Real-World Clinical Outcomes of Ribociclib in Combination with a Non-Steroidal Aromatase Inhibitor and a Luteinizing Hormone-Releasing Hormone Agonist in Premenopausal HR+/HER2− Advanced Breast Cancer Patients: An Italian Managed Access Program

Round 1

Reviewer 1 Report

Dear Authors,

I appreciate the efforts you made to analyze the clinical outcomes of the use of ribociclib in combination with an aromatase inhibitor and a LHRH agonist, in women with HR+/HER2- advanced breast cancer.

Indeed, it could be useful to know the impact in real word of this drug but I think also that the paper needs a revision prior to be published. Even if a MAP is not a clinical trial, it would be useful to provide more information about the women enrolled, especially if the paper focuses on premenopausal women. For example, why did you enroll a woman of 31 years old? Was she in a pre-menopausal condition?

The results section is a bit confusing. For example, the number of patients with a known response is 57 but this is stated only in the abstract and in table 2. Consequently, table 2 is not clear (what does number 2 refers to?). I think also that discussion section could be expanded with a briefly comparison with the outcomes of other known treatments of the same kind of patients.

Please, check the English language since there are some typos and some sentences are not clear.

Kind regards.

Author Response

Reviewer #1

Dear reviewer,

We appreciate the time and effort spent to review our manuscript. We thank you for your suggestions, below you’ll find a point by point response

Dear Authors,

I appreciate the efforts you made to analyze the clinical outcomes of the use of ribociclib in combination with an aromatase inhibitor and a LHRH agonist, in women with HR+/HER2- advanced breast cancer.

Indeed, it could be useful to know the impact in real word of this drug but I think also that the paper needs a revision prior to be published. Even if a MAP is not a clinical trial, it would be useful to provide more information about the women enrolled, especially if the paper focuses on premenopausal women. For example, why did you enroll a woman of 31 years old? Was she in a pre-menopausal condition?

The MAP program was designed specifically for pre- and peri-menopausal women, using the same definition as in the MONALEESA 7 trial, i.e.

Premenopausal status is defined as either:

• Patient had last menstrual period within the last 12 months, OR
• If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, OR
• In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
• Patients who have undergone bilateral oophorectomy are not eligible.

 

• Perimenopausal status is defined as neither premenopausal nor postmenopausal

 

Since the definition of perimenopausal is a definition by exclusion, we report the definition of postmenopause as well:

 

Postmenopausal status is defined either by:

• Prior bilateral oophorectomy OR
• Age ≥60 OR
• Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range.
• If taking tamoxifen or toremifene, and age <60, then FSH and plasma estradiol level in postmenopausal ranges per local laboratory normal range.

Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure menopausal status.

 

Having cleared the enrollment criteria, to answer your specific question, the 31 year old patients fitted the premenopausal category.

 

In line with your comment, we have now cleared the source for menopausal definition applied to this MAP in the material and methods section.

 

The results section is a bit confusing. For example, the number of patients with a known response is 57 but this is stated only in the abstract and in table 2. Consequently, table 2 is not clear (what does number 2 refers to?). I think also that discussion section could be expanded with a briefly comparison with the outcomes of other known treatments of the same kind of patients.

We realize that there may be some confusion due to the different number of enrolled patients and the ones for which a response is known. We have now reported the number of patients with a known response in the result section as well, as such the number detailed and the one reported in the second table present in the paper are now aligned. As for the comparison with literature data, we feel that the small sample size and the fact that we have no data regarding survival outcome, either as progression free or as overall, are structural limits of our MAP that would not allow for a meaningful comparison with randomized controlled trials. We confronted clinical benefit rate with that of MONALEESA 7, where a direct comparison helps the reader to give context and perspective to the MAP data.

Please, check the English language since there are some typos and some sentences are not clear.

We will revise English lang

Reviewer 2 Report

The duration of follow-up is unclear; 38 women were still on all or on any (of 3) treatments, ribo/LHRH/ NSAI at data cut-off?

The number of patients with progressive disease is unclear; 9 in table 2 and 15 in table 3. Confusing! Also in the text line 150 and line 173

In "material and methods" the authors state 'postmenopausal women who had received ...'/ do they mean 'premenopausal'?

Question: Was a biopsy of the metastatic site to proof ER-positive breast cancer required prior to study entry?

The second sentence of the discussion is unclear: Time and again, ...?

Table 1.: How many patients had 1L chemotherapy prior to study entry?

How did they define 'premenopausal' status at study entry as 22 of 31 patients were treated with chemotherapy in the adjuvant setting?

Of 31 patients with recurrent disease, how did disease free survival, expressed in 'months since first diagnosis' correlate with response?

 

Author Response

Reviewer #2

Dear reviewer,

We appreciate the time and effort spent to review our manuscript. We thank you for your suggestions, below you’ll find a point by point response.

The duration of follow-up is unclear; 38 women were still on all or on any (of 3) treatments, ribo/LHRH/ NSAI at data cut-off?

The MAP program was opened in April 2018 and closed in May 2020 when Health Authorities expanded ribociclib indication in premenopausal women as well. Given that progression free survival in this subset of patients with ribociclib is 27.5 months (MONALEESA 7 trial), it is expected that most of the patient were still receiving treatment as of May 2020. Given that there is a granted time bias due to program closure, we felt that expressing a median follow up would be misleading in term of treatment duration.

The number of patients with progressive disease is unclear; 9 in table 2 and 15 in table 3. Confusing! Also in the text line 150 and line 173

We apologies for the confusion. It stems from the different source of the data: the 9 patients in table 2 and line 150 refers to 9 out of 57 for which the radiological response is known. The 15 patients are the one for which the MAP program was interrupted by clinician due to disease progression, but that was not always documented with a radiological evaluation. We have clarified the different source of the numbers.

In "material and methods" the authors state 'postmenopausal women who had received ...'/ do they mean 'premenopausal'?

Yes, sorry for the typo, it has now been corrected.

Question: Was a biopsy of the metastatic site to proof ER-positive breast cancer required prior to study entry?

No, a biopsy was required only for patients with de novo metastatic disease to assess ER status. If the ER status was known from previous surgery, re-biopsy, although suggested, was not mandatory.

As for menopausal status, we followed the inclusion criteria of MONALEESA 7:

• Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory (based on most recently analyzed biopsy).
• Patient has HER2-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.

The second sentence of the discussion is unclear: Time and again, ...?

We have reworded the sentence to clarify it.

Table 1.: How many patients had 1L chemotherapy prior to study entry?

4 patients received first line chemotherapy. The data is now included both in table 1 and in the result section.

How did they define 'premenopausal' status at study entry as 22 of 31 patients were treated with chemotherapy in the adjuvant setting?

We applied the same criteria of the MONALEESA 7 trial, i.e.

• In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.

 

Of 31 patients with recurrent disease, how did disease free survival, expressed in 'months since first diagnosis' correlate with response?

We strongly agree that this data would be of great interest. Unfortunately we do not have it. The MAP enrollment form did not collect DFI/TFI for recurring patients, as such we are unable to perform this analysis.

Round 2

Reviewer 1 Report

Dear Authors,

Thank you for having considered my concerns and for the explanations.
As a result, the paper may be accepted in its present form.

Sincerely,

Reviewer 2 Report

all comments taken into account

strange they didn't register the disease free interval