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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
or v
olum
e (m
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
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