of Clinical Oncology. 2022;40(4_suppl):12-12.