Executive Summary
Lorlatinib (also known as PF-06463922) is a small molecule inhibitor of the Anaplastic
Lymphoma Kinase (ALK) and c-ROS oncogene 1 (ROS1) kinase activities. Pfizer seeks approval of lorlatinib for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) previously treated with one or more ALK tyrosine kinase inhibitors (TKIs). The proposed lorlatinib dosing regimen is 100 mg orally once daily (QD) with or without food.
The recommended dosing regimen was selected based on safety and tolerability results of the phase 1 dose escalation portion of Study B7461001, which determined that 100 mg QD was well tolerated.The primary evidence of efficacy supporting the 100 mg QD dose is based on the overall response rate (ORR) and intracranial ORR (IC-ORR) in Study B7461001, which is 48% and 55%, respectively. An exposure-response (E-R) relationship was not observed between
lorlatinib steady state exposure metrics and ORR and IC-ORR. However, the E-R analysis is mainly based on exposure at the proposed approved dosage and limited range of exposure. E-R relationships for Grade 3-4 hypercholesterolemia and for any Grade 3-4 adverse reaction were observed at exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure.
Recommendations
The Office of Clinical Pharmacology has reviewed the information submitted in NDA 210868.
This NDA is approvable from a clinical pharmacology perspective. The key review issues with specific recommendations/comments are summarized below:
Review Issue Recommendations and Comments
Pivotal and Supportive evidence of effectiveness
The primary evidence of effectiveness comes from dose expansion cohorts of Study B7461001.
General dosing instructions The proposed lorlatinib dosing regimen of 100 mg QD with or without food is effective and has a manageable safety profile.
• Statistically significant exposure-response relationships for Grade 3-4 hypercholesterolemia and for any Grade 3-4 adverse reactions were observed at exposures achieved at the
recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure. These findings support the selection of the proposed dosing regimen along with the dose modification and toxicity management strategy outlined in the label.
• In the Phase 2 portion of B7461001, 7.6% of patients
permanently discontinued treatment due to an AEs and 23.3%
Review Issue Recommendations and Comments
• The most frequent adverse reactions that led to dose reductions or interruptions were edema (9%), cognitive effects (5%), hypertriglyceridemia (5%), hypercholesterolemia (4.1%), peripheral neuropathy (4.1%), increased lipase (3.1%), dyspnea (2.7%), mood effects (2.7%), pneumonia (2.4%), hallucinations (2%), and fatigue (2.0%).
Dosing in patient subgroups (intrinsic and extrinsic factors)
• No dose adjustment is needed for patients with mild hepatic impairment. The PK of lorlatinib in patients with moderate and severe hepatic impairment is unknown. See Post-Marketing Requirements and Commitments for the PMR regarding hepatic impairment.
• No dose adjustment is needed for patients with mild and moderate renal impairment. The PK of lorlatinib in patients with severe renal impairment is unknown. See Post-Marketing Requirements and Commitments for the PMR regarding severe renal impairment.
Drug-drug interactions • Concomitant use of LORBRENA decreases the concentration of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures.
• Itraconazole, a strong CYP3A inhibitor, increases exposure of lorlatinib after a single dose. Avoidance of strong CYP3A inhibitors or a dose reduction to 75 mg lorlatinib is
recommended based on clinical DDI data and supportive PBPK simulations.
• Rifampicin, a strong CYP3A inducer, decreases the exposure of lorlatinib after a single dose. In addition, 83% of healthy subjects who received multiple daily doses of rifampicin concomitantly with a single dose of lorlatinib had severe hepatotoxicity with Grade 3-4 AST/ALT elevations. A possible mechanism for hepatotoxicity is through activation of the Pregnane X Receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists. The risk of hepatotoxicity with
concomitant use of lorlatinib and moderate CYP3A inducers is unknown.
• Lorlatinib is contraindicated with strong CYP3A inducers.
Avoidance of the concomitant use of moderate CYP3A inducers is recommended. See Post-Marketing Requirements and Commitments for the PMR to investigate the mechanism of the observed severe hepatotoxicity.
Labeling Generally acceptable. The review team has specific content and formatting change recommendations.
Review Issue Recommendations and Comments Bridge between the
to-be-marketed and clinical trial formulations
The anhydrous free-base tablet formulation was used in the clinical pharmacology studies, whereas the tablet formation was used in Trial B7461001. In Study B7461005, a PK bridge was estimated between the and anhydrous free-base formulations and demonstrated
bioequivalence. In Study B7461016, the anhydrous free-base tablet formulation was bioequivalent to the to-be-marketed commercially scaled formulation, which is also an anhydrous free-base tablet.
Post-Marketing Requirements and Commitments PMR or
PMC Key Issue(s) to be Addressed
Rationale Key Considerations for
Design Features
Hepatic metabolism plays a major role in the elimination of lorlatinib.
The recommended dose of lorlatinib in patients with moderate to severe hepatic impairment has not been established. The clinical study will determine whether dose
adjustment is needed in these specific populations.
Severe renal impairment can affect the renal clearance of lorlatinib; it may also affect the expression of hepatic drug metabolism enzymes and transporters. The
recommended dose of lorlatinib has not been established for patients with severe renal impairment. The clinical study will determine
whether dose adjustment is needed in this specific population.
Complete ongoing PK Study B7461010 to determine whether dose adjustment is needed in patients with severe renal impairment.
(b) (4) (b) (4)
PMR or
PMC Key Issue(s) to be Addressed
Rationale Key Considerations for
Design Features in subjects following multiple daily doses of rifampicin and a single co-administered dose of lorlatinib. A plausible mechanism for this hepatotoxicity may be through the synergistic activation of the PXR by lorlatinib and rifampin, which are both PXR agonists. PXR agonists are generally CYP3A inducers. Since the mechanism of the hepatotoxicity is unknown, there is a potential safety risk for severe hepatotoxicity when lorlatinib is co-administered with CYP3A inducers and PXR agonists. A preclinical study should be designed to assess this mechanism and provide labeling information
Summary of Clinical Pharmacology Assessment Pharmacology and Clinical Pharmacokinetics
Steady-state lorlatinib maximum plasma concentration (Cmax) and area under the curve (AUC) increased proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dose). At the recommended dosage, the mean [coefficient of variation (CV) %] Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ng·h/mL (39%) in patients with cancer, and there was no accumulation.
Absorption
The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady state.
The mean absolute bioavailability is 81% (90% confidence interval [CI] 75.7%, 86.2%) after oral administration compared to intravenous administration.
Distribution
In vitro, protein binding of lorlatinib to human plasma proteins, including serum albumin and α1-acid glycoprotein, was 66% at a concentration of 2.4 µM and the blood-to-plasma ratio was 0.99. The mean (CV%) steady state volume of distribution (Vss) was 305 L (28%) following a single intravenous 50 mg dose (0.5 times the recommended dose).
Elimination
The mean plasma half-life (t1/2) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib. The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady state, suggesting autoinduction.
Metabolism: In vitro, lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating
radioactivity in a human [14C] mass balance study. The oxidative cleavage metabolite, M8, is pharmacologically inactive. Therefore, data related to M8 are not further presented in this review.
Excretion: Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (< 1% as unchanged) and 41% in feces (about 9% as unchanged).
General Dosing and Therapeutic Individualization General Dosing
Pfizer proposed a dosing regimen of 100 mg administered orally, daily, with or without food.
The MTD was not reached in the dose escalation portion in Study B7461001 which dosage of 10 mg to 200 mg lorlatinib QD were evaluated. Grade 1/2 CNS toxicity occurred in 1 of 3 patients enrolled in the 200 mg QD cohort during the first cycle of treatment. Additionally, in the 150 and 200 mg QD cohorts, the majority of patients experienced adverse reactions resulting in temporary discontinuation and/or dose reduction. Patients did not tolerate the 75 mg or 100 mg BID dosing regimens. Lorlatinib was considered tolerable at the next highest dose, 100 mg QD, which was selected as the recommended phase 2 dose (RP2D) and was evaluated in the dose expansion portion in Study B7461001.
Therapeutic Individualization Specific Populations:
No clinically meaningful differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min), mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST >
ULN or total bilirubin > 1.5 × ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment or severe renal impairment on lorlatinib pharmacokinetics is unknown.
Drug-Drug Interactions:
CYP3A Inducers: Twelve healthy subjects received rifampicin, a strong CYP3A inducer that also activates PXR, 600 mg once daily for 8 days (Days 1 to 8) and a single oral 100 mg dose or LORBRENA on Day 8. The co-administration of rifampin with LORBRENA reduced the mean lorlatinib AUCinf by 85% and Cmax by 76%. Grade 2-4 increases in ALT/AST occurred within 3 days of lorlatinib dosing. Grade 4 ALT/AST elevations occurred in 50% of subjects, Grade 3 ALT/AST elevations in 33%, and Grade 2 ALT/AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within 7 to 34 days (median 15 days). The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity with the concomitant use of moderate CYP3A inducers is unknown. LORBRENA is contraindicated with strong CYP3A inducers. Discontinue strong CYP3A inducers for
3 plasma half-lives of the strong CYP3A inducers prior to initiating
treatment with lorlatinib. Avoid concomitant use of LORBRENA with moderate CYP3A inducers.
If concomitant use of moderate CYP3A inducers cannot be avoided, monitor ALT, AST and bilirubin as recommended.
CYP3A Inhibitors: Itraconazole, a strong CYP3A inhibitor, resulted in a 42% increase in AUCinf and a 24% increase in Cmax of a single oral 100 mg dose of lorlatinib. Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of lorlatinib. Avoid the concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce LORBRENA dose as recommended.
CYP3A Substrates: LORBRENA 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate). Concomitant use of LORBRENA decreases the concentration of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures.
(b) (4)
(b) (4)
Outstanding Issues
The mechanism of the hepatotoxicity observed in the rifampicin drug interaction study (B7461011) will be evaluated within a PMR stated as follows: Evaluate the risk for hepatotoxicity when lorlatinib is co-administered with CYP3A inducers (PXR and non-PXR agonists) and non-CYP3A inducers (PXR agonist and non-PXR agonists) using a
pharmacologically-relevant animal model capable of demonstrating the clinically observed hepatotoxicity signal. The study should be designed to
provide labeling information or instructions for hepatotoxicity.
Comprehensive Clinical Pharmacology Review
General Pharmacology and Pharmacokinetic Characteristics
The general overview of lorlatinib ADME and clinical PK information are presented in the table below.
Physiochemical properties Chemical structure and molecular weight
Chemical Structure of lorlatinib (Source: NDA210868, Figure 3.2.S.1-1) Molecular weight: 406.41 g/mol
Log P: 2.45 at pH 9
LogD: 2.23 at pH 5, 2.47 at pH 7, and 2.45 at pH 9
Aqueous solubility Lorlatinib is a weak base with a pKa of 4.92 and exhibits pH dependent solubility characteristics.
(Source: NDA210868, Table 3.2.S.1.3-1) Pharmacology
Mechanism of
Action Lorlatinib is a small molecule inhibitor of the (ALK) (IC50 values ranging from 0.65 to 65 nM for wild-type and mutated ALK) and c-ROS oncogene 1 (IC50 values ranging from 0.23 to 1.3 nM) kinase activities.
Active Moieties Lorlatinib and its benzoic acid metabolite (PF-06895751 or M8), resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib, were observed to be the major species in plasma,
(b) (4)
QT/QTc
Prolongation In 272 patients who received lorlatinib at the recommended dose and had a baseline PR assessment in activity-estimating portion of Study B7461001, of whom 7 had a baseline PR > 200 ms, the maximum mean change from baseline for PR interval was 14.2 ms (two-sided 90% upper CI 16.2 ms). Among the 265 patients with PR interval < 200 ms, 14% had PR interval prolongation > 200 ms after starting LORBRENA. The prolongation of PR interval occurred in a concentration-dependent manner.
Atrioventricular block occurred in 1.1% of patients.
In 275 patients who received lorlatinib at the recommended dose in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTc interval (i.e., > 20 ms) were detected.
General Information
Bioanalysis Lorlatinib and its metabolite, M8, were measured using validated LC-MS/MS methods. A summary of the method validation reports is included as an appendix (19.4 OCP Appendices).
Healthy Volunteers vs.
Patients
PK characteristics were similar between healthy subjects and the target populations based on population PK analyses.
Based on the results of the dose escalation trial B7461001 ), the observed geometric mean (CV%) AUC0-tau,ss and Cmax,ss of lorlatinib in patients treated at the 100 mg QD dosing regimen is 5121 ng·h/mL (30%) and 550.2 ng/mL (32%).
Minimal effective
dose or exposure Not determined. Lorlatinib 100 mg was the only dose regimen tested in patients with NSCLC.
Maximal tolerated
dose or exposure In Study B7461001, patients with NSCLC were treated with lorlatinib up to doses of 200 mg QD. The MTD was not reached or determined.
Dose
Proportionality Lorlatinib showed dose-proportional increase in both Cmax and AUC across the dose range of 10 to 200 mg following a single dose and multiple doses. See 19.4 OCP Appendices for detail.
Accumulation The mean accumulation ratio (Rac) following lorlatinib 100 mg QD was 1.07 (29%).
Variability Following 100 mg QD dose, the inter-subject variability (CV%) of steady state AUCtau and Cmax was 30%
and 32%, respectively.
Absorption
Bioavailability In Study B7461007, the absolute bioavailability of lorlatinib was 80.78% (90% CI: 75.73-86.16%) in healthy volunteers.
Tmax In Study B7461001, the median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady state in patients with NSCLC.
1.08 (1.04-1.12) 1.30 (1.21-1.39) Solution
1.0 (0.5-1.5) Tablet 1.5 (0.5-2.0) In Study B7461008, the exposure of lorlatinib was not altered following a single dose of 100 mg oral solution and a single dose of 100 mg immediate-release tablet (Anhydrous free-base) in healthy volunteers under fasting conditions.
(b) (4)
Food effect
In Study B7461008, no clinically relevant food effect was observed on the exposure of lorlatinib following the concomitant administration of single 100 mg immediate-release tablet (anhydrous free-base) with a high-fat (approximately 50% of total caloric content of the meal) and high calorie (approximately 150 protein calories, 250 carbohydrate calories, 500-600 fat calorie totaling approximately 1000 calories) meal in healthy volunteers.
In Study B7461008, no clinically relevant PPI effect was observed on the exposure of lorlatinib following the concomitant administration of single 100 mg immediate-release tablet (anhydrous free-base) with repeated doses of rabeprazole in healthy volunteers under fasting condition.
Relative Bioavailability (Different formulations)
In Study B7461005, the relative bioavailability of the old tablet formulation ) was compared to the two extemporaneous tablet formulations (anhydrous free base and
vs. anhydrous free base formulations AUC0-inf
(GMR, 90% CI) Cmax
(GMR, 90% CI) Tmax (hours)
(range)
0.95 (0.90-1.00) 0.85 (0.78-0.93) Anhydrous free base
1.5 (1.0-3.0) 1.5 (1.0-3.0)
The exposure of lorlatinib was not altered following a single dose of 100 mg anhydrous free base tablet and a single dose of 100 mg tablet in healthy volunteers under fasting condition.
vs. anhydrous free base formulations AUC0-inf
(GMR, 90% CI) Cmax
(GMR, 90% CI) Tmax (hours)
(range)
0.99 (0.94-1.04) 1.01 (0.92-1.09) Anhydrous free base
1.5 (1.0-2.0) 1.5 (1.0-3.0) The exposure of lorlatinib was not altered following a single dose of 100 mg tablet and a single dose of 100 mg tablet in healthy volunteers under fasting condition.
(b) (4)
Relative Bioavailability (commercial formulation)
In Study B7461016, the relative bioavailability of the anhydrous free base tablet from clinical batches was compared to the commercial scaled anhydrous free base tablets (25, 100 mg).
100 mg commercial (4×25 mg) vs. 100 mg clinical (4×25 mg) anhydrous free base formulations AUC0-inf
(GMR, 90% CI) Cmax
(GMR, 90% CI) Tmax (hours)
(range)
1.01 (0.98-1.05) 1.07 (0.96-1.18) Commercial
1.0 (1.0-4.0) Clinical 1.5 (1.0-2.0)
The exposure of lorlatinib was not altered following a single dose of 4×25 mg commercial anhydrous free base tablets and a single dose of 4×25 mg clinical anhydrous free base tablets in healthy volunteers under fasting condition.
100 mg commercial vs. 100 mg clinical (4×25 mg) anhydrous free base formulations AUC0-inf
(GMR, 90% CI) Cmax
(GMR, 90% CI) Tmax (hours)
(range)
1.01 (0.98-1.05) 1.01 (0.91-1.12) Commercial
1.0 (1.0-4.0) Clinical 1.5 (1.0-2.0)
The exposure of lorlatinib was not altered following a single dose of mg commercial anhydrous free base tablets and a single dose of 4×25 mg clinical anhydrous free base tablets in healthy volunteers under fasting condition.
100 mg commercial (1×100 mg) vs. 100 mg clinical (4×25 mg) anhydrous free base formulations AUC0-inf
(GMR, 90% CI) Cmax
(GMR, 90% CI) Tmax (hours)
(range)
1.05 (1.01-1.09) 1.07 (0.97-1.18) Commercial
1.0 (1.0-4.0) Clinical 1.5 (1.0-2.0) The exposure of lorlatinib was not altered following a single dose of 1×100 mg commercial anhydrous free base tablets and a single dose of 4×25 mg clinical anhydrous free base tablets in healthy volunteers under fasting condition.
Distribution Volume of
Distribution Based on non-compartmental analysis in Study B7461007, the geometric mean volume of distribution (Vd) was 305 L (28%) following a single intravenous 50 mg dose.
Plasma Protein
Binding In vitro, protein binding of lorlatinib to human plasma proteins, including serum albumin and α1-acid glycoprotein, was 66% at a concentration of 2.4 µM.
Blood to Plasma
Ratio The mean blood-to-plasma ratio was 0.99 for lorlatinib.
Elimination
Half-life In Study B7461007, the mean plasma half-life (t1/2) was 27 hours (19%) following a single intravenous 50 mg dose. In Study B7461001, the mean apparent plasma half-life (t1/2) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib.
Clearance In Study B7461001, the mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady state, suggesting autoinduction.
Metabolism
(b) (4)
(b) (4)
(b) (4)
Primary metabolic
pathway(s) In vitro, lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3 to 3 lorlatinib metabolites, M6, M1a, and M2a. CYP3A4 (100%) is responsible for M6 formation. CYP3A4 (34-60%), CYP3A5 (40%), CYP2C8 (0-24%), CYP2C19 (0-35%), and (0-8%) are responsible for M2a formation. UGT1A4 (90%) and UGT1A3 (10%) are responsible for M1a formation. In plasma, M6, M1a, and M2a represent 4.5%, 8.0%, and 2.3%, respectively, and are not consider the major lorlatinib metabolite. M8, resulting from cleavage of the amide and aromatic ether bonds of lorlatinib, is the major lorlatinib metabolite representing 21% in plasma, but is inactive. The pathway leading to the M8 formation is unknown.
Inhibitor/Inducer In vitro, lorlatinib activates PXR (EC50 value of 2.85 µM and Emax value of 13.8) and CAR (EC50 and Emax
values were not estimated due to atypical dose-response curves).
Lorlatinib induces CYP3A4 mRNA (>40-fold), which is comparable to rifampin (45-fold). Lorlatinib induces CYP3A4 activity, but is not comparable to rifampin. In human hepatocytes, lorlatinib appears to have time-dependent inhibition characteristics (KI value of 7.92 µM and kinact value of 0.081 min-1) at higher lorlatinib concentrations. Lorlatinib also induces CYP2B6 mRNA and activity.
Lorlatinib and M8 do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Lorlatinib inhibits CYP3A, but does not induce CYP1A2, CYP2B6, and CYP3A. M8 does not inhibit CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A.
Lorlatinib and M8 do not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15.
Lorlatinib inhibits P-glycoprotein (P-gp), organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP).
Lorlatinib does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OCT2, MATE2K, and systemic BCRP. M8 does not inhibit for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K.
Excretion Primary excretion pathways (% dose)
±SD
In a human mass balance Study B7461004 with mean total radioactivity recovery of 89%, radioactivity recoveries in feces and urine were 41% (9% unchanged lorlatinib) and 48% (<1% unchanged lorlatinib), respectively.
Clinical Pharmacology Questions
Does the clinical pharmacology program provide supportive evidence of effectiveness?
Yes. Pfizer stated that in Study B7461001, the MTD was not reached in the dose escalation portion. Patients were treated at a dosage of up to 200 mg QD lorlatinib. However, 1 of 3 patients experienced Grade 1 or 2 CNS toxicity during the first cycle of treatment. However, in the 150 and 200 mg QD cohorts, the majority of patients experienced adverse reactions resulting in temporary discontinuations and/or dose reductions. Patients also did not tolerate the 75 mg or 100 mg BID dosing regimens. As a result, lorlatinib was considered tolerable at the next highest dose, 100 mg QD, which was the recommended phase 2 dose (RP2D) evaluated in
Yes. Pfizer stated that in Study B7461001, the MTD was not reached in the dose escalation portion. Patients were treated at a dosage of up to 200 mg QD lorlatinib. However, 1 of 3 patients experienced Grade 1 or 2 CNS toxicity during the first cycle of treatment. However, in the 150 and 200 mg QD cohorts, the majority of patients experienced adverse reactions resulting in temporary discontinuations and/or dose reductions. Patients also did not tolerate the 75 mg or 100 mg BID dosing regimens. As a result, lorlatinib was considered tolerable at the next highest dose, 100 mg QD, which was the recommended phase 2 dose (RP2D) evaluated in