First trial regarding molecular down-staging in breast cancer and First neoadjuvant approach in Luminal B early stage breast cancer

1. Tunio’s Oncology Journals Review

2. CORALLEEN Phase 2 Trial
Ribociclib plus Letrozole vs. Chemotherapy
for Postmenopausal women with
HR-positive, HER2-negative, Luminal B
Breast Cancer
SOLTI investigators from Spain

3. Background
70%
Within this group clinical and biological heterogeneity exists
OncotypeDX, EndoPredict, & PAM50 (Prosigna) to identify patients at
low risk of DM without neo/adjuvant chemotherapy

4. MONALEESA-7 trial has shown a survival benefit with addition of
Ribociclib (CDK4/6 inhibitor) in addition to endocrine therapy in
advanced, HR-positive, Her2-negative breast cancer
Arguably, CDK4/6 inhibitors delay the use of chemotherapy
in the advanced stage setting, now being tested in adjuvant setting
Background

5. • PENELOPE-B phase 3 trial is evaluating the value of 1 year of
adjuvant palbociclib in patients with non-pCR following standard
neoadjuvant chemotherapy.
• The PALLAS and MonarcHER phase 3 trials are assessing the
value of 2 years of adjuvant palbociclib and abemaciclib,
respectively
• NATALEE phase 3 trial is testing the efficacy of 3 years of
adjuvant ribociclib in clinically high-risk disease.
Background

6. Neoadjuvant approach with ribociclib plus endocrine therapy for
early stage, HR-positive, HER2-negative luminal B breast cancer
would be of interest because;
30% of all breast are luminal B
DM at 10 years from diagnosis range 10-20%
Heterogeneity needs to be understood to to de-escalate or
escalate locoregional and systemic therapies
Background

7. CORALLEEN tested the hypothesis that the ribociclib (KISQALI)
plus Letrozole offers high biological & clinical activity in the
neoadjuvant setting in patients with PAM50 luminal B early
stage breast cancer.
Objectives

8. Parallel-arm, multicenter, randomized, open-label, phase 2 trial
conducted in 21 hospitals of Spain
Methods
Inclusion criteria: patients were postmenopausal women with
confirmed invasive luminal B by PAM50 assay , HER2-
negative, stage I-IIIA breast cancer with adequate CBC, LFTs
and renal function tests
Excluded: Stage IV disease, multifocal/bilateral breast cancer,
synchronous malignancy, cardiac disease, including prolonged
QT interval, and uncontrolled hypertension.

9. Randomization was 1:1 using a secure web-based system
Methods
Stratification according to tumor size (T1-T2 vs.T3), nodal
involvement using permuted blocks of 25
Double blind
All outcomes assessors were masked to clinical data.

10. Standardized PAM50 analysis was done at a central laboratory.
Subtype other than luminal B at screening were excluded from
the trial
Methods
ARM A
ARM B
Ribociclib 600 mg OD x 3 weeks one week off q 28 d
Letrozole 2.5 mg OD continuous q 28 d
4 cycles of AC (60/600) q 21 d followed by
Weekly Paclitaxel 80 mg/m2 x 12 weeks
Duration of neoadjuvant therapy was 24 weeks.

11. Dose reductions were allowed for doxorubicin,
cyclophosphamide, paclitaxel, and ribociclib for toxicities
Methods
Dose reductions were not permitted for Letrozole because
only the 2·5 mg pill is approved

12. Baseline MRI and USG breast/ axilla were done. USG-guided
FNA/core bx only in case of suspicious axilla LN
Methods
After 12 weeks of neoadjuvant treatment, USG was repeated to
rule out progression; However, MRI was necessary to confirm it
Surgery was done within 7 days after the last dose of ribociclib
or 2 weeks after the last dose of chemotherapy. Letrozole was
continued until day of surgery

13. At baseline, day 15, and surgery, collection of tissue samples
were mandatory to used to measure the expression of the PAM50
genes
Methods
Low-ROR disease
40 points if LN negative
15 points if 1-3 LN positive
(risk of <10% of developing distant
metastasis at 10 years if treated
without chemotherapy)
Intermediate-ROR disease
41–60 points if node-
negative
16–40 points if 1-3 LN
positive
High-ROR disease
61–100 points if node
negative
41–100 points if 1-3 LN
positive
4 LN positive irrespective of
score

14. Primary endpoint
Proportion of patients switching from intermediate or high-
ROR disease to low-ROR disease after neoadjuvant
treatment
Methods
Secondary endpoints (4/9)
> pCRB (ypT0/Tis ypNx) & pCRBL (ypT0/Tis ypN0)
> Residual cancer burden score (0–1)
> Preop: endocrine prognostic index (PEPI) score of 0
> Proportion switching to luminal A

15. Assuming 20–25% of pts in each arm would reach low-ROR
disease, the study would require a sample size of 47/arm.
Expecting 10% of pts drop out, a total of 104 pts was
planned to be recruited
Methods
Analysis was intention to treat

16. Methods
Study conception & Design: SOLTI investigators
Study Funding and provision of ribociclib: Novartis
Prosigna tests: NanoString
The funders had no role in study design, data collection, data
analysis, data interpretation, or writing of the report

17. 106
pts

18. Results
Median age: 63·5 yrs (58-71)
Median T size(MRI): 31mm (25-
43)

19. Conversion to luminal A occurred
in 43 (82·7% [95% CI 69·7–91·8])
in CT & 43 (87·8% [75·3–95·4]) in
ribociclib + Letrozole arm
Correlation coefficients between
ROR score at surgery and Ki67
was 0·35 in the CT & 0·71 in the
ribociclib + Letrozole
All residual tumors were ER+ with
Allred scores of 5–8
Results

20. Absolute changes in
ROR score between
baseline and surgery
in both groups
At time of
surgery
Ribociclib
+Letrozole
chemotherapy
Overall 25 (19.5-
30.5)
29.4 (23.5-
35.3)
Low 14 (10.3-
17.6)
14 (9.3-18.6)
Intermediate 28.9 (21.4-
36.3)
35 (28.5-
41.5)
High 42.8 (24.7-
60.9)
54.9 (42.1-
67.7)

21. The proportion of patients who had breast conserving surgery
39 (72·2%; 95% CI 58·4–83·5) in CT
44 (85·7%; 73·3–92·9) in Ribociclib + Letrozole
Results

22. ROR score at day 15
24 (37%) patients had switched to luminal A subtype in CT
47 (96%) patients had switched in the ribociclib + Letrozole
Absolute changes in ROR score from day 15 to surgery in
ribociclib plus Letrozole, 44% had a decrease, 21% had an
increase of 1–10 ROR points, & 29% had an increase of > 10 ROR
points
Patients treated with CT, 87% had a decrease, 4% had an
increase of 1–10 ROR points, & 9% had an increase of > 10 ROR
points
Results

23. 8% required a dose
reduction of ribociclib
31% required a dose
reduction of Paclitaxel
No deaths in any arm
Results

24. Key points
Conversion to luminal A occurred in 87·8% in ribociclib plus letrozole arm
pCRB was 2%, pRCBL 0% & RCB 6.1% in the ribociclib plus letrozole arm
ROR score at day 15, 96% switched to luminal A in ribociclib plus letrozole arm

25. NEOPAL TRIAL
NeoPAL phase 2 trial randomly assigned 106 patients with luminal A or B disease
to 19 weeks of palbociclib and letrozole or FEC for 3 cycles followed by docetaxel
for 3 cycles.
The primary objective was the proportion of patients who had a residual cancer
burden of 0–1.
Residual cancer burden of 0–1 was observed in 8% in the palbociclib group & 16%
in the CT group.
PEPI of 0 was observed in 18% in palbociclib group & 8% in the CT group.
NeoPAL trial suggested that less than 20% of patients might not need CT.

26. LIMITATIONS
• CORALLEEN has exploratory nature; did not formally
compare the proportion of pts with low-ROR disease in both
arms
• Trial ended after surgery, no long-term follow-up
• Prognostic value of PAM50 after neoadjuvant CDK4/6
inhibition and endocrine therapy is unclear
• Small sample warrants more large trial

27. Contact me
Mutahir A. Tunio
FRCR (clinical Oncology)
Email:
drmutahirtonio@hotmail.com