CDK4/6 inhibitors in oncology

Ongoing clinical trials

Antonio FrassoldatiUniversità di Ferrara

Deregulation in CDK4/6-Rb Pathwayis present in several tumors

Knudsen, Trends in cancer, 2017

Clear reasons for exploring the effectivenss of CDK4/6 inhibitors also in non-breast cancers

Types of trials exploring the role of CDK4/6 inhibitors in oncology

Basket trials

Umbrella trials

Conventional trials

Diagnosis-agnostic basket trialNCI-MATCH

Diagnosis-agnostic basket trialNCI-MATCHStarting date Aug 2015

Signature program

Signature programPreliminary results

Peguero, ASCO 2016

Preliminary antitumor activity in 4 pts: 1 urothelial ca (CCND1 amp), 1 sarcoma (CDK4 amp), 1 unknown primary (CDK6 amp), 1 ovarian ca (CDK6 mut)

S1400 Lung-MAP Study• First-in-kind master protocol, coordinated by SWOG on behalf of

NCTN, which is designed to simultaneously and independently test multiple biomarker-driven therapies

• Trial continues accrual and new sub-studies are being planned

aMust include a platinum-based regimenNCTN, National Clinical Trials Network; PS, performance status; CCGA, cell cycle genetic alterations; FGFR, fibroblast growth factor receptor

Papadimitrakopoulou. J Clin Oncol 2016ClincalTrials.gov

NCT02154490

• Stage IV squamous NSCLC• No mixed histologies, EGFR

mutation or ALK fusion allowed

• PS ≤1• Eligible for screening:– at progression following ≥1

line of systemic therapya for any stage disease

– prior to progression on ≥1 dose of current therapya for stage IV disease

Biomarker present

Biomarker absent

S1400B: PI3K+GDC-0032

S1400C: CCGA+palbociclib

S1400D: FGFR+AZD4547

S1400I: Nivolumab/ipilimumab

vs. nivolumab

Randomized phase III studies

planned

Single-arm phase II studies

Planned analysis of PROs

GEN

OM

IC S

CR

EEN

ING

Aims• To establish an NCTN process for genomic screening of large homogeneous populations of patients with cancer • To evaluate new targeted therapy-based regimens, using matched predictive biomarker-drug pairs• Expedite FDA approval of safe and effective regimens

Match sub-study

Non-match sub-study

Start Jun 2104

Lung-MAP Study Current Status:Biomarker Profiles

CCGA, cell cycle genetic alterations; CCND, Cyclin D;FGFR, fibroblast growth factor receptor; Papadimitrakopoulou. J Clin Oncol 2016

Of the 714 patients registered by June 5, 2016, 622 (87%) had biomarker results and were eligible for a sub-study

The prevalence of patients with cell cycle-associated biomarkers was 19%, higher than anticipated in the study protocol (14%)

42 93

3 13

Prevalence of biomarkers

9% of patients were PIK3CA+ (n=55)

19% of patients were CCGA+ (n=116)

1

9

82

Prevalence of cell cycle-associated biomarkers in patients assigned to palbociclib arm

Genes amplified Patients (n=116)

CCND1 78CCND2 22CDK4 6CCND3 5CCND1, CCND3 2CCND1, CCND2, CCND3 1CCND1, CDK4 1CCND2, CCND1 1

16% of patients were FGFR+ (n=99)

National Lung Matrix Trial: Palbociclib Molecular Cohorts

• Multi-arm, non-randomized, non-comparative, phase II umbrella trial• Patients allocated to targeted therapy according to molecular genotype of their

tumor• Recruitment is ongoing at 18 Experimental Medicine Cancer centers across the

UK

• Histologically or cytologically confirmed stage III-IV NSCLC

• Completed SOC therapy• ≥1 line of treatment (not

applicable for patients who have progressed within 6 months of completing adjuvant treatment or definitive chemoradiation) M

OLE

CU

LAR

SC

REE

NIN

G Primary endpoints:•ORR •PFSSecondary endpoints: •Best percentage change in sum of target lesion diameters•TTP•OS•Toxicity

Collaborators: Cancer Research UK, Pfizer, AstraZeneca, Experimental Cancer Medicine Cancer Network

NCT02664935

Arm C2ADC: proficient Rb

+ P16 lossArm C3

ADC: proficient Rb + CDK4 amplification

Arm C4NSCLC: proficient Rb

+ CCND1 amplificationArm C6

NSCLC: proficient Rb + KRAS mutation

Arm C1SCC: proficient Rb

+ P16 loss

All patients treated with palbociclib (usual dosage)Middleton, Ann Oncol 2015

National Lung Matrix Trial: Palbociclib Molecular Cohorts

Collaborators: Cancer Research UK, Pfizer, AstraZeneca, Experimental Cancer Medicine Cancer Network

NCT02664935

No efficacy

data reported

yet

Conventional Trials with CDK4/6 inhibitorsin non-breast cancers

• CDK4/6i single agent

• CDK4/6i combination– With chemotherapy

– With other targeted agents

5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0

0

3 0 0

6 0 0

9 0 0

1 2 0 0

1 5 0 0

D a y P o s t T u m o r I n n o c u l a t i o n

Tum

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olum

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m3 )

V e h ic le

P a l b o c i c l ib ( 7 0 m p k , Q D , 5 d o n / 2 d o f f , p . o . )

C is p la t i n ( 6 m p k , Q 7 D , i . p . )

P a lb o c i c l i b + C i s p l a t in ( R x d i s c o n t i n u e d )

P a lb o c i c l ib + C is p la t i n ( P a lb o m a in t e n a n c e )

Palbo maintenance

Ongoing Trials with CDK4/6i in solid tumorsType of tumor Trial

ph.Drugs

Solid tumors III

Ribocilcib+trametinib; palbocilcib+taselisib/pictilisibGemcitabine+ribocilcib; Oxaliplatin+FU+palbociclib

NSCLC/SCLC I, II Ribocilib+ceritinib; Palbocilib+binimetinib; Palbociclib+PD0325901Carboplatin+etoposide+atezolizumab+trilaciclib

H&N cancers I,II IMRT+cetuximab+palbocilib

Melanoma II Ribociclib+encorafenib; Ribociclib+bimetinib; abemaciclib;

Sarcomas I, II Doxorubicin+ribociclib; ribociclib; abemaciclib

Pancreatic cancer I Nab-paclitaxel+palbociclib; ribociclib+trametinib; ERK1/2 Inhibitor (LY3214996)+abemaciclib

Ovarian cancer II Ribociclib+letrozole

Prostate cancer II Palbociclib; Docetaxel+ribociclib;

GlioblastomaOligodendroglioma

I, IIII

Ribociclib; abemaciclib; abemaciclib+temozolamide or ramucirumab; palbociclib

Several potential combination of CDK4/6in with other drugs

ClinicalTrial.gov, 9/2017;

Lung cancerTumor type Alterations

Cyclin D CDK4/6 CDKN2A/p16 Rb

NSCLC Amplification 5–30% Overexpression (48% early-stage)

– p16 loss (53% early-stage )

Rb loss (17% early-stage )

Phase II, single-arm trial with palbociclib in lung cancer with inactivated CDKN2A (NCT01291017)

Simon’s 2-stage design – 20 patients enrolled during first stage; 19 previously treated NSCLC (negative for p16): palbociclib 125 mg/day (3 wks on 1 wk off), 11 with adenocarcinoma, 8 with squamous cell carcinoma

• No responses observed in 16 evaluable patients• 8 patients (50%) had SD for 16–42 weeks• 6 patients (37.5%) had SD for ≥24 weeks• median PFS was 12.5 weeks

Gopalan, ASCO 2014

Grade 3-4 adverse events

Exploring multiple combination with Abemaciclib in lung cancer

Garrido et al WCLC 2017; Kelly et al; WCLC 2015DCR: disease control rate

1-3 priorlines

Lung cancer harboring KRAS mutation

• KRAS mut are present in 15% to 25% of metastatic NSCLC• In preclinical models of NSCLC, KRAS mutations exhibit synthetic lethal interaction with genetic inactivation of CDK4 • CDK4/6in showed antitumor activity in multiple human NSCLC xenografts, especially in models with KRAS activating mutations

Goldman, Clin Lung Trials 2016

Pylayeva-Gupta, Nat Rev Cancer 2011

Juniper trial

Phase I-II trial with palbociclib + binimetinib in NCSLC with KRAS mutation conducted at Dana Farber

Palbociclib + the MEK Inhibitor PD-0325901 for KRAS-mutant NSCLC and Solid Tumors

• Ongoing open-label study (NCT02022982)• Primary outcome measures: safety and tolerability, MTD,

and RP2D • Secondary outcome measures: PK, target engagement of

palbociclib and PD-0325901 in pre- and on-treatment tumor biopsies, and ORR

ORR, overall response rate; RP2D, recommended phase II dose

Palbociclib starting at 75 mg QD (3/1 schedule) and increased until MTD and RP2D are established

+PD-0325901 starting at 2 mg BID (3/1 schedule) and increased until MTD and RP2D are established

Phase IPatients with solid tumors or KRAS-mutant NSCLC

CDK4/6in in brain metastases• Brain metastases occur in a significant number of cancer patients, with the incidence being highest in lung cancer (40% - 50%), breast cancer (15% - 25%), and melanoma (5% - 20%)

Tolaney, ASCO 2017

• In radiolabeled studies in rats, [14C]LY2835219-derived radioactivity was measurable in CNS through 24 hourspostdose.

• In phase I study, abemaciclib concentrations in CSF were consistent with unbound plasma concentrations

OIRR: objective intracranial response rate

Glioblastoma and other CNS tumors

Tumor type Alterations

Cyclin D CDK4/6 CDKN2A/p16 Rb

Glioblastoma multiforme

– CDK4/6 amplification (15.5%)

CDKN2A deletion (57.8%)

RB1 mutation or deletion (7.6%)

Trial Ph Population Treatment OutcomeNCT02345824 I Glioblastoma

GliomaRibociclib Inhib. of CDK4/6 pathway

Ribociclib concentr.in tissue & plasmaTumor progressionSurvivalsafety

NCT02607124 I/II High grade glioma (pontine; bithalamic)

Ribociclib Adverse eventsPts alive at 1yrTTF & PFSpseudoPD rate

NCT02532320 II OligodendrogliomaOligoastrocytoma

Palbociclib PFSSafetyORRSurvivalbiomarkers

ClinicalTrials.gov, aug2017

Head & Neck cancer• P16 inactivation (genetic and epigenetic) present in >80% • Rb mutated or deleted in only around 5% of cases• CCND1 amplifications in >20% of tumors• HPV-positivity (5–20% of all SCCHN) associated with high P16

expression HPV+ patients excluded

• Phase I trial exploring cetuximab + palbociclib combination:PR was observed in 2 patients (22%) and SD in 6 (67%)• Median TTP was 112 days (range, 28−224)• Median OS was 361 days (range, 124 – 588+)

After 2 cyclesTarget lesion: 2.7 cm

BaselineTarget lesion: 4.0 cm

Patient 4 (dose level 2): chest CTPatient 8 (dose level 2): neck CT

Responses after 2 cycles

Michel, Oral Oncol 2016

Phase I/II Trial of the Addition of Palbociclib to Cetuximab in Patients with Incurable SCCHN

Phase II component

Sub-studies will be performed to: • Assess changes in P16 expression, Ki67 (IHC), pRb (IHC), Cyclin D1 (IHC), and apoptosis (TUNEL assay) following palbociclib + cetuximab• Correlate these molecular changes with clinical endpoints (ORR, TTP, PFS, and OS); RNA sequencing will also be performed• Monitor patient QoL using the FACT H&N and EORTC QLQ-C30

NCT02101034

• Primary: ORR• Secondary: PFS &

OS

Palbociclib 125 mg QD 3/1Cetuximab: loading:400 mg/m2 IV

Weekly: 250 mg

Patients with incurable,

HPV-unrelated SCCHN

Arm 1: platinum resistant

Arm 2: cetuximab resistant

Pancreatic cancerTumor type Alterations

Cyclin D CDK4/6 CDKN2A/p16 Rb

Pancreatic cancer Amplification (25%)

CDK4 overexpression (60–75% in pancreatic intra-epithelial

neoplasia)

p16 alterations (27–95%)

Mutations (5%)

Pre-clinical models demonstrated anti-proliferative activity with CDK 4/6 inhibitors alone; synergistic effects observed when combined with a PI3K/mTOR (Ly3023414) or TGF-βR1 inhibitor (galunisertib)

Chiorean, ASCO 2016

CDKin + PIK3CA-mTOR inhibitors

CDKin + TGF-βR1 inhibitors

Palbociclib + nab-paclitaxel in metastic pancreatic cancer

PDX* Models of PDACHidalgo, AACR 2015

* PDX: patient derived xenograft

Ovarian cancersTumor type Alterations

Cyclin D CDK4/6 CDKN2A/p16 Rb

Epithelial Amplification (2%)Overexpression (5%)

CDK4 amplification (2%) Overexpression (15%)

CDKN2A deletions (35%) CDKN2A methylation (40%) p16 loss (34%)

Altered expression (3%)

Endometrioid Overexpression (13.3%)

CDK4 overexpression (27%)

Overexpression (36%) No Rb loss (0%)

Serous Overexpression (4%) Overexpression CDK4(12%)

Overexpression (78%) Loss in 4–20%

• Palbociclib demonstrated antiproliferative effects in ovarian cancer cell lines, mainly in Rb-proficient cell lines with low p16

• This profile was observed in 37% of ovarian cancer, and was independently associated with poor PFS NCT01536743

Single-agent Palbociclib in Patients with Recurrent Ovarian Cancer: preliminary efficacy data

Konecny, J Clin Oncol 2016

Efficacy endpoint Outcome (n=40)CA125 response rate, n (%)

CR/PR 2/3 (5.0/7.5)SD 21 (52.5)PD 13 (32.5)RECIST best overall response, n (%)a

PR 2 (5.7)SD 15 (42.9)PD 18 (51.4)

67% of cases had received >3 previous lines

Trial Ph Population Treatment Outcome measureMC1561/NCT02657928

II Patients with ER+ relapsed ovarian, fallopian tube, primary peritoneal, or endometrial cancer

Letrozole plus ribociclib

Proportion of patients alive

PFS at 12 weeks

LiposarcomaTumor type Alterations

Cyclin D CDK4/6 CDKN2A/p16 Rb

Liposarcoma (dedifferentiated/ well-differentiated)

Overexpression (70%)

CDK4 amplification (>95%)

Loss of p16 (3–8%)

Low Rb expression

(40%)

• Preliminary data with palbociclibin Rb+ liposarcoma

– Palbociclib considered active if ≥ 9/28 pts progression free at 12 wks

• 19/29 pts reached 12 wks PFS – Estimated 12-wk PFS: 66% (1-sided

90% CI: 51% to 100%)

Dickson, J Clin Oncol. 2013 After 12 mos

Liposarcoma

Dickson, Jama Oncol 2016

CLEE011-HMO-CTIL/NCT02571829a II

Patients with locally advanced or metastatic, well/dedifferentiated liposarcoma with documented disease progression ≤6 months

Ribociclib Response to therapy

CHDM201X2103C/ NCT02343172 Ib/II

Patients with locally advanced or metastatic, well/dedifferentiated liposarcoma whose disease has progressed on at least one prior systemic therapy

Ribociclib + HDM201 (restoring p53 activity)

DLT and PK (Phase I)/ PFS (Phase II)

MelanomaTumor type Alterations

Cyclin D CDK4/6 CDKN2A/p16 Rb

Melanoma Amplification (~17% in BRAFV600E-mut metastatic

Elevated mRNA (63%)

Elevated CDK4mRNA (76%)

Mutations in CDKN2A (19%) Deletion of CDKN2A (38%)

RB1 mutation (10% of NF1-mutant cutaneous melanomas)

Familial melanoma – CDK4 mutations (0.7%)

CDKN2A mutations (~19%) (8)

–

Cutaneous melanoma (triple-WT)

Amplification (3–11%) CDK4 amplification (3–15%)

CDKN2A mutation, deletion, or hypermethylation (40–70%)

Mutation (2–11%)

Centrality of RAS signaling, with activating mutations occurring in BRAFV600 (35–50%),NRAS (10–25%), NF1 (15%)

Binimetinib, MEK inhibitor), and Encorafenib (selective BRAF inhibitor), demonstrated activity as single agents in NRAS- and BRAF-mutant melanomas

CDK4/6in + MEKin in NRAS mut melanoma

Sullivan, CCR 2015 Kwong, Nature 2012

New roles for CDK4/6 InhbitorsEnhancement of immune-response

Goel, Nature 2017mouse models of breast carcinoma and other solid tumours treated with CDK4/6 inhibitors

CDK4/6 inhibitors can cooperate with anti-PDL1 antibodies

Goel, Nature 2017

Conclusions

• CDK4/6-Rb pathway is frequently deregulated in several solid tumors

• CDK4/6 inhibitors showed preliminary efficacy results, alone or combined with other targeted agents or chemotherapy, in lung, H&N, ovarian and melanomatous cancers, as well as on CNS lesions.

• Several biomarkers are under evaluation as predictive of sensitivity or resistance

• New intriguing combinations with immune-checkpoint inhibitors could be explored in the near future