Review
`
`Molecular
`Cancer
`Therapeutics
`
`Genomically Driven Tumors and Actionability
`across Histologies: BRAF-Mutant Cancers
`as a Paradigm
`Michelle L. Turski1, Smruti J. Vidwans1, Filip Janku2, Ignacio Garrido-Laguna3,
`Javier Munoz4, Richard Schwab5, Vivek Subbiah2, Jordi Rodon6, and Razelle Kurzrock5
`
`Downloaded from http://aacrjournals.org/mct/article-pdf/15/4/533/1850394/533.pdf by guest on 14 August 2022
`
`Abstract
`
`The diagnosis, classification, and management of cancer are
`traditionally dictated by the site of tumor origin, for example,
`breast or lung, and by specific histologic subtypes of site-of-
`origin cancers (e.g., non–small cell versus small cell
`lung
`cancer). However, with the advent of sequencing technologies
`allowing for rapid, low cost, and accurate sequencing of clinical
`samples, new observations suggest an expanded or different
`approach to the diagnosis and treatment of cancer—one driven
`by the unique molecular features of the tumor. We discuss a
`genomically driven strategy for cancer treatment using BRAF as
`an example. Several key points are highlighted: (i) molecular
`aberrations can be shared across cancers; (ii) approximately
`
`15% of all cancers harbor BRAF mutations; and (iii) BRAF
`inhibitors, while approved only for melanoma, have reported
`activity across numerous cancers and related disease types
`bearing BRAF aberrations. However, BRAF-mutated colorectal
`cancer has shown poor response rate to BRAF inhibitor mono-
`therapy, striking a cautionary note. Yet, even in this case,
`emerging data suggest BRAF-mutated colorectal cancers can
`respond well to BRAF inhibitors, albeit when administered
`in combination with other agents that
`impact
`resistance
`pathways. Taken together, these data suggest that molecular
`aberrations may be the basis for a new nosology for cancer. Mol
`Cancer Ther; 15(4); 533–47. Ó2016 AACR.
`
`Introduction
`A wealth of data now suggests that molecular aberrations may
`be shared across multiple histologies (1). As an example, BRAF
`mutations can be detected in melanoma, colorectal tumors, lung
`and ovarian cancers, hairy cell leukemia, histiocytosis and many
`other related disease types (2; Fig. 1; Table 1). Indeed, a small
`subset of almost all types of malignancies may harbor a BRAF
`mutation (3, 4). Of special importance in this regard is the fact
`that several drugs that effectively target the BRAF-mutant protein
`product have been developed (Table 2). For instance, the BRAF
`inhibitors, vemurafenib and dabrafenib, have both been
`approved for BRAF-mutant melanoma based on results from the
`phase III BRIM-3 study (5) and the phase III BREAK-3 study (6),
`respectively.
`A key conundrum now debated in the cancer community is
`whether or not targeted drugs approved for one type of histol-
`ogy should be administered to other histologies harboring the
`cognate aberration. For instance, should a BRAF inhibitor
`
`1CollabRx Inc., San Francisco, California. 2Department of Investiga-
`tional Cancer Therapeutics – a Phase I Clinical Trials Program, The
`University of Texas MD Anderson Cancer Center, Houston, Texas.
`3Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
`4Banner MD Anderson Cancer Center, Gilbert, Arizona. 5Center for
`Personalized Cancer Therapy, Moores Cancer Center, University of
`California, San Diego, California. 6Vall d'Hebron Institut d'Oncologia
`and Universitat Autonoma of Barcelona, Barcelona, Spain.
`
`Corresponding Author: Razelle Kurzrock, UCSD Moores Cancer Center, UCSD
`Moores Cancer Center, 3855 Health Sciences, MC #0658, La Jolla, CA 92093.
`Phone: 858-246-1102; Fax: 858-246-1915; E-mail: rkurzrock@mail.ucsd.edu
`
`doi: 10.1158/1535-7163.MCT-15-0643
`Ó2016 American Association for Cancer Research.
`
`approved for BRAF-mutant melanoma be given to a patient
`with a BRAF-mutant tumor other than melanoma? A corollary
`to this question is the precise criteria needed in order to
`extrapolate predictive data on a biomarker for a given targeted
`therapy in one cancer to another cancer. These questions are of
`tremendous importance for the following reasons: (i) molec-
`ular aberrations, in particular amplifications, loss, and muta-
`tions, do not appear to segregate well by histology (1, 2, 4); (ii)
`numerous targeted drugs are becoming clinically available and
`they have been developed to inhibit a specific cancer signal that
`may be found in multiple tumor types, hence their rational
`application would be in tumors bearing the cognate target (3);
`and (iii) molecular anomalies are found in a very small per-
`centage of diverse cancers (7), and the rarity in each histologic
`type presents a near-impossible challenge for classic random-
`ized or even nonrandomized trials to determine efficacy his-
`tology by histology.
`Newer study designs are beginning to accommodate these
`challenges. For instance, histology-agnostic trials (so-called buck-
`et or basket trials) might include patients with a wide variety of
`histologies as long as they all harbor the cognate aberration. As an
`example, a histology-agnostic trial of the BRAF inhibitor vemur-
`afenib can include diverse types of cancers, providing that they
`carry BRAF mutation (e.g., VE BASKET study; 8). However, these
`types of trials are still often perceived as signal finding. If a variety
`of histologies respond, what should be the next steps to approval
`and/or pay or coverage? To what extent can we be certain or do we
`need to be certain that each histology bearing the mutation will
`respond before it is acceptable to administer drugs across cancers
`based on their molecular, rather than histologic, classification?
`Does molecular classification actually represent a biology-based
`nosology?
`
`www.aacrjournals.org
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`Figure 1.
`Examples of organ of origin tumors that have different types of BRAF aberrations. For a comprehensive list of tumor types having BRAF aberrations, please refer
`to Table 1.
`
`Herein we review this topic, using BRAF-mutant malignancies
`as a paradigm. The choice of BRAF was considered apt for the
`following reasons: (i) BRAF mutations as well as other BRAF
`anomalies (amplifications, fusions) have been described in a wide
`variety of tumors; (ii) two BRAF inhibitors and a MEK inhibitor
`have already been approved for BRAF-mutant melanoma; and
`(iii) there is a rich literature demonstrating responses, albeit at
`times in small numbers of patients, with the use of BRAF inhi-
`bitors in a variety of BRAF-mutation bearing cancers (9, 10). On
`the other hand, BRAF-mutant colorectal cancers have proved
`more resistant to BRAF inhibitor monotherapy, hence striking a
`cautionary note. The observations in BRAF-mutant tumors may
`
`therefore inform future conceptualization of genomically driven
`treatment.
`
`BRAF Mutations in Diverse Cancers
`BRAF is mutated in about 15% of all cancers (3, 11) and BRAF
`mutations can be found in solid tumors, hematologic malignan-
`cies, and related disease types (Table 1). For some cancers, BRAF
`mutations are very frequently detected: melanoma [40%–60% of
`patients (12)] and hairy cell leukemia [100% (13)].
`The predominant mutation detected in BRAF-mutated cancers
`is the V600E mutation, representing approximately 70% to 90%
`
`534
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`Genomically Driven Cancer Classification
`
`Source
`Goeppert et al (93)
`Tannapfel et al (94)
`
`Jebaraj et al (95)
`Pakneshan et al (96)
`Domingo et al (97)
`Samowitz et al (98)
`Benlloch et al (99)
`Haroche et al (100)
`Gupta et al (101)
`Hostein et al (102)
`Miranda et al (103)
`cBioPortal (25,26)
`Sakata-Yanagimoto (104)
`Tiacci et al (13)
`COSMIC (23)
`
`Cooper et al (105)
`Paik et al (106)
`
`Go et al (107)
`Haroche et al (100)
`Davies et al (12)
`Hodis et al (108)
`
`Lohr et al (109)
`
`Grisham et al (110)
`Bosmuller et al (111)
`
`Schultz et al (112)
`COSMIC (23)
`
`Korshunov et al (28)
`Gupta et al (101)
`Schindler et al (113)
`COSMIC (23)
`
`Comments
`BRAF V600E (60%)
`BRAF V600D (13%)
`Other codons (27%)
`
`BRAF V600E
`
`BRAF V600E
`BRAF V600E
`BRAF V600E
`
`BRAF V600E
`BRAF V600E
`
`BRAF V600E (85%)
`Other codons (5%)
`BRAF V600E (50%)
`BRAF G469A (39%)
`BRAF D594G (11%)
`BRAF V600E
`
`BRAF V600E (80%)
`BRAF V600K (8%)
`BRAF V600R (1%)
`Other codons (10%)
`BRAF V600E (38%)
`Other codons (62%)
`BRAF V600E
`
`Schultz et al reported all
`mutations detected were non-
`BRAF V600E (112). COSMIC
`reported 55% of BRAF
`mutations were BRAF V600E.
`BRAF-KIAA1549 fusion
`
`Table 1. BRAF mutations in diverse cancersa
`Cancer
`Cholangiocarcinoma
`
`BRAF mutation frequency
`3%–22%
`
`Chronic lymphocytic leukemia
`Colorectal cancer
`MSI unstable
`MSI stable
`
`Erdheim-Chester disease
`Ganglioglioma
`GIST
`
`Glioblastoma
`Hairy cell leukemia
`
`Kidney cancer
`
`Lung cancer adenocarcinoma
`
`Langerhans cell histiocytosis
`
`Melanoma
`
`Multiple myeloma
`
`Ovarian cancer
`Serous borderline
`Low-grade serous
`Pancreatic cancer
`
`2.8%
`5%–15%
`27.8%–51.8%
`5%–7.5%
`
`54%
`43%
`2%–13%
`
`1.7%
`100%
`
`3%
`
`3%
`
`25%–38%
`60%
`
`6%
`
`35%–60%
`44.6%–71%
`5.3%–14%
`1%–16%
`
`Pilocystic astrocytoma
`
`70%–80%
`
`Pleomorphic xanthoastrocytoma
`Prostate cancer
`
`66%
`1.6%
`
`BRAF V600E
`BRAF V600E (<1%)
`BRAF V600X (84%)
`30%–80%
`BRAF V600E
`Xing (114)
`Papillary thyroid cancer
`aMultiple other tumors may have a small incidence of BRAF mutations not described here. Additionally some tumors may have BRAF amplification or fusions as noted
`in the comments column or as discussed in the section entitled "Abnormalities in the BRAF gene other than Mutations".
`
`of all mutations in BRAF (12, 14–16). Substitution of glutamic
`acid (E) for valine (V) at codon 600 of the BRAF protein affects the
`activation segment of the protein by mimicking the phosphory-
`lation of the kinase domain, causing a change in structure that
`favors the active conformation (14, 17). Experimental studies
`have confirmed that the BRAF V600E mutations are activating,
`resulting in increased BRAF kinase activity in in vitro studies, as
`well as activation of downstream effectors and oncogenic trans-
`formation in cell-based studies (12, 18, 19).
`Other activating mutations in BRAF include additional muta-
`tions affecting codon 600 that result in substitutions other than
`glutamic acid. In BRAF-mutated melanoma, the BRAF V600K
`mutation is found at a frequency of approximately 7% to 19%
`(16, 20). Other rare mutations affecting codon 600 include BRAF
`V600D (0.1%), BRAF V600R (1%), and BRAF V600M (0.3%;
`20). Furthermore, activating mutations in BRAF that affect codons
`other than 600 include L597 substitutions (0.5%), and K601E
`(0.7%; 20). Table 1 lists several other non-V600 mutations in
`BRAF and their frequencies in detected cancers (for responsiveness
`
`of non-V600E mutations to BRAF inhibitors, see section entitled
`"BRAF mutations other than V600E").
`In addition, inactivating or "low-activity" mutations in BRAF
`have been identified and characterized; they typically involve
`substitutions at codon 594 (19, 21), although missense mutations
`at other codons (including codon 466) have also been shown to
`result in BRAF kinase inactivation or reduced activation (18).
`
`Abnormalities in the BRAF Gene Other Than
`Mutations
`In addition to mutations, other types of BRAF aberrations are
`found in cancer, including amplification and BRAF fusions. BRAF
`amplification involving either the wild-type gene or mutant
`versions of the gene is predicted to result in increased BRAF
`activity in tumor cells (22). In some cases where BRAF mutations
`are rare, BRAF amplifications dominate. For example, while
`mutations in BRAF are found in only 1% of breast cancers
`(23), BRAF amplification has been reported in 30% of basal-like
`
`www.aacrjournals.org
`
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`(Continuedonthefollowingpage)
`
`mutation(NCT01877811)
`eitherBRAFV600EorBRAFV600K
`melanomaorcolorectalcancerwith
`
`(BRAF)c
`
`>2,000nmol/L
`
`V600E)
`
`ABL1,RET,EPHA2
`BRAF,ABL1,BCR-
`
`Jamesetal(123)
`
`PhaseIIportionoftrialselectingfor
`
`PhaseI/II
`
`Investigational
`
`60nmol/L(BRAF
`
`BRAFV600E,
`
`CEP-32496
`
`mutations(NCT01225536)
`solidtumorswithBRAFand/orNRAS
`
`2.6nmol/L(BRAF)b
`
`V600E)
`
`Chenetal(122)
`
`InaphaseItrial(nowcompleted)for
`
`PhaseI
`
`Investigational
`
`2.7nmol/L(BRAF
`
`BRAF,RAF1
`
`ARQ736
`
`BRAFinhibitor
`
`-Notvalidatedclinicallyasaneffective
`only40%inhibitionofBRAFV600E
`inhibitionofwild-typeBRAFversus
`V600E;at1mmol/Lcanachieve80%
`(NCT01713972)
`advancedmalignanttumors
`dabrafenibforBRAF-mutant
`
`-LesseffectiveatinhibitionofBRAF
`
`Kitagawaetal(121)
`
`-AlsoinphaseItrialincombinationwith
`
`-Notvalidatedclinicallyasaneffective
`
`BRAFinhibitor
`
`(NCT02175654)
`mutantcolorectalcancer
`
`Wilhelmetal(120)
`
`-AlsoinphaseIItrialforBRAF-orRAS-
`
`BRAFinhibitor
`
`-Notvalidatedclinicallyasaneffective
`
`solidtumors(NCT02029001)
`(excludingBRAFV600mutations)
`
`Wilhelmetal(119)
`
`-AlsoinphaseIItrialforBRAF-mutant
`
`-Advancedsofttissuesarcoma
`-Advancedrenalcellcarcinoma
`
`aberrations
`BRAF
`notrelatedto
`
`Approvedbut
`
`410nmol/L(BRAF)
`
`-Locallyadvanced,unresectable,ormetastaticGIST
`-Metastaticcolorectalcancer
`
`aberrations
`BRAF
`notrelatedto
`
`28nmol/L(BRAF)
`
`V600E)
`
`Approvedbut
`
`19nmol/L(BRAF
`
`differentiatedthyroidcarcinoma
`
`-Locallyrecurrent,ormetastatic,progressive,
`-Advancedrenalcellcarcinoma
`-Unresectablehepatocellularcarcinoma
`
`aberrations
`BRAF
`notrelatedto
`
`25nmol/L(BRAF)
`
`V600E)
`
`Approvedbut
`
`38nmol/L(BRAF
`
`CSF1R,LCK,ITK
`FGFR1,FGFR3,
`PDGFRB,KIT,
`FLT4,PDGFRA,
`BRAF,FLT1,KDR,
`
`MAPK11,ABL1
`FGFR2,NTRK1,
`PDGFRB,FGFR1,
`PDGFRA,
`FLT4,KIT,TEK,
`BRAF,FLT1,KDR,
`
`RAF1,FLT1
`FLT4,FLT3,RET,
`PDGFRB,KIT,
`PDGFRA,
`BRAF,KDR,
`
`Pazopanib
`
`Regorafenib
`
`Sorafenib
`
`Turski et al.
`
`FDAlabel(62,118)
`
`FDAlabel(117)
`
`Bollagetal(116)
`FDAlabel(115)
`Refs
`
`V600E/Kmutation
`unresectableormetastaticmelanomawithBRAF
`Singleagentorincombinationwithdabrafenibfor
`
`V600E/K
`BRAF
`
`Approvedfor
`
`mutation
`metastaticmelanomawithBRAFV600E/K
`
`-Incombinationwithtrametinibforunresectableor
`
`melanomawithBRAFV600Emutation
`
`-Singleagentforunresectableormetastatic
`
`BRAFV600E
`
`Approvedfor
`
`N/A
`
`MAP2K1,MAP2K2
`
`Trametinib
`
`3.2nmol/L(BRAF)
`
`V600E)
`
`RAF1
`V600K,BRAF,
`V600D,BRAF
`
`1.84nm(BRAF
`
`BRAFV600E,BRAF
`
`Dabrafenib
`
`Comments
`
`UnresectableormetastaticmelanomawithBRAF
`Indications/Stageofdevelopmenta
`
`Approvedfor
`status
`Development
`
`V600Emutation
`
`BRAFV600E
`
`100nm(BRAF)
`
`V600E)
`
`31nmol/L(BRAF
`forBRAF
`ApproximateIC50
`
`MAP3K5
`TNK2,FGR,
`ARAF,SRMS,
`BRAF,RAF1,
`BRAFV600E,
`Target(s)
`
`Vemurafenib
`Drugname
`
`Table2.ExamplesofclinicallyavailableBRAFinhibitorsandtheirapplications
`
`536
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`Genomically Driven Cancer Classification
`
`mutations(NCT01086267)
`mutationorwithKRAScodon12or13
`colorectalcancerwithBRAFV600E
`combinationwithcetuximabfor
`
`InphaseI/IItrialasmonotherapyorin
`
`mutationrequirements
`
`-NotyetfeaturedintrialswithBRAF
`
`(NCT00773526)
`patientswithsolidtumors
`
`cCellularIC50value.
`bIC50valuespresentedareforARQ680,whichistheactivemoietyoftheprodrugARQ736.
`aRelevantexamplesofdevelopmentaregiven.
`
`PhaseI/II
`
`Investigational
`
`Informationnot
`
`BRAF,RAF1
`
`XL281
`
`available
`
`160nmol/L(BRAF)
`
`V600E)
`
`MAP2K1,MAP2K2
`
`Martinez-Garcia(126)
`
`-InphaseItrial(nowcompleted)for
`
`PhaseI
`
`Investigational
`
`8.2nmol/L(BRAF
`
`BRAF,RAF1,
`
`RO5126766
`
`Stuartetal(124)
`Refs
`
`V600Emutation(NCT01143753)
`
`InphaseItrialforsolidtumorswithBRAF
`
`cellleukemia(NCT02012231)
`BRAF-mutatedsolidtumorsandhairy
`
`PhaseIIportionoftrialselectingfor
`
`mutationrequirements
`
`-NotyetfeaturedintrialswithBRAF
`
`melanoma(NCT01425008)
`
`-Clinicaltestinginsolidtumorsand
`
`(NCT01981187)
`withBRAFV600mutation
`cancer)andhematologicmalignancies
`(excludingmelanomaandcolorectal
`
`-InaphaseIItrialforsolidtumors
`
`mutatedmelanoma(NCT01909453)
`
`-InphaseIIItrialforBRAFV600E-
`Comments
`
`PhaseI
`
`Investigational
`
`Informationnot
`
`BRAFV600E,BRAF
`
`PLX3603
`
`PhaseI/II
`
`Investigational
`
`Informationnot
`
`available
`
`BRAF,RAF1
`BRAFV600E,
`
`PLX8394
`
`PhaseI
`
`Investigational
`
`Informationnot
`
`BRAF,ARAF,RAF1
`
`MLN2480
`
`available
`
`PhaseIII
`Indications/Stageofdevelopmenta
`
`Investigational
`status
`Development
`
`V600E)c
`
`4nmol/L(BRAF
`forBRAF
`ApproximateIC50
`
`BRAFV600E,BRAF
`Target(s)
`
`LGX818
`Drugname
`
`Table2.ExamplesofclinicallyavailableBRAFinhibitorsandtheirapplications(Cont'd)
`
`(NCT01352273)
`V600EorNRASorKRASmutations
`withsolidtumorscontainingBRAF
`combinationwithMEK162forpatients
`
`Stuartetal(125)
`
`InaphaseItrial(nowcompleted)in
`
`PhaseII
`
`Investigational
`
`V600E)c
`
`140nmol/L(BRAF
`
`V600E,BRAF)
`
`<100nmol/L(BRAF
`
`available
`
`BRAF,RAF1,KDR
`
`RAF265
`
`www.aacrjournals.org
`
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`Turski et al.
`
`breast tumors (24). Other cancers where BRAF amplification is
`more frequent than BRAF mutations include ovarian serous cysta-
`denocarcinoma (12% vs. 0.6%, respectively; 25, 26) as well as
`prostate adenocarcinoma (5% vs. 1.6%, respectively; 25, 26).
`BRAF fusions such as KIAA1549-BRAF and FAM131B-BRAF are
`frequently found in gliomas with the KIAA1549-BRAF fusion
`detected in up to 70% of pilocytic astrocytomas (27, 28). The
`KIAA1549-BRAF is an arrangement created by a tandem duplica-
`tion event, while FAM131B-BRAF is generated by a large deletion
`event; however, both result in constitutive activation of BRAF
`through duplication of the BRAF activation domain, but with
`deletion of the N-terminal inhibitory domain (29, 30). The
`KIAA1549-BRAF fusion has been reported in preclinical studies
`to be resistant to PLX4720, the research analog of vemurafenib,
`due to RAF dimerization, but remains sensitive to a second-
`generation BRAF inhibitor (31). In addition, one case study
`described a patient with a spindle cell neoplasm harboring the
`KIAA1549-BRAF fusion as well as a homozygous deletion of
`PTEN, and frameshift mutations in CDKN2A, SUFU, and MAP3K1
`who had a 25% reduction in tumor volume following a combi-
`nation therapy consisting of sorafenib (a weak BRAF inhibitor),
`temsirolimus, and bevacizumab, suggesting that the KIAA1549-
`BRAF fusion may be responsive to certain BRAF inhibitors in the
`clinic, though the precise reason for response is confounded by
`the other drugs in the regimen (32). The responsiveness of
`FAM131B-BRAF is currently not reported in the literature. While
`infrequent as compared with mutations, BRAF fusions have also
`been observed in melanoma in anywhere from 4% to 8% of "pan-
`negative" cases (defined as tumors negative for mutations in
`BRAF, NRAS, KIT, GNAQ, and GNA11). Two BRAF fusions,
`PAPSS1-BRAF and TRIM24-BRAF, were both shown to result in
`activation of the MAPK pathway, and were both reported to be
`sensitive to the MEK inhibitor trametinib but not the BRAF
`inhibitor vemurafenib as assessed by inhibition of MEK1/2 phos-
`phorylation (33).
`In summary, multiple alterations in the BRAF gene can occur.
`The sensitivity or lack thereof to BRAF or MEK inhibitors may vary
`depending on the alteration.
`
`Clinically Available BRAF Inhibitors and
`Their Applications
`The connection between BRAF-mutant, specifically BRAF
`V600E-mutant, cancers and response to BRAF inhibitors was
`first established in melanoma patients, where it was observed
`that anywhere from 50% to 60% of melanomas harbor the
`activating BRAF V600E mutation (12, 34). A phase I study
`reported that, in comparison with the 10% to 20% response
`rates for nontargeted therapies approved for the treatment of
`melanoma, a response rate of up to 81% was observed for BRAF
`V600E-mutated melanoma patients given the BRAF inhibitor
`vemurafenib (35). Furthermore, matched targeted therapy in
`heavily pretreated melanoma patients in the phase I setting
`(using mainly BRAF and MEK inhibitors), showed longer PFS as
`compared with each patient's first-line standard therapy (36).
`The phase II BRIM-2 study reported a best overall response rate
`of 53% and median duration of response of 6.8 months from
`treatment with dabrafenib for previously treated melanoma
`patients whose tumor harbored the BRAF V600E mutation (37,
`38). Finally, on the basis of a phase III trial comparing vemur-
`afenib to dacarbazine,
`in which it was reported that
`the
`
`response rate for vemurafenib was 48% as compared with the
`5% response rate for decarbazine (5), vemurafenib received
`FDA approval for treatment of patients with melanoma whose
`tumors harbor the BRAF V600E mutation (39).
`On the heels of vemurafenib, another BRAF inhibitor that
`proved to be efficacious in treating BRAF V600E-mutated mela-
`noma patients was dabrafenib (6, 40), which received FDA
`approval for the treatment of patients with melanoma having
`the BRAF V600E mutation (41). Vemurafenib and dabrafenib
`are perfect examples of the superior efficacy that can be achieved
`by employing drugs that target a biomarker that drives oncogen-
`esis; in patients with BRAF V600E-mutated melanoma, BRAF-
`directed therapy results in substantially better outcomes as com-
`pared with nontargeted therapy approaches.
`Other approved drugs that act as BRAF inhibitors but are not
`specifically approved for BRAF-mutant cancers include regorafe-
`nib, which is approved for colorectal cancer and gastrointestinal
`stromal tumors (GIST); it is also currently in a phase II trial
`recruiting for colorectal cancer patients with any BRAF or RAS
`mutation (42).
`Additional BRAF inhibitors that are either approved or current-
`ly in clinical development are summarized in Table 2. Some of
`these drugs are in trials selecting for BRAF-mutant cancers. For
`example, LGX818 is in a phase III trial for BRAF V600E- or BRAF
`V600K-positive melanoma (43) and in a phase II trial for BRAF
`V600-positive cancers (44).
`
`Clinically Available MEK1/2 Inhibitors and
`Their Applications
`Trametinib is currently the only approved MEK1/2 inhibitor.
`However, there are several other investigational MEK1/2 inhibi-
`tors being evaluated in clinical trials, including binimetinib
`(MEK162), cobimetinib (GDC-0973, XL518), pimasertib, refa-
`metinib, selumetinib (AZD6244), and PD-0325901.
`
`Melanoma
`Another drug approved for melanoma with BRAF V600E or
`BRAF V600K mutations is the MEK1/2 inhibitor trametinib
`(GSK1120212). Trametinib was approved on the basis of results
`from a phase III trial (NCT01245062) of 322 melanoma patients
`who harbored either BRAF V600E, BRAF V600K, or both muta-
`tions that were randomized to receive either a chemotherapy
`regimen (paclitaxel or dacarbazine) or trametinib. Patients receiv-
`ing trametinib had a superior PFS as compared with patients
`receiving chemotherapy, with a median PFS of 4.8 months versus
`1.5 months, respectively (45). Trametinib in combination with
`dabrafenib for melanoma with BRAF V600E or BRAF V600K
`mutations was subsequently approved on the basis of a trial of
`162 melanoma patients who harbored either the BRAF V600E or
`BRAF V600K mutations, who were randomized to either trameti-
`nib 2 mg daily in combination with dabrafenib, trametinib 1 mg
`daily in combination with dabrafenib, or single-agent dabrafenib.
`The trametinib 2 mg daily in combination with dabrafenib yielded
`superior objective response rates and response duration (76% and
`10.5 months, respectively, as compared with 54% and 5.6 months,
`respectively, in the single-agent dabrafenib arm; P < 0.05; 46).
`
`Colorectal cancer
`In colorectal cancer, dabrafenib and trametanib combinations
`have also shown activity in BRAF-mutated disease (47). Of 43
`
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`Genomically Driven Cancer Classification
`
`Comments
`Phase II
`
`Reference
`Hyman et al (8)
`
`Case reports
`
`Haroche et al (10)
`Tzoulis et al (127)
`
`Case report
`
`Bubolz et al (128)
`
`Phase II
`
`Hyman et al (8)
`
`Case reports
`
`Bautista et al (55)
`del Bufalo et al (129)
`
`Phase II
`
`Hyman et al (8)
`
`Case report and
`phase I study
`
`Falchook et al (53)
`Falchook et al (40)
`
`Case report
`
`Robinson et al (54)
`
`Case reports for
`dabrafenib; phase
`II study for
`vemurafenib
`
`Phase II for
`vemurafenib;
`phase I study for
`dabrafenib
`
`Vergote et al (130)
`Samuel et al (56)
`Munoz et al (9)
`Follows et al (131)
`Dietrich et al (57)
`Tiacci et al (132)
`Andrulis et al (133)
`
`Hyman et al (8)
`Falchook et al (40)
`
`Farley et al (134)
`Falchook et al (40)
`Hyman et al (8)
`
`Phase II for
`selumetinib
`study; phase II for
`vemurafenib;
`phase I for
`dabrafenib
`
`Case report
`
`Skrypek et al (135)
`
`Phase II and case
`reports
`
`Hyman et al (8)
`Lee et al (136)
`Chamberlain (137)
`
`Erdheim-Chester
`disease (ECD)
`
`54%
`
`Vemurafenib
`
`Langerhans
`histiocytosis (LCH)
`
`25%–38%
`
`Vemurafenib
`
`ECD/LCH
`
`Ganglioglioma
`
`N/A
`
`43%
`
`Vemurafenib
`
`Vemurafenib
`
`Glioma
`
`GIST
`
`Varies depending
`on type of glioma
`2%–13%
`
`Vemurafenib
`
`Dabrafenib
`
`Glioblastoma
`
`Hairy cell leukemia
`
`1.7%
`100%
`
`Multiple myeloma
`
`NSCLC
`
`6%
`
`3%
`
`Ovarian cancer
`
`35%–60%
`
`Vemurafenib
`
`Dabrafenib;
`Vemurafenib
`
`Vemurafenib
`
`Vemurafenib;
`dabrafenib
`
`Selumetinib;
`dabrafenib;
`vemurafenib
`
`Table 3. Predictive value of BRAF mutations for BRAF and/or MEK inhibitor therapy in diverse cancers
`Cancer
`% BRAF mutated
`Treatment regimen
`Reported outcomes
`12.5% with PR (1 of 8) or SD  6
`3%–22%
`Cholangiosarcoma
`Vemurafenib
`months. All patients with either PR
`or SD had tumors with BRAF
`V600E mutations.
`Rapid clinical and biological
`improvement with tumor
`response (N ¼ 4).
`All 4 patients had BRAF V600E
`mutations.
`One patient with SD and almost
`complete metabolic remission.
`Disease positive for BRAF V600E
`mutation.
`7% CR (1 of 14); 36% PR (5 of 14); 29%
`with SD  6 months (4 of 14). All
`patients with V600E.
`2 patients with PR (2 months PFS in
`one patient; 20þ months PFS in
`another; N ¼ 2). 1 patient had
`radiological and clinical response
`sustained after 6 months from
`vemurafenib (N ¼ 1).
`All patients had BRAF V600E mutant
`tumors.
`1 of 8 patients had SD  6 months.
`Patient had V600E.
`One patient with tumor regression
`(PFS ¼ 8 months). One SD with
`17% decrease in tumor volume
`(N ¼ 1). Both tumors positive for
`BRAF V600E.
`CR (PFS ¼ 6þ months).
`Tumor positive for BRAF V600E.
`CR (N ¼3) and PR (N ¼2) in
`dabrafenib studies.
`38% CR (19 of 50) and 60% with PR
`(30 of 50). All patients in clinical
`reports had BRAF V600E
`mutation.
`Case: 1 PR in patient with BRAF
`V600E mutation.
`Phase II study: 42% with PR (8 of 19)
`and (3 of 19) with SD  6 months;
`all patients except one who was
`BRAF V600 unknown had the
`V600E mutation.
`Phase I study:1 PR (N ¼ 1) with 83%
`decrease in tumor volume from
`dabrafenib.
`No patients demonstrated a tumor
`response to selumetinib (N ¼ 2). 1
`SD (N ¼ 1) with 28% decrease in
`tumor volume from treatment
`with dabrafenib in phase I study. 1
`PR in a serous ovarian cancer
`patient (N ¼ 1) in phase II
`vemurafenib study. All patients in
`these studies had BRAF V600E
`disease.
`Tumor regression. Tumor was BRAF
`V600E mutation positive.
`Phase II: 75% PR (3 of 4).
`Case report: near clinical response
`(N ¼ 1).
`Case report: 1 PR and 1 SD  6
`months (N ¼ 4).
`Patients in all studies had BRAF
`V600E
`
`Pilomyxoid astrocytoma
`
`Rare
`
`Anaplastic pleomorphic
`xanthoastrocytoma
`
`66%
`
`Vemurafenib
`
`Vemurafenib
`
`(Continued on the following page)
`
`www.aacrjournals.org
`
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`
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`
`Turski et al.
`
`Table 3. Predictive value of BRAF mutations for BRAF and/or MEK inhibitor therapy in diverse cancers (Cont'd )
`Cancer
`% BRAF mutated
`Treatment regimen
`Reported outcomes
`30%–80%
`Phase II: Longer PFS on selumetinib
`Papillary thyroid cancer
`Selumetinib;
`observed in BRAF V600E-
`dabrafenib;
`mutated patients versus BRAF
`vemurafenib
`wild-type patients (33 vs. 11 weeks,
`respectively, P ¼ 0.3).
`Phase I: 1 PR and 2 SD reported in one
`dabrafenib study (N ¼ 3). 33% (3
`of 10) with PR and 10% (1 of 10)
`with PD in another dabrafenib
`study.
`Phase I: 3 of 5 evaluable with CR or
`PR from vemurafenib; remaining 2
`had SD.
`All patients in these studies had
`BRAF V600E-positive disease.
`14% CR (1 of 7) and 14% PR (1 of 7);
`both patients with V600E
`One V600E-positive patient with SD
`lasting 7 months (1 of 1)
`One V600E-positive patient with CR
`(1 of 1)
`One V600E-positive patient with CR
`(1 of 1)
`NOTE: Key to drug actions: Dabrafenib ¼ BRAF inhibitor; Selumetinib ¼ MEK inhibitor; Vemurafenib ¼ BRAF inhibitor.
`Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
`
`Anaplastic tyhyroid cancer
`
`23% (139)
`
`Vemurafenib
`
`Pancreatic cancer
`
`1%–16%
`
`Vemurafenib
`
`Thoracic clear cell sarcoma
`
`4.5% (140)
`
`Vemurafenib
`
`Salivary gland cancer
`
`7% (141)
`
`Vemurafenib
`
`Comments
`Phase II for
`selumetinib
`study; Phase I for
`dabrafenib
`studies; Phase I
`for vemurafenib
`study
`
`Phase II
`
`Phase II
`
`Phase II
`
`Phase II
`
`Reference
`Hayes et al (138)
`Kim et al (52)
`Falchook et al (40)
`Flaherty et al (35)
`
`Hyman et al (8)
`
`Hyman et al (8)
`
`Hyman et al (8)
`
`Hyman et al (8)
`
`patients, five (12%) achieved a partial response or better, includ-
`ing one (2%) complete response, with duration of response > 36
`months; 24 patients (56%) achieved stable disease as best con-
`firmed response. Ten patients (23%) remained in the study > 6
`months.
`
`Companion Diagnostics for BRAF
`Detection
`There exist FDA-approved companion diagnostics for vemur-
`afenib (COBAS 4800 BRAF V600 Mutation Test) to identify those
`melanoma patients harboring the BRAF V600E mutation (39, 48)
`and for the approved combination regimen of dabrafenib and
`trametinib (THxID BRAF kit) for those melanoma patients har-
`boring the BRAF V600E or BRAF V600K mutation (41). However,
`these diagnostics, while well validated, are limited by their inability
`to detect other mutations, as well as amplifications and rearrange-
`ments in BRAF. They also cannot detect additional genomic
`abnormalities that coexist in most patient tumors. Other technol-
`ogies such as next-generation sequencing are better suited to the
`more comprehensive analysis that is often needed (49).
`
`Predictive Value of BRAF Mutations for
`BRAF and/or MEK Inhibitor Therapy in
`Diverse Cancers and Related Conditions
`BRAF V600E mutation
`Since the approval of vemurafenib for BRAF V600E-mutated
`melanoma, accumulating evidence presented in published reports
`supports the idea that what works for BRAF V600E-mutated mel-
`anoma is often also effective for other cancers characterized by the
`BRAF V600E aberration (Table 3). Dabrafenib was granted the
`Breakthrough Therapy designation for treatment of patients with
`metastatic BRAF V600E mutation-positive non–small cell lung
`cancer (NSCLC; 50) based on a phase II study that reported a
`response rate of 54% for BRAF V600E mutation—positive, pre-
`
`treated NSCLC patients receiving treatment with dabrafenib (51). A
`phase I study reported three papillary thyroid cancer patients whose
`disease was characterized by BRAF V600E, had either a partial
`response or stable disease in response to treatment with dabrafenib
`(52), a gastrointestinal stromal patient whose tumor harbored the
`BRAF V600E mutation experienced continuing tumor regression
`while being treated with dabrafenib (53), a child with glioblastoma
`multiforme harboring the BRAF V600E aberration had complete
`clinical regression from treatment with vemurafenib (54), glioma
`patients whose tumors carried the BRAF V600E mutation were
`reported to respond to treatment with vemurafenib (55), and
`several case studies have reported clinical benefit from treatment
`with vemurafenib for BRAF V600E-mutated hairy cell leukemia
`patients (9, 56–58). One study consisting of three BRAF V600E-
`mutated multisystemic and refractory Erdheim-Chester disease
`patients reported substantial and rapid clinical and biologic
`improvement from treatment with vemurafenib lasting 4 months
`(10, 59). In addition, a phase II trial of vemurafenib in BRAF V600-
`mutated Erdheim-Chester disease (a non-Langerhans histiocytosis)
`and Langerhans cell histiocytosis reported an overall response rate
`(defined as percentage of patients with either complete or partial
`response) of 36.4%, with one patient achieving a complete response
`(9.1%) and three patients with partial response (27.3%); none of
`the 11 evaluable patients had progressive disease (60).
`Of interest, a basket study of vemurafenib reported clinical
`activity of vemurafenib in predominantly BRAF V600E-mutated
`nonmelanoma cancers. Complete or partial responses, tumor
`regression and prolonged disease sta