Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.

PURPOSE: Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF- or K-RAS/N-RAS-mutated solid tumors.
METHODS: During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion.
RESULTS: The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF-mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF-mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS-mutated endometrial cancer and K-RAS codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS-mutated colorectal cancer (n = 20).
CONCLUSION: Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS-mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

INTRODUCTION

The RAS-RAF-mitogen-activated protein kinase (MAPK) pathway plays a prominent role in tumorigenesis.[1] K-RAS mutations are common in pancreatic, colorectal, lung, and biliary tract tumors and occur in 15%–30% of endometrioid carcinomas.[1,2] H-RAS mutations are common in salivary gland tumors[1]; N-RAS mutations are frequent in melanomas. Among RAF serine/threonine kinases, B-RAF has the greatest inherent kinase activity.[1,3] B-RAF mutations occur in approximately 50% of malignant melanomas,[4] 40% of thyroid carcinomas,[3] between 2% and 38% of low-grade serous ovarian cancers (LGSOCs),[5-8] and approximately 10% of metastatic colorectal cancers (CRCs).[9] Despite this evident role in tumor biology, pursuit of RAS as a therapeutic target has proven difficult.[10]

First-generation B-RAF inhibitors have demonstrated clinical benefit in B-RAFV600E metastatic melanoma[11,12] but not as monotherapy in B-RAFV600E CRC.[13,14] Cutaneous squamous cell carcinoma (SCC) develops in 10%-26% of patients who receive B-RAF inhibitors, including treatment-related keratoacanthomas that result from paradoxical MAPK signal activation.[15,16] Most patients who receive these therapies develop resistance and ultimately experience relapse.[17]

In melanoma, resistance to first-generation B-RAF inhibitors stems from several mechanisms, including epidermal growth factor receptor (EGFR)–mediated reactivation of MAPK signaling,[18] RAS-independent RAF kinase dimerization induced by B-RAFV600E splice variants,[19,20] AKT-dependent signaling pathways,[17,21] and MAPK-redundant signaling pathways.[17,22] In patients with B-RAF–mutated CRC, nonresponsiveness to first-generation B-RAF inhibitors is associated with EGFR-mediated reactivation of the MAPK pathway.[14]

Lifirafenib (BGB-283) is a novel, first-in-class, investigational RAF dimer inhibitor with potent, reversible inhibition of wild-type A-RAF, B-RAF, C-RAF, and B-RAFV600E as well as EGFR[15,23] and K-RAS.[24,25] Preclinical studies have suggested that lifirafenib leads to a greater number of responses in B-RAF–mutated cancers than first-generation B-RAF inhibitors, including vemurafenib and dabrafenib.[15] This study was designed to investigate safety/tolerability, examine pharmacokinetics (PK), establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) during dose escalation, and evaluate preliminary antitumor activity of lifirafenib in patients with tumors that harbor B-RAF, N-RAS, or K-RAS mutations.

METHODS

Study Design and Participants

This first-in-human, dose-escalation/dose-expansion, phase I study was conducted from November 20, 2013, to October 19, 2017, across 20 sites in Australia and New Zealand. Adult patients with histologically/cytologically confirmed advanced/metastatic solid tumors and an Eastern Cooperative Oncology Group performance status ≤ 1 were eligible if no effective standard therapy was available and they had locally assessed B-RAF, N-RAS, or K-RAS mutation-positive solid tumors or pancreatic cancer with unknown mutation status. Exclusion criteria included untreated leptomeningeal or brain metastases, major surgery within 28 days or radiotherapy within 14 days of enrollment, or unresolved toxicity grade > 1 from prior cancer therapy. All inclusion/exclusion criteria are presented in the Data Supplement (online only).

During dose escalation, patients were enrolled in successive dose-escalation cohorts of 3-6 patients each. Lifirafenib was administered on day 1 followed by a 2-day treatment-free period to allow for single-dose PK sample collection; on days 4-24, patients received once-daily lifirafenib. After cycle 1, patients received continuous treatment with once-daily lifirafenib in 21-day cycles. The first patient received 15 mg lifirafenib twice daily, but the dosing regimen was changed to 5 mg once daily after reviewing the safety and PK profile in that patient. Subsequent dose escalation cohorts examined 5, 10, 20, 30, 40, 50, and 60 mg lifirafenib once daily. Because modeling and PK data suggested that discontinuous dosing regimens resulted in comparable or increased lifirafenib plasma concentrations versus continuous dosing schedules, an alternate 50-mg once-daily regimen on a week on/off cycle was examined (n = 3).

During dose expansion, patients with B-RAF and K-RAS/N-RAS mutations received lifirafenib 30 mg/d (RP2D) administered in 21-day cycles; patients could have melanoma (treatment naïve or resistant to B-RAF/MEK inhibitor therapy), CRC, non–small-cell lung cancer (NSCLC), thyroid cancer, endometrial cancer, pancreatic cancer, or other solid tumors. For both phases, patients continued treatment until unacceptable toxicity or patient withdrawal. Treatment beyond progression was permitted in patients who derived clinical benefit. Criteria for dose reductions/interruptions and treatment discontinuation are outlined in the Data Supplement.

End Points and Assessments

The primary end point during dose escalation was safety and tolerability, including dose-limiting toxicity (DLT) assessments and treatment-emergent adverse events (TEAEs). Adverse events (AEs) were graded by severity and evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Secondary end points included PK parameters from blood plasma samples obtained at prespecified time points, objective response rates (ORRs; complete response [CR] + partial response [PR]) and stable disease (SD) on the basis of RECIST version 1.1, progression-free survival (PFS), duration of response (DoR), and duration of SD. Exploratory end points included 18F-fluorodeoxyglucose (FDG) uptake using FDG positron emission tomography-computed tomography (FDG-PET-CT) scans at screening and on cycle 2, day 1 (± 3 days).

The primary end point during dose expansion was investigator-assessed ORR. Secondary end points included PFS, DoR, duration of SD, disease control rate (DCR), clinical benefit rate (CR + PR + durable SD [SD ≥ 24 weeks]), safety/tolerability, and steady-state predose lifirafenib plasma concentration at prespecified time points.

Statistical Analysis

Dose escalation sample size was determined by dose levels and emerging toxicities; 30 patients were required to establish the RP2D and schedule. Expansion cohorts were to include ≤ 20 patients (total: up to 200 patients); enrollment in some arms stopped early because of difficulties in patient recruitment. Descriptive statistics summarized continuous and categorical variables; Kaplan-Meier estimators summarized time-to-event variables. The safety analysis set consisted of patients who received ≤ 1 dose of lifirafenib. The DLT analysis set included patients who experienced DLTs (or patients who received ≥ 80% of planned lifirafenib doses) during cycle 1.

Study Oversight

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and the requirements of public registration of clinical trials. The protocol was approved by site-specific institutional review boards. Written informed consent was obtained from each patient at enrollment.

RESULTS

Patient Disposition

During dose escalation (n = 35), 31 patients received once-daily lifirafenib (5 mg, n = 3; 10 mg, n = 3; 20 mg, n = 3; 30 mg, n = 3; 40 mg, n = 10; 50 mg, n = 6; 60 mg, n = 3). Four patients received alternate lifirafenib dosing regimens (15 mg twice daily, n = 1; 50 mg/d on a week on/off schedule, n = 3). All 35 patients were included in the safety analysis set; 31 patients comprised the DLT analysis set. Reasons for treatment discontinuation included disease progression (n = 24), AEs (n = 5), investigator/sponsor decision (n = 1), and other (transition to lifirafenib compassionate use [thyroid cancer, n = 2; melanoma, n = 1]; clinical progression, n = 1; DLT, n = 1). During dose expansion (n = 96), reasons for treatment discontinuation included disease progression (n = 57), AEs (n = 19), withdrawal of consent (n = 4), investigator/sponsor decision (n = 3), death (n = 2), and other (transition to lifirafenib compassionate use [melanoma, n = 2; thyroid cancer, CRC, NSCLC, and LGSOC, n = 1 each], clinical progression, n = 5; noncompliance, n = 1). Across the entire study, 11 patients were treated > 2 weeks beyond progression (B-RAF, n = 7; K-RAS, n = 4); mean duration of treatment beyond progression was 157 days (range, 41-420 days) for patients with B-RAF mutations and 215 days (range, 100-256 days) for those with K-RAS mutations.

Demographic and Baseline Characteristics

Demographic and baseline characteristics are listed in Table 1. Patients were heavily pretreated, with approximately 50% receiving ≥ 3 lines of anticancer therapy and ≥ 75% having prior anticancer surgery (dose escalation, 77.1%; dose expansion, 87.5%). Twelve patients with B-RAF mutations received prior B-RAF inhibitor treatment. During dose escalation, 31.4% of patients harbored B-RAF mutations, and 57.1% harbored K-RAS mutations; similar proportions of patients harbored B-RAF (43.8%) or K-RAS (40.6%) mutations during dose expansion.

TABLE 1.

Demographic and Baseline Characteristics During Dose Escalation and Dose Expansion

Safety and Tolerability

During dose escalation, the most frequent TEAEs were fatigue (n = 24; 68.6%) and dermatitis acneiform (n = 15; 42.9%; Table 2). Five patients (14.3%) experienced TEAEs that led to discontinuation. Treatment-related TEAEs were predominantly grades 1-2. The most common grade ≥ 3 treatment-related TEAEs during dose escalation were thrombocytopenia (14.3%), hypertension (11.4%), and fatigue (11.4%; Data Supplement). Among patients eligible for DLT assessment (n = 31), 6 experienced reversible DLTs, 5 of which occurred at doses ≥ 40 mg/d (Data Supplement). Observed DLTs included grade 3 increased ALT (n = 1) and grade 4 thrombocytopenia (n = 5); thrombocytopenia typically occurred within 2-3 weeks of initial dosing. Comprehensive investigations (including bone marrow biopsies) in the first 2 patients with thrombocytopenia revealed normal bone marrow morphology and reserve, which suggested a peripheral cause. Patients were treated with platelet transfusion (n = 1) or prednisolone administration (n = 4) and withholding of lifirafenib; platelet counts recovered within 6-20 days. Grade ≥ 3 TEAEs (including DLTs) occurred in 26 patients (74.3%), with more patients reporting grade ≥ 3 TEAEs in the 40, 50, and 60 mg/d cohorts (61.5%) versus lower-dose cohorts (38.5%). Grade ≥ 3 TEAEs that occurred in patients who received ≥ 40 mg/d are listed in the Data Supplement. The MTD was established at 40 mg/d. Eighty percent (4 of 5 patients) of dose-limiting thrombocytopenia occurred in patients who received 40 and 60 mg/d (n = 2 each), and 70% of patients treated with 40 mg/d had dose interruptions/reductions as a result of drug toxicity, typically between days 13 and 28 of cycle 1. On the basis of these data, the RP2D was established at 30 mg/d.

TABLE 2.

Incidence of Treatment-Emergent Adverse Events That Occurred in More Than 10% of Patients in Either Phase

Of 96 patients who received lifirafenib during dose expansion, the most commonly reported TEAEs were fatigue (n = 47; 49%) and decreased appetite (n = 35; 36.5%; Table 2). During the entire study, cutaneous SCC or keratoacanthoma was not reported. Grade ≥ 3 TEAEs occurred in 68 patients (70.8%), and serious TEAEs occurred in 56 patients (58.3%). TEAEs led to discontinuation in 19 patients (19.8%), most commonly fatigue (n = 5) and thrombocytopenia (n = 2; Data Supplement). Fifty patients (52%) experienced AEs that led to a dose adjustment, which resulted in a median relative dose intensity of 95.0%. Four patients (4.2%) experienced 6 TEAEs considered unrelated to treatment that led to death: pericardial effusion, sepsis, pleural effusion, intracranial hemorrhage, intestinal perforation as a result of disease progression, and small intestinal obstruction (n = 1 each). During dose expansion, the most common grade ≥ 3 treatment-related AEs were hypertension (8.3%) and fatigue (7.3%); 2 patients discontinued because of treatment-related grade ≥ 3 thrombocytopenia.

Antitumor Activity

Patients with B-RAF and K-RAS mutations from both phases had responses (Table 3). Among patients with B-RAF mutations, 8 (15.1%) of 53 achieved PR, including 1 patient with melanoma who received prior RAF inhibitor therapy, and 27 (50.9%) of 53 had SD; time to response and DoR of patients with select tumors are shown in Figure 1. During dose escalation, 1 patient with B-RAF–mutated melanoma (40 mg/d) achieved CR (Data Supplement). Across the entire study, 5 of 23 patients with B-RAFV600 melanoma achieved confirmed PR, including 4 treatment-naïve patients and 1 who progressed after 6 months of prior B-RAF inhibitor therapy (Fig 1; Data Supplement). Confirmed PRs occurred in patients with B-RAF–mutated thyroid cancer/PTC (n = 2) and B-RAFV600E LGSOC (n = 1). One patient with B-RAF–mutated NSCLC achieved unconfirmed PR.

TABLE 3.

Patient Responses by Mutation Status

FIG 1.

(A and B) Responses in patients with B-RAF–mutated cancers (both phases). (>) Ongoing treatment indicates ongoing response at time of data cutoff. An additional 6 patients not included in this figure had prior B-RAF inhibitor treatment (4 had melanoma, 1 had colorectal cancer, and 1 had adenocarcinoma with unknown primary origin). (*) Patients who received prior B-RAF/MEK inhibitor treatment. CR, complete response; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.

Across the entire study, 2 patients with K-RAS mutations (endometrial cancer [20 mg/d] and codon 12–mutated NSCLC [30 mg/d], n = 1 each) had confirmed responses, which resulted in an ORR of 3.4%; 32 patients (54.2%) with K-RAS mutations had SD (Fig 2). Twelve patients with K-RAS– or N-RAS–mutated CRC had SD (Data Supplement); 5 patients with K-RAS–mutated endometrial cancer (codon 12 mutated, n = 4; codon 2 mutated, n = 1) and 2 patients with K-RAS–mutated NSCLC (codon 12 mutated and K-RAS G13D, n = 1 each) had SD (Data Supplement). Median DoR was 31.7 months (95% CI, 6.8 to 31.7 months) during dose escalation and 11.1 months (95% CI, 1.9 months to not reached) during dose expansion. Median duration of SD during dose expansion was 4.1 months (95% CI, 3.5 to 4.9 months). Duration of treatment was > 1 year for several patients with B-RAF (n = 10) and K-RAS mutations (n = 5).

FIG 2.

(A and B) Responses in patients with K-RAS–mutated cancers (excluding colorectal cancer; both phases). NE, not evaluable; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.

PK Outcomes

Systemic exposure increased from 5 to 50 mg on cycle 1, day 1, and cycle 2, day 1 (Data Supplement). Although not powered to assess proportionality, the log-log regression model accounted for > 80% of the observed variation from 10 to 60 mg for cycle 1, day 1. Lifirafenib was rapidly absorbed, with a median time to reach maximum plasma concentration of 3 hours. The accumulation ratio for maximum serum concentration (Cmax), area under the plasma concentration curve from 0-9 hours (AUC0-9), and AUC0-24 estimated from cycle 2, day 1/cycle 1, day 1, was similar from 10 to 50 mg (Data Supplement). Average accumulation ranged from 3.3- to 6.1-fold for Cmax and 3.6- to 7.6-fold for AUC0-9 and AUC0-24. Three patients had measurable terminal half-life (range, 15-59 hours); terminal half-life estimates should be interpreted with caution because samples were not collected beyond 72 hours after dosing.

FDG-PET-CT Scans

During dose escalation, 34 patients (including those who received lifirafenib 15 mg twice weekly or 50 mg once daily on a week on/off cycle) had tumor imaging on cycle 2, day 1. FDG-PET-CT scans showed no FDG uptake in 1 patient, low FDG uptake in 1 patient, moderate FDG uptake in 10 patients, and high FDG uptake in 15 patients (7 patients were missing postbaseline results). Complete metabolic reduction was observed in 1 patient with a B-RAF mutation who received 40 mg/d; 11 patients had partial metabolic reduction per European Organization for Research and Treatment of Cancer criteria.[26] Decreases in maximum and average standardized uptake volumes, indicative of significant pharmacodynamic activity, were generally observed at lifirafenib doses ≥ 30 mg. At cycle 2, day 1, changes in FDG uptake from baseline were observed in 9 patients, including 7 (20.6%) who changed from high to moderate uptake, 1 (2.9%) who changed from high to low uptake, and 1 (2.9%) who changed from low to no uptake. All patients with confirmed clinical responses (n = 3; 8.6%) had FDG-PET-CT responses, but not all patients with FDG-PET-CT responses had clinical responses (6 had SD). Among patients who received once-daily lifirafenib (n = 31), FDG-PET-CT responses were observed in patients with B-RAF, K-RAS, and N-RAS mutations (Fig 3).

FIG 3.

Responses across lifirafenib dose cohorts by 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) analysis. Two patients were missing a postbaseline PET scan. (*) Patients who were treated beyond progression. CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SUVave, average standardized uptake volume.

DISCUSSION

This first-in-human dose-escalation/dose-expansion study evaluated lifirafenib, a novel investigational oral RAF family kinase inhibitor, in patients with B-RAF–, K-RAS–, or N-RAS–mutated solid tumors. The MTD was determined as 40 mg once daily; DLTs included reversible thrombocytopenia and increased ALT.

Lifirafenib had an acceptable risk-benefit profile. The dose-escalation phase suggested that once-daily lifirafenib was better tolerated at doses ≤ 30 mg than ≥ 40 mg, irrespective of schedule. Treatment-related dermatologic toxicities were observed, but cutaneous SCCs and keratoacanthomas reported with other B-RAF inhibitor treatments[27] were not. Treatment-related thrombocytopenia and hypertension were manageable and likely stemmed from off-target inhibition of kinases other than B-RAF, including EGFR and PDGF. A prior report demonstrated that lifirafenib inhibited additional kinases, including EGFR, DDR1, DDR2, EPHA3, FLT3, VEGFR2, ABL1, RET, EPHGA7, EPHB2, MNK2, and ZAK, with half-maximal inhibitory concentrations (IC50s) within 10-fold of that for B-RAFV600E.[15] With an IC50 of 108 nM, inhibition of VEGFR2 by lifirafenib could potentially account for the clinically observed hypertension in our study and was similar to off-target effects of other kinase inhibitor therapies.[15,28] The precise mechanism of thrombocytopenia remains unclear but seems dose related because a higher proportion of patients experienced thrombocytopenia at doses ≥ 40 versus ≤ 30 mg/d. Thrombocytopenia resolved rapidly with drug interruption, and although steroids were initiated on the basis of an assumed peripheral (possibly immune-mediated) mechanism, the specific impact this intervention had remains unclear. A more direct kinase-mediated effect, particularly given lifirafenib’s novel kinase inhibition profile, remains possible and warrants additional exploration. Kinases, including EGFR and PDGF, have individually, but rarely, been implicated in platelet dysfunction,[29-31] and the effect of collectively inhibiting these kinases is unclear. Of note, thrombocytopenia was manageable at or below the RP2D and did not recur with ongoing dosing in patients who continued treatment. Additional exploration of alternate dose schedules and underlying causative mechanisms remains an important priority in the ongoing development of lifirafenib.

Lifirafenib was rapidly absorbed, and systemic exposure increased during cycles 1 and 2 from 10 to 50 mg/d. During dose escalation, FDG-PET-CT scans were used as a surrogate marker of MAPK pathway inhibition to define optimal biologic dosing.[32] Partial/complete metabolic reductions by FDG-PET-CT scan were observed in 12 of 34 patients, including 11 who received ≥ 30 mg/d lifirafenib, which suggests significant pharmacodynamic activity at doses ≥ 30 mg/d. The accumulation ratio was similar from 10-50 mg/d. On the basis of the safety/tolerability, antitumor activity, PK profile, and pharmacodynamic activity, the RP2D was established at 30 mg/d.

While the overall antitumor activity of lifirafenib was modest, antitumor activity was observed in patients with B-RAF–mutated solid tumors, including melanoma, thyroid cancer, and LGSOC. Limited information with regard to pharmacodynamic markers of response and/or resistance were collected; detailed genetic information for responders/nonresponders (beyond underlying B-RAF and K-RAS mutations) was unavailable for most patients. Additional investigation may be needed to understand the underlying mechanism of response and resistance to this novel agent and to inform future treatment decisions and/or trial design. During dose expansion, 4 of 7 patients with B-RAFV600–mutated melanoma who had not received prior B-RAF/MEK inhibitor therapy had confirmed PR (ORR, 57.1%; DCR, 85.7%). Because 2 patients with responses and no PD transferred to a compassionate use program, DoR was not reached. One of 3 patients with B-RAFV600–mutated thyroid cancer had confirmed PR (ORR, 33.3%; DCR, 100%; Data Supplement), comparable to reported clinical activities for first-generation B-RAF inhibitors, such as vemurafenib and dabrafenib, which demonstrated an ORR of 48% and 50% (DCR, 91%), respectively, in patients with B-RAF–mutated melanoma.[12,33] Importantly, antitumor activity was observed in K-RAS–mutant cancers, including NSCLC and endometrial carcinoma (Data Supplement), with prolonged disease control. In contrast, lifirafenib had limited clinical activity in patients with K-RAS–mutated CRC or pancreatic cancer. This observation was unlikely due to differences in K-RAS mutations between NSCLC and CRC or pancreatic cancer because these results were similar to phase I results of a novel RAF/MEK inhibitor, RO5126766, that showed promise in KRAS-mutated NSCLC and endometrial/ovarian cancers but not in K-RAS–mutated CRC.[34,35] This suggests that oncogenic K-RAS may be context dependent, potentially requiring different approaches on the basis of tumor types. Two novel investigational K-RASG12C covalent inhibitors, AMG 510 and MRTX849, recently demonstrated preliminary antitumor activity in K-RAS–mutant tumors.[36,37] Albeit early, the data showed promising efficacy signals and may represent a breakthrough in treatment of K-RAS–mutant tumors. However, targeting only K-RASG12C mutations limits the utility of these new therapies, resulting in a continued unmet medical need for tumors with oncogenic K-RAS mutations beyond K-RASG12C.

In summary, lifirafenib demonstrated an acceptable risk-benefit profile given the safety results and responses in patients with B-RAF–mutated melanoma, thyroid cancer, and LGSOC and K-RAS–mutated NSCLC and endometrial cancer. Our findings suggest that lifirafenib could potentially benefit patients with MAPK pathway–associated kinase alterations beyond B-RAFV600 mutations, including activated K-RAS. Additional investigation of the safety/efficacy of lifirafenib as monotherapy or in combination is warranted, especially in K-RAS–mutated solid tumor malignancies other than CRC; a phase I/II trial of lifirafenib in combination with a MEK inhibitor in patents with B-RAF– and RAS-mutant tumors (ClinicalTrials.gov identifier: NCT03905148) has recently commenced enrollment.