CDK4/6 inhibitors in oncology
Ongoing clinical trials
Antonio Frassoldati
Università di Ferrara
Deregulation in CDK4/6-Rb Pathway is 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 trial
NCI-MATCH
Diagnosis-agnostic basket trial NCI-MATCH
Starting date Aug 2015
Signature program
Signature program Preliminary 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 regimen
NCTN, National Clinical Trials Network; PS, performance status; CCGA, cell cycle genetic alterations; FGFR, fibroblast growth factor receptor
Papadimitrakopoulou. J Clin Oncol 2016 ClincalTrials.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 therapyafor 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
GENOMIC SCREENING
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 78
CCND2 22
CDK4 6
CCND3 5
CCND1, CCND3 2
CCND1, CCND2, CCND3 1
CCND1, CDK4 1
CCND2, 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) MO
LECULAR SCREENING
Primary endpoints:
•ORR
•PFS
Secondary 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 C2 ADC: proficient Rb
+ P16 loss Arm C3 ADC: proficient Rb + CDK4 amplification
Arm C4
NSCLC: proficient Rb + CCND1 amplification
Arm C6
NSCLC: proficient Rb + KRAS mutation
Arm C1 SCC: 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 inhibitors in 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
Tumor volume (mm3 )
V e h i c l e
P a l b o c i c l i b ( 7 0 m p k , Q D , 5 d o n / 2 d o f f , p . o . ) C i s p l a t i n ( 6 m p k , Q 7 D , i . p . )
P a l b o c i c l i b + C i s p l a t i n ( R x d i s c o n t i n u e d ) P a l b o c i c l i b + C i s p l a t i n ( P a l b o m a i n t e n a n c e )
Palbo maintenance
Ongoing Trials with CDK4/6i in solid tumors
Type of tumor Trial ph.
Drugs
Solid tumors II
I
Ribocilcib+trametinib;
palbocilcib+taselisib/pictilisib Gemcitabine+ribocilcib;
Oxaliplatin+FU+palbociclib NSCLC/SCLC I, II Ribocilib+ceritinib;
Palbocilib+binimetinib;
Palbociclib+PD0325901
Carboplatin+etoposide+atezolizuma b+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;
Glioblastoma
Oligodendroglioma
I, II II
Ribociclib; abemaciclib;
abemaciclib+temozolamide or ramucirumab; palbociclib
Several potential combination of CDK4/6in with other drugs
ClinicalTrial.gov, 9/2017;
Lung cancer
Tumor 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 2015
DCR: disease control rate
1-3 prior lines
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 I
Patients 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 hours postdose.
• 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 Outcome
NCT02345824 I Glioblastoma Glioma
Ribociclib Inhib. of CDK4/6 pathway
Ribociclib concentr.in tissue & plasma Tumor progression
Survival safety NCT02607124 I/II High grade glioma
(pontine;
bithalamic)
Ribociclib Adverse events Pts alive at 1yr TTF & PFS pseudoPD rate NCT02532320 II Oligodendroglioma
Oligoastrocytoma
Palbociclib PFS
Safety ORR Survival biomarkers
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 cycles Target lesion: 2.7 cm Baseline
Target lesion: 4.0 cm
Patient 4 (dose level 2): chest CT Patient 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 3/1 Cetuximab: loading:400 mg/m2IV
Weekly: 250 mg
Patients with incurable, HPV-unrelated
SCCHN
Arm 1: platinum resistant
Arm 2: cetuximab resistant
Pancreatic cancer
Tumor 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 PDAC
Hidalgo, AACR 2015
* PDX: patient derived xenograft
Ovarian cancers
Tumor 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 measure
MC1561/
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
Liposarcoma
Tumor 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 palbociclib in 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)
Melanoma
Tumor type Alterations
Cyclin D CDK4/6 CDKN2A/p16 Rb
Melanoma Amplification (~17% in BRAFV600E-mut metastatic Elevated mRNA (63%)
Elevated CDK4
mRNA (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 Inhbitors
Enhancement of immune-response
Goel, Nature 2017
mouse 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
