Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600E–Mutated Colorectal Cancer

Kopetz, Scott; Grothey, Axel; Yaeger, Rona; Cutsem, Éric Van; Desai, Jayesh; Yoshino, Takayuki; Wasan, Harpreet; Ciardiello, Fortunato; Loupakis, Fotios; Hong, Yong Sang; Steeghs, Neeltje; Guren, Tormod Kyrre; Arkenau, Hendrik Tobias; García‐Alfonso, Pilar; Pfeiffer, Per; Orlov, Sergey; Lonardi, Sara; Élez, Elena; Kim, Tae Won; Schellens, Jan H.M.; Guo, Christina; Krishnan, Asha; Dekervel, Jeroen; Morris, Van K.; Ferrándiz, Aitana Calvo; Tarpgaard, Line Schmidt; Braun, Michael; Gollerkeri, Ashwin; Keir, Christopher Hunt; Maharry, Kati; Pickard, Michael D.; Christy-Bittel, Janna; Anderson, Lisa R.; Sandor, Victor; Tabernero, Josep

doi:10.1056/nejmoa1908075

Cited by 1,126 publications

(917 citation statements)

References 34 publications

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“…In BRAF mutant melanoma and NSCLC, inhibition of two components of the same oncogenic pathway (BRAF+MEK, referred to as “vertical targeting”) has been shown to provide more lasting clinical benefit compared to inhibition of only BRAF 10, 11 . More recently, both clinical 12, 13 and pre-clinical 14 studies have shown that inhibition of three components of the same oncogenic pathway further increases therapeutic benefit. In these scenarios the drugs are used at maximum tolerated dose (MTD).…”

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confidence: 99%

“…In the present MLD schedule, we target the MAPK pathway of the tumour itself, as growth inhibition in all cases parallels inhibition of the MAPK pathway (as judged by pRSK). Three-drug combinations given at MTD have been used before in pre-clinical 14 and clinical studies 12, 13 for BRAF V600E mutant tumours, showing clear therapeutic benefits, but such regimen have an associated cost of toxicity.…”

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confidence: 99%

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Multiple Low Dose (MLD) therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Neto

Nadal²,

Ooft

et al. 2019

Preprint

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32deliver long-term benefit due to the emergence of resistant cells 1,2 . This is thought 33 to be the consequence of strong selective pressure exerted on the cancer drug 34 target by a Maximum Tolerated Dose (MTD) of a drug [3][4][5] . We hypothesized that 35 partial inhibition of multiple components in the same oncogenic signalling 36 pathway might add up to complete pathway inhibition, while at the same time 37 decreasing the selective pressure on each individual component to acquire a 38 resistance mutation. We report here testing of this Multiple Low Dose (MLD) 39 model of drug administration in Epidermal Growth Factor Receptor (EGFR) mutant 40 non-small cell lung cancer (NSCLC). We show that as little as 20% of the 41 individual drug doses required for full inhibition of cell viability is sufficient to 42 completely block MAPK signalling and proliferation when used in 3D 43 (RAF+MEK+ERK inhibitors) or 4D (EGFR+RAF+MEK+ERK inhibitors) 44 combinations. Importantly, EGFR mutant NSCLC cells treated with EGFR 45 inhibitors at a high dose rapidly developed resistance in vitro, but the cells treated 46with 3D or 4D MLD therapy did not. Moreover, NSCLC cells that had gained 47 resistance to high dose anti-EGFR therapies were still sensitive to MLD therapy. 48Using several animal models, including patient derived xenografts of NSCLC 49 tumours that are resistant to EGFR inhibitors erlotinib and osimertinib 6,7 , we 50 found durable responses to MLD therapy without associated toxicity. These data 51 support the notion that partial inhibition of multiple components of cancer-52 activated signalling pathways is difficult to circumvent and suggest that MLD 53 therapy could deliver clinical benefit. We propose that MLD strategy could be an 54 effective treatment option for EGFR mutant NSCLC patients, especially those 55 having acquired resistance to even third generation EGFR inhibitor therapy. 57Inhibition of signalling pathways that are activated by oncogenic mutations elicit 58 therapeutic responses due to "addiction" of the cancer to the activated pathway 8 . 59However, in advanced cancers, development of resistance is practically inevitable due to 60 secondary mutations that restore signalling through the drug-inhibited pathway. Such 61 acquired resistance mutations affect either the drug target itself or components that act 62 4 upstream, downstream or parallel to the activated signalling component 1,9 . In BRAF 63 mutant melanoma and NSCLC, inhibition of two components of the same oncogenic 64 pathway (BRAF+MEK, referred to as "vertical targeting") has been shown to provide 65 more lasting clinical benefit compared to inhibition of only BRAF 10,11 . More recently, both 66 clinical 12,13 and pre-clinical 14 studies have shown that inhibition of three components of 67 the same oncogenic pathway further increases therapeutic benefit. In these scenarios 68 the drugs are used at maximum tolerated dose (MTD). The increase in the number of 69 drugs being used in combination is usually accompanied by an increase in to...

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confidence: 99%

Multiple Low Dose (MLD) therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Neto

Nadal²,

Ooft

et al. 2019

Preprint

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“…For example, the Bayesian model highlighted the association between BRAF mutation in colorectal cancer and BRAF inhibitor response. Targeting BRAF signaling has recently been confirmed as a viable option for metastatic colorectal cancer cases with BRAF mutations 38 . In contrast, the Bayesian model excluded a suggestion from ANOVA of association between KRAS mutation with lenalidomide response in melanoma.…”

Section: Discussionmentioning

confidence: 99%

A statistical framework for assessing pharmacological response and biomarkers using uncertainty estimates

Wang¹,

Hensman²,

Kutkaite

et al. 2020

Preprint

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Drug high-throughput screenings across large molecular-characterised cancer cell line panels enable the discovery of biomarkers, and thereby, cancer precision medicine. The ability to experimentally generate drug response data has accelerated. However, this data is typically quantified by a summary statistic from a best-fit dose response curve, whilst neglecting the uncertainty of the curve fit and the potential variability in the raw readouts. Here, we model the experimental variance using Gaussian Processes, and subsequently, leverage this uncertainty for identifying associated biomarkers with a new statistical framework based on Bayesian testing. Applied to the Genomics of Drug Sensitivity in Cancer, in vitro screening data on 265 compounds across 1,074 cell lines, our uncertainty models identified 24 clinically established drug response biomarkers, and in addition provided evidence for 6 novel biomarkers. We validated our uncertainty estimates with an additional drug screen of 26 drugs, 10 cell lines with 8 to 9 replicates. Our method is applicable to drug high-throughput screens without replicates, and enables robust biomarker discovery for new cancer therapies.

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“…The likely reason for resistance is that targeting BRAF results in loss of negative feedback to the EGFR/RAS/RAF pathway, and that the additional EGFR signals can confound treatment with RAF inhibitors (42,43), possibly due to paradoxical activation of RAF due to the increased wild-type RAS-GTP (44)(45)(46). Subsequent studies have found BRAF mutant colorectal cancer can benefit from cotreatment with RAF, MEK, and EGFR inhibitors (47,48). It is still unknown whether the benefit from EGFR is solely due to inhibition of wild-type RAS or follows from the other pathways that EGFR can activate (49).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

McFall

Trogdon

Sisk-Hackworth

et al. 2019

Preprint

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Multiple KRAS G12C inhibitors are in development, and the identification of effective combination treatment regimens should maximize the benefit these agents have on cancer patients. Here, we find that KRAS G12C heterozygous mutated colorectal cancer cells are sensitive to targeting with EGFR therapeutic antibodies. We find that KRAS G12C is partially impaired in binding to tumor suppressor NF1 and also to RAF, and our computational simulations reveal how these deficiencies result in partial sensitivity to EGFR inhibition. For the combination of EGFR and G12C inhibitors we observe synergy and reductions in active forms of both wild-type and mutant RAS. Our simulations reveal the synergy involves both wild-type and mutant RAS. Overall, our work suggests that the addition of an EGFR inhibitor to a KRAS G12C inhibitor regimen should be further evaluated as a strategy for KRAS G12C colorectal cancer patients.

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Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer

Cited by 1,126 publications

References 34 publications

Multiple Low Dose (MLD) therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Multiple Low Dose (MLD) therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

A statistical framework for assessing pharmacological response and biomarkers using uncertainty estimates

Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

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