Date of first round report: 1 September 2016 Date of second round report: 30 January 2017



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Question 16 for sponsor


16. Is there any indication that palbociclib and letrozole may have a pharmacodynamics interaction that could explain higher rates of headache, hot flushes and hypertension in the placebo-containing arm?

Additional AEs that were imbalanced, with >1 report, from consideration of all causality grade 3-4 AEs, include:



  • AST increased (2.5% versus 0.9%), an imbalance consistent with:

    • the total number of treatment-related AST elevation AEs (6.8% versus 2.7%) and

    • the frequency of laboratory abnormalities for AST increased (52% versus 34%, including grade 3 findings in 3% versus 1%)

  • ALT increased (2.2% versus 0%), an imbalance consistent with

    • the total number of treatment-related AST elevation AEs (6.8% versus 1.8%)

    • the frequency of laboratory abnormalities for ALT increased (43% versus 30%, including grade 3-4 findings in 2.5% versus 0%)

  • Acute kidney injury (0.5% versus 0%)
      1. Question 17 for sponsor


17. In the supplemental Clinical Overview with Dossier version [0004], Table 8 shows ADRs (which are usually equated with treatment-related AEs). The frequency of some ADRs in that Table differs from the frequency of treatment-related AEs in the CSR; the data cut-off date is the same. For example, in Clinical Overview Table 8, ALT increased is reported as occurring in 9.9% of patients in the palbociclib-containing arm. In CSR Table 40, ALT increased is reported as occurring in 6.8%. It is noted a slightly different MedDRA coding version is used. Please account for the differences observed.

It is also noteworthy in the EMA Second JRAR that:

2 cases of fatal hepatic toxicity (Vuppalanchi, R., Saxena, R., Storniolo, A. M. V. and Chalasani, N. (2016), Pseudocirrhosis and liver failure in patients with metastatic breast cancer after treatment with palbociclib. Hepatology. doi:10.1002/hep.28720) have been recently reported with palbociclib associated to letrozole.

These cases are noted in the response to Safety Question 18, with the assertion made that pseudocirrhosis is more closely related to underlying disease than treatment.


      1. Treatment related adverse events (adverse drug reactions)


These were qualitatively similar to all-causality AEs described above.

Treatment-related infections were reported in 19.1% (palbociclib-containing arm) versus 8.1% (placebo-containing arm), and treatment-related rashes were reported in 10.8% versus 5.4% respectively.


      1. Deaths and other serious adverse events


Deaths are reported above, under ‘overall survival’. Most were due to disease progression. Narratives of deaths in CSR Section 14.3.3.1 amounted to CIOMS forms not consolidated narratives. For some reports it was difficult to discern whether the patient had received palbociclib or placebo.
      1. Questions 18-20 for sponsor


18. Indicate the location within the CSR, or provide separately, consolidated narratives for patients who died on treatment (or within 28 days of last dose), including information about whether palbociclib or placebo was given. Draft CIOMS forms are not considered sufficient, especially when treatment allocation is not revealed.

19. Regarding subject ID [information redacted], the autopsy concluded cardiogenic shock of unknown origin. Had this patient had QTcS assessment during the study, e.g. baseline? Was there QTc prolongation? It is noted this patient was on venlafaxine amongst other agents.

20. Regarding subject ID [information redacted], the autopsy found acute cardiovascular insufficiency. Which arm was the patient randomised to? Had this patient had QTcS assessment during the study, e.g. baseline? Was there QTc prolongation?

Serious AEs including deaths were reported in 19.6% (palbociclib-containing arm) versus 12.6% (placebo-containing arm), including data up to 28 days after last dose of study drug. Infections, febrile neutropenia and pulmonary embolism were the most common serious AEs.

An 84 year old female on palbociclib had an AE of syncope which was explained by ‘mild subarachnoid haemorrhage’ and a term called ‘bifrontal cortical confusion’ on CT.

      1. Question 21-22 for sponsor


21. In tabulation of AEs, was this event classified only as ‘syncope’, or also as ‘subarachnoid hemorrhage’ or some related term? It is noted that in Table 14.3.1.1.2, there are also events of cerebral haemorrhage (1 x grade 2) and cerebrovascular accident (1 x grade 3). How many distinct patients in the palbociclib versus placebo arms had any intracranial bleeding events on treatment? Is it known whether these bleeds were associated with intracranial metastases?

22. It is also noted in the SCS [Dossier version [0004]] that in Study 1010, SAEs included cerebral haemorrhage and subarachnoid haemorrhage (the latter, fatal). Please provide a signal analysis across randomised studies of palbociclib for ‘serious bleeding’ terms.


      1. Discontinuations due to adverse events


The following table (from CSR) shows all-causality AEs leading to permanent discontinuation (for more than one patient):

Table 58: All causality AEs leading to permanent discontinuation

Dose reduction in the palbociclib-containing arm was typically due to neutropenia / low neutrophils (in 131/444, 29.5%) and less commonly due to febrile neutropenia (1.4%), anaemia (1.6%), leukopenia (1.1%) and fatigue (1.1%).


      1. Evaluation of issues with possible regulatory impact

        1. Renal function and renal toxicity


Lab-based creatinine outcomes showed grade 3-4 elevations in 1.4% (palbociclib-containing arm) versus 0% (placebo-containing arm), consistent with the imbalance in the AE of acute kidney injury (0.5% versus 0%) reported earlier.
        1. Other clinical chemistry


Clinical chemistry lab-based outcomes (CSR; OTR indicates a non-missing lab value outside the grading range, i.e. normal value) are shown below:

Table 59: Clinical chemistry outcomes

Given the difference in duration of treatment across arms, there were no dramatic imbalances, although grade 3-4 hypocalcaemia was more prominent in the palbociclib-containing arm (2.0% versus 0.5%).



While three patients in the palbociclib-containing arm met lab criteria for potential Hy’s Law cases, none fully met Hy’s Law criteria. One had a stricture in the common bile duct requiring a stent; one had hepatic metastases and chronic cholecystitis; one had hepatic steatosis. There were no reports of drug-induced liver injury or hepatic failure.
        1. Haematology and haematological toxicity


The AE profile described in above clearly indicates that palbociclib has a major effect on haematology indices, confirmed by lab-based assessment (CSR; OTR indicates a non-missing lab value outside the grading range, i.e. normal value):

Table 60: Haematology outcomes


        1. Electrocardiograph findings and cardiovascular safety


There were no dramatic imbalances in frequency of QT prolongation, although prolongation of QTc interval ≥ 60 msec was observed in 3/441 (0.7%) versus 0/220, using a study-specific correction factor reasonably deemed more suitable at compensating for heart rate than QTcF or QTcB.

In PALOMA-2, more intensive ECG subgroup analysis was conducted in 125 patients (77 in the palbociclib-containing arm, 48 in the placebo-containing arm). Cycle 1 day 14 outcomes (in msec) are shown below:



Table 61: Cycle 1 Day 14 outcomes in 125 patients

While there is no positive control in this substudy, the outcomes do not suggest a strong effect of palbociclib on QTc interval. The 6 hr time point where the widest difference between palbociclib and placebo arms lay coincides with Tmax of 4-8 hrs. The threshold of regulatory concern described in the TGA-adopted EU guideline CHMP/ICH/2/04 is 5 ms (or upper bound of 95% CI 10 ms). Also, in this subgroup analysis, outlier analysis indicated no differences across arms.
      1. Question 23 for sponsor


23. Ninety percent (90%) CIs are calculated in the above Table. Please provide 95% CIs around the LS mean change from baseline for each time point and each arm.
        1. Other safety parameters


Concomitant use of some drug classes was imbalanced by >10% (CSR):

Table 62: Concomitant use of other drugs

Class

Palbociclib + letrozole

Placebo + letrozole

Antibacterials for systemic use

47.5%

35.1%

Otologicals

35.4%

23.0%

Ophthalmologicals

65.1%

52.7%

Immunostimulants, e.g. filgrastim

12.2%

0%

Vasoprotectives, e.g. dexamethasone

29.7%

17.6%

Corticosteroids (skin)

29.5%

17.6%

Ophthalmological and otological

25.0%

14.0%

Antibiotics (skin)

26.8%

16.2%

Nasal preparations

36.3%

25.7%

Gynaecological antiinfectives and antiseptics

27.5%

17.1%
      1. Evaluator’s overall conclusions on clinical safety


Prominent AEs were myelosuppression, alopecia and stomatitis, the same as those seen with cytotoxic chemotherapy. Quantitatively there were differences between AEs seen with palbociclib and those seen with more traditional chemotherapy. Alopecia was not reported uniformly; and severe stomatitis was not common. The frequency of serious infection was not clearly increased in the palbociclib-containing arm (noting imbalances in duration of treatment across arms).

Given that in PALOMA-2, palbociclib was ‘added on’ to the letrozole standard of care, it is not surprising that AEs in the palbociclib + letrozole were significantly imbalanced versus comparator. The impact of additional toxicity must be seen in the light of palbociclib’s anti-tumour efficacy.


    1. First round benefit-risk assessment for PALOMA-2

      1. First round assessment of benefits


        Indication

        Benefits

        Strengths and Uncertainties

        Large PFS benefit

        Moderate ORR benefit

        Large benefit in preventing disease progression as best objective response

        Uncertainty: do benefits in PFS and ORR translate into OS benefit?

        Uncertainty: impact on OS

        Uncertainty: extent of impact on QoL is not clear (no major differences seen)
      2. First round assessment of risks


        Risks

        Strengths and Uncertainties

        Myelosuppression (neutropenia, anaemia, thrombocytopenia)

        Alopecia

        Stomatitis

        Cataracts

        Modest increase in LFT derangements

        Uncertainty: extent to which neutropenia causes additional infection

        Uncertainty: extent to which thrombocytopenia causes additional bleeding

        Uncertainty: a few typically letrozole-related AEs were recorded at lower frequencies in the palbociclib + letrozole arm; it is unclear if this is a real effect
      3. First round assessment of benefit-risk balance


A detailed assessment of risk-balance is reserved for the Delegate’s Overview.
      1. First round recommendation regarding authorisation


Recommendations regarding authorisation are reserved for the Delegate’s Overview.
    1. Clinical questions


1. It is noted in the EMA’s Second Joint Rapporteur’s Assessment Report (JRAR) that:

The sponsor also commits to submit the final OS results from Study 1008 when they become available. Based on current projections, the readout is estimated to occur in May 2020 and the final report would be submitted by November 2020, as a type 2 variation.

Please provide an update about when the final OS outcomes are anticipated, and when the CSR reporting final OS outcomes will be available.

2. Beyond the OS analyses conducted at the time of the initial and final PFS analysis, are any OS analyses to be conducted (by the E-DMC, sponsor, or any other party) prior to the final OS analysis?

3. How many patients continued to receive palbociclib beyond RECIST-defined PD? Provide a summary of the benefits (if any) observed in PALOMA-2 with such treatment, e.g. median duration of treatment post-progression; PFS relative to others with PD who did not receive palbociclib post-PD; evidence of any tumour response after progression.

4. Please confirm that for the ‘investigator’ assessment of PFS, assignment of the overall response category was not made by the investigator, but was ‘independent of the overall response category provided by the investigator’. Who – sponsor, DMC or other agent – assigned the overall response category for the purpose of investigator-assessed PFS and related investigator-assessed outcomes?

5. Please describe the level of concordance between the investigator’s overall response category and the overall response category designated by the sponsor / DMC / other agent based on lesion measurements / assessments provided by the investigator. For example, how many patients per arm had discordance between an objective response and stable disease, or between stable disease and progressive disease?

6. Please point to a tabulation in the CSR (or create a tabulation) of the use of commoner prohibited concomitant medications (capturing type of medication, typical reason/s for use and extent of use), allowing comparison across arms.

7. In CSR Table 19 using CRF data, the study population is divided by disease free interval (‘since completion of prior (neo) adjuvant therapy’) into: De Novo (n=167 versus 81); ≤12 months (n=99 versus 48); and >12 months (n=178 versus 93). Could the sponsor confirm that by ‘de novo’ in this classification, what is meant is ‘no prior systemic therapy’ presumably equating to no prior neoadjuvant or adjuvant systemic therapy (rather than ‘de novo metastatic disease’)? Reference is also made to CSR Table 15, where n=167 versus 81 had no prior systemic therapies (either chemotherapy or hormonal), and to CSR Table 18, where n=139 versus 71 had ‘newly diagnosed’ recurrence type (other categories involving ‘recurrence’ whether locoregional or distant imply earlier diagnosis of breast cancer).

How many patients per arm had no prior systemic therapy for advanced disease despite not having ‘de novo metastatic disease’ on enrolment into the study? Why had these patients not received endocrine or at least systemic therapy at initial diagnosis of ‘advanced’ breast cancer? What was this group’s median length of time since diagnosis? Provide PFS and ORR outcomes per arm for this subgroup. Also provide PFS and ORR outcomes per arm for the subgroup described in CSR Table 18 as ‘newly diagnosed’ (taken by this evaluator to be truly ‘de novo’ advanced disease), based on investigator and BICR assessments (and according to both IMPALA and CRF analyses).

8. Provide the interim OS analysis that was performed at the time of the final PFS analysis, and any update. Provide 12- and 24-month OS rates per arm, estimated median OS per arm, an estimated OS hazard ratio, and estimated KM curves for OS.

9. Please comment in detail on the apparent discordance between mature PFS and immature OS outcomes.

10. The SAP version 3.0 states:

A supportive analysis will be performed by combining the OS data from this study and from the randomized Phase II Study A5481003 with similar approaches described above. The Study as a stratification factor (A5481003 vs. A5481008) will also be included in the analysis. Since the median OS time for the studied patient population is relatively long and it is anticipated a small fraction of OS events would be available at the time of OS interim analysis, this analysis will certainly increase the power of detecting the OS difference between two treatment arms, given both randomized studies have similar patient populations and OS follow up processes.

This implies that the supportive analysis will be conducted prior to OS final analysis.

Please provide this supportive analysis of OS outcomes across studies 1003 and 1008.

11. In PALOMA-3, there was a delay in time to deterioration for pain symptoms, in the palbociclib-containing arm. What outcomes were observed for pain symptoms in PALOMA-2?

12. The Clinical Evaluator for the main Dossier writes that assessment of benefit in patients with bone-only disease relies on measures of quality of life such as improvement in pain, reduced skeletal event rates, etc. What patient-reported outcomes for pain symptoms were observed in patients with bone-only disease?

13. In relation to alopecia, please characterise this further. For affected patients in the palbociclib-containing arm, was there typically ‘complete’ hair loss as might be seen with some chemotherapies or ‘thinning’ as might be seen with, for example, letrozole? Was there scalp tenderness? Did hair re-grow normally on treatment discontinuation?

14. It was noted from the CSR that there were several cases of intracranial haemorrhage in the palbociclib-containing arm (patient IDs 13331001 and 10131001). Were there other cases of significant bleeding? Was any case associated with thrombocytopenia of any grade?

15. Was sufficient information gathered to understand whether the imbalance in cataract surgery extended more than 28 days after the last dose?

16. Is there any indication that palbociclib and letrozole may have a pharmacodynamics interaction that could explain higher rates of headache, hot flushes and hypertension in the placebo-containing arm?

17. In the supplemental Clinical Overview with Dossier version [0004], Table 8 shows ADRs (which are usually equated with treatment-related AEs). The frequency of some ADRs in that Table differs from the frequency of treatment-related AEs in the CSR; the data cut-off date is the same. For example, in Clinical Overview Table 8, ALT increased is reported as occurring in 9.9% of patients in the palbociclib-containing arm. In CSR Table 40, ALT increased is reported as occurring in 6.8%. It is noted a slightly different MedDRA coding version is used. Please account for the differences observed.

18. Indicate the location within the CSR, or provide separately, consolidated narratives for patients who died on treatment (or within 28 days of last dose), including information about whether palbociclib or placebo was given. Draft CIOMS forms are not considered sufficient, especially when treatment allocation is not revealed.

19. Regarding subject ID 11921004, the autopsy concluded cardiogenic shock of unknown origin. Had this patient had QTcS assessment during the study, e.g. baseline? Was there QTc prolongation? It is noted this patient was on venlafaxine amongst other agents.

20. Regarding subject ID 10551006, the autopsy found acute cardiovascular insufficiency. Which arm was the patient randomised to? Had this patient had QTcS assessment during the study, e.g. baseline? Was there QTc prolongation?

21. An 84 year old female on palbociclib had an AE of syncope which was explained by ‘mild subarachnoid haemorrhage’ and a term called ‘bifrontal cortical confusion’ on CT.

In tabulation of AEs, was this event classified only as ‘syncope’, or also as ‘subarachnoid hemorrhage’ or some related term? It is noted that in Table 14.3.1.1.2, there are also events of cerebral haemorrhage (1 x grade 2) and cerebrovascular accident (1 x grade 3). How many distinct patients in the palbociclib versus placebo arms had any intracranial bleeding events on treatment? Is it known whether these bleeds were associated with intracranial metastases?

22. It is also noted in the SCS [Dossier version [0004]] that in Study 1010, SAEs included cerebral haemorrhage and subarachnoid haemorrhage (the latter, fatal). Please provide a signal analysis across randomised studies of palbociclib for ‘serious bleeding’ terms.

23. Ninety percent (90%) CIs are calculated in the above Table [refer to Section 8.3.4 above]. Please provide 95% CIs around the LS mean change from baseline for each time point and each arm.

24. Could the sponsor clarify their best estimate of the frequency of febrile neutropenia in PALOMA-2 (refer also to the footnote #11 earlier in this CER).

The sponsor’s answers to these questions were reviewed by the Delegate and taken into consideration during the decision process.



Therapeutic Goods Administration

PO Box 100 Woden ACT 2606 Australia

Email: info@tga.gov.au Phone: 1800 020 653 Fax: 02 6232 8605



https://www.tga.gov.au



1 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015.

3 Clarification: There was a case report of hepatic failure assessed by the Sponsor to be unrelated to blinded therapy and fulvestrant and to any clinical trial procedure. For this case the investigator considered drug induced hepatitis could not be excluded and therefore two separate AEs were collected for this event. For further discussion see Response to Safety Question 18.

4 Clarification: There was a case report of hepatic failure assessed by the sponsor to be unrelated to blinded therapy and fulvestrant and to any clinical trial procedure. For this case the investigator considered drug induced hepatitis could not be excluded and therefore two separate AEs were collected for this event. For further discussion see Response to Safety Question 18.

5 Clarification: There was a case report of hepatic failure assessed by the Sponsor to be unrelated to blinded therapy and fulvestrant and to any clinical trial procedure. For this case the investigator considered drug induced hepatitis could not be excluded and therefore two separate AEs were collected for this event. For further discussion see Response to Safety Question 18.

6 Clarification: There was a case report of hepatic failure assessed by the Sponsor to be unrelated to blinded therapy and fulvestrant and to any clinical trial procedure. For this case the investigator considered drug induced hepatitis could not be excluded and therefore two separate AEs were collected for this event. For further discussion see Response to Safety Question 18.

7 For discussion see responses to Clinical safety questions 5 and 7.

8 Sponsor correction: There was no case of fatal ischaemic colitis.

9 Clarification: There was a case report of hepatic failure assessed by the sponsor to be unrelated to blinded therapy and fulvestrant and to any clinical trial procedure. For this case the investigator considered drug induced hepatitis could not be excluded and therefore two separate AEs were collected for this event. For further discussion see Response to Safety Question 18.

10 Sponsor clarification: The investigator considered the event was possibly related to clinical trial procedure: bone scan. Both the investigator and the sponsor considered there was not a reasonable possibility that the event of renal disorder was related to study medication or concomitant medication (resolved and did not recur following re-introduction of therapy).

11For discussion see Response to Clinical Safety Question 17.

12 Clarification: There was a case report of hepatic failure assessed by the sponsor to be unrelated to blinded therapy and fulvestrant and to any clinical trial procedure. For this case the investigator considered drug induced hepatitis could not be excluded and therefore two separate AEs were collected for this event. For further discussion see Response to Safety Question 18.

13 Table 4.9 of the pharmacology evaluation report.

14 Anand, O., Yu, L. X., Conner, D. P., & Davit, B. M. (2011). Dissolution Testing for Generic Drugs: An FDA Perspective. The AAPS Journal, 13(3), 328. http://doi.org/10.1208/s12248-011-9272-y

15 EMA guideline on investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1), effective from 01/08/2010.

16 Table 5.5.1 of the pharmacology evaluation report

17Ford RR, O’ Neal M, Moskowitz SC, Fraunberger J (2016) Adjudication Rates between Readers in Blinded Independent Central Review of Oncology Studies. J Clin Trials 6:289. doi: 10.4172/2167-0870.1000289

18Sponsor Response to the relevant PI question: The sponsor acknowledges the evaluator’s position regarding the claims of Global Health Status/QoL and emotional functioning in the Product Information and recognises that the change from baseline does not exceed the 10 point threshold that has been established as a minimum to reach clinical significance. As such the sponsor has removed the claims from the PI.Instead the sponsor proposes to include information on a prespecified time-to-event analysis for deterioration in pain (TTD), defined as first occurrence of an increase of at least 10 points in pain symptom scores. Statistically convincing and plausible results were achieved with a difference in median time to deterioration of 8.0 vs 2.8 months, HR 0.6, p <0.001.

“Time to Deterioration (TTD) was prespecified as time between baseline and first occurrence of ≥10-point increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a symptom benefit by significantly delaying TTD in pain symptom scores compared with placebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; p<0.001).”



The sponsor considers this useful information for prescribers and the TTD statement proposed is approved in the SmPC.

19 Aktas, B., Kasimir-Bauer, S., Müller, V., Janni, W., Fehm, T., Wallwiener, D., … on behalf of the DETECT Study Group. (2016). Comparison of the HER2, estrogen and progesterone receptor expression profile of primary tumor, metastases and circulating tumor cells in metastatic breast cancer patients. BMC Cancer, 16, 522. http://doi.org/10.1186/s12885-016-2587-4

20 Rossi S, Basso M, Strippoli A, Dadduzio V, Cerchiaro E, Barile R, D'Argento E, Cassano A, Schinzari G, Barone C. Hormone Receptor Status and HER2 Expression in Primary Breast Cancer Compared With Synchronous Axillary Metastases or Recurrent Metastatic Disease. Clin Breast Cancer. 2015 Oct;15(5):307-12. doi:10.1016/j.clbc.2015.03.010. Review. PubMed PMID: 25922284.

21 Yau, HSC. (2008) Oxidation Sensitive ER Transcriptional Regulation in Hormone-dependent Breast Cancer. Joint Doctor of Philosophy dissertation with the University of California, San Francisco.

22 Sighoko, D., Liu, J., Hou, N., Gustafson, P., & Huo, D. (2014). Discordance in Hormone Receptor Status Among Primary, Metastatic, and Second Primary Breast Cancers: Biological Difference or Misclassification? The Oncologist, 19(6), 592–601. http://doi.org/10.1634/theoncologist.2013-0427

23 Van Poznak, C, Harris, LN and Somerfield, MR. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline (2015). doi: 10.1200/JOP.2015.005215. Available: http://ascopubs.org/doi/abs/10.1200/JOP.2015.005215

24 Edmonds CE and Mankoff DA (2016) “Progesterone Receptor Imaging” in Molecular Pathology of Breast Cancer (Badve S and Gokmen-Polar Y [eds]). Ch 13.3.2; p 194

25 http://www.breastcancer.org/symptoms/diagnosis/hormone_status/read_results

26 Yazici O, Erdem GU, Aksoy S at el. (2016) Comparison of clinical outcomes in patients with early stage ER-/PR+, HER2- breast cancer patients with triple negatives. J Clin Oncol 34, 2016 (suppl; abstr e12556)

27 NCCN Quick Guide Stage IV breast cancer https://www.nccn.org/patients/guidelines/quick_guides/breast/stage_iv/index.html#2

28 Hefti MM, Hu R, Knoblauch NW et al. (2013) Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype. Breast Cancer Research 2013. 15:R68. DOI 10.1186/bcr3462

29 Guth U, Myrick ME, Reisch T, Bosshard G and Schmid SM (2011) Suicide in breast cancer patients: An individual-centered approach provides insight beyond epidemiology. Acta Oncologica. 50(7), 1037-1044. http://dx.doi.org/10.3109/0284186X.2011.602112

30 Kissane DW, Grabsch B, Love A, Clarke DM, Bloch S and Smith GC (2004). Psychiatric disorder in women with early stage and advanced breast cancer: a comparative analysis. Australian and New Zealand Journal of Psychiatry 2004; 38:320–326

31 Schairer C, Brown LM, Chen BE, Howard R, Lynch CF, Hall P, Storm H, Pukkala E, Anderson A, Kaijser M, Andersson M, Joensuu H, Fosså SD, Ganz PA, Travis LB. Suicide after breast cancer: an international population-based study of 723,810

32 TBL = total bilirubin

33 An R value less than 2 indicates cholestatic injury per the NIH: https://livertox.nih.gov/glossary.html#jumpr

34 Giannini EG, Testa R, Savarino V. Liver enzyme alterations: a guide for clinicians. CMAJ, 2005 Feb 1; 172(3): 367-379

35 Vuppalanchi R, Saxena R, Storniolo AMV, Chalasani N. Pseudocirrhosis and Liver Failure in Patients with Metastatic Breast Cancer after Treatment With Palbociclib. Hepatology [doi: 10.1002/hep.28720]

36 The EU RMP includes Male patients as Missing Information, but does not specify the additional wording‘including use in male breast cancer’.

37Nephropathy was Grade 1

38 From this table it can be calculated that n=28 had prior chemotherapy only, n=64 had prior hormonal therapy only, and n=185 had prior chemotherapy and hormonal therapy, as neo(adjuvant) therapy, in the palbociclib + letrozole arm

39 IMPALA was the name of the study interactive randomization technology; CRF = case report form; randomization in IMPALA occurred prior to the data being verified by the Sponsor, so there were “minor discrepancies” in the distribution of patients by the stratification factors following data cleaning activities based on the CRF data. “For this reason, the CRF source document verified data were considered more accurate…” [s31 response]

40 Actual dose intensity divided by intended dose intensity x 100%

41 Crudely limited to those AEs in Table 8 with a >>50% frequency relative to placebo, to offset the imbalance in exposure

42 From https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf:

43CSR Table 14.3.1.3.2.1 reports 1.6% with febrile neutropenia in the palbociclib + letrozole arm, however Table 14.3.1.8.1.1 reports 1.8% with grade 3-4 febrile neutropenia (all causality), and on page 209 of the CSR it states that febrile neutropenia was experienced by 11 (2.5%) in that arm, sourced from Table 14.3.1.1.3 (TEAEs, all causality, all cycles, with a comment that “reported cases of grade 1-2 febrile neutropenia are currently under review since CTC AE criteria may not have been met for this event”. The SCS further states that “reported cases of grade 1 or grade 2 febrile neutropenia (3 patients) did not meet CTCAE version 4.0 criteria for febrile neutropenia and were subsequently corrected (were considered not to be consistent with febrile neutropenia) in the clinical database after the database snapshot. It is not entirely clear whether the 3 patients have already been removed to arrive at 11 (2.5%) or whether, once removed, 8 patients remain (1.8%).

44 From https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf:

45 From https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf:

46 From https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf:
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