When is Perjeta given in the USA?

Hi stephincanada:

SpecialK referred to the content of the FDA label and then to circumstances "other than those guidelines" (meaning in circumstances or uses other than the approved uses in the FDA label.)

Just to expand on that for newer members, the FDA-approved uses described in the FDA label for a drug or biologic may or may not be coextensive with the uses included in clinical consensus guidelines. Occasionally, our local consensus guidelines (e.g., NCCN Guidelines for breast cancer) include uses that are not included in the FDA label and are thus considered "off-label" uses (i.e., not approved by FDA). Obtaining insurance coverage is a separate question.

Re your question: "If I were in the United States, would I be offered this additional therapy?"

As a layperson with no medical training, I cannot answer the question of what would be recommended to a particular patient by a medical oncologist familiar with all relevant medical details and the most recent available data.

Here is some some general background information. It is not comprehensive and may contain errors in understanding. This information is not a substitute for current, case-specific expert professional advice from a medical oncologist familiar with all the details of your case and more recent studies that might be out there.

NOTE: The below is NOT a summary of all adjuvant uses of pertuzumab under NCCN guidelines.

In the adjuvant setting, for IDC that is hormone receptor-negative (ER- PR-), HER2-positive, and node-negative ("N0"), where the Tumor >1 cm, in general, local NCCN guidelines for breast cancer (Version 2.2016) provide for Adjuvant chemotherapy with trastuzumab (category 1), with a footnote regarding the addition of pertuzumab in certain subsets:

(bb) "A pertuzumab-containing regimen can be administered to patients with ≥T2 or ≥N1, HER2-positive, early-stage breast cancer."

T2 = Tumor > 20 mm but ≤ 50 mm in greatest dimension

N1 = Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected***

The NCCN guidelines provide for a variety of pertuzumab-containing regimens. However, consensus guidelines do not mandate individual treatments. In the appropriate case, doctors may depart from what the guidelines provide, based on various factors, such as personal risk/ benefit profile or co-morbidities. Thus, individual patients who meet the criteria above may not receive a recommendation for pertuzumab. Meanwhile, some patients who do not meet the criteria may receive a pertuzumab-containing regimen in the adjuvant setting. This is why we cannot say what you would be offered.

The use of pertuzumab (Perjeta) in the adjuvant setting was incorporated into the NCCN guidelines for treatment of breast cancer in 2014, per this ASCO Post article which also comments on the stated rationale for this change based on results in the metastatic and neoadjuvant settings:

http://www.ascopost.com/issues/may-15-2014/nccn-clinical-practice-guidelines-in-oncology-2014-updates/

On-going studies are evaluating pertuzumab in the adjuvant setting.

Re your question: "I don't understand why giving a drug before or after my lumpectomy makes such a difference".

A 2016 ASCO guideline, which is modeled after Cancer Care Ontario guidelines, indicates that "the role of pertuzumab in HER2-positive disease" in adjuvant therapy of breast cancer needs "further clarification", "because demonstration of survival benefit awaits completion of randomized trials":

http://jco.ascopubs.org/content/early/2016/04/13/JCO.2016.67.0182.full#xref-ref-3-1

The accelerated FDA approval of pertuzumab in the neoadjuvant setting was based on a demonstration of an improvement in the endpoint of pathologic complete response (pCR) rate. That trial did not demonstrate an improvement in event-free survival or overall survival.

It appears that the use of pCR as an surrogate endpoint in the neoadjuvant setting is based on another large pooled analysis of various neoadjuvant treatments that found some correlation between pCR and better overall survival and event-free survival on a patient-based level, particularly among patients with ER-negative, HER2-positive disease, although these results were not observed on a trial-based level:

Cortazar, Lancet (2014)

For additional discussion, here is a Canadian document (2015) which discusses various trials and illustrates the viewpoint of some professional groups that additional data is needed to support the use of pertuzumab in the adjuvant setting:

https://www.cadth.ca/sites/default/files/pcodr/pcodr_pertuzumab_perjeta_nbc_fn_cgr.pdf

So, my layperson's thinking is that this might reflect a lack of evidence that affirmatively demonstrates a survival benefit in the neoadjuvant setting, and further extrapolation to the adjuvant setting.

As noted above, the NCCN guidelines include adjuvant pertuzumab in some cases of higher risk disease (≥T2 or ≥N1).

A second opinion at a highly regarded hospital may provide you with more information and input about what is right for you.

BarredOwl

Hi kayb:

That is a very good explanation, and is consistent with information in the links I posted above.

I note that success in obtaining insurer approval may not necessarily reflect the rate at which medical oncologists would (or do) recommend adjuvant pertuzumab in their best judgment, and these boards may not reflect that rate either.

Various clinical consensus guidelines are not in accord about the adjuvant use of pertuzumab. This may in part reflect concerns stemming from the use of the surrogate endpoint of pCR in the neoadjuvant trial, and whether an improvement in pCR may or may not be either predictive of survival benefit in the neoadjuvant setting or in the further removed adjuvant setting.

As noted in my previous post, NCCN's inclusion of the use of adjuvant pertuzumab in certain cases is not based solely on an improvement in pCR in the neoadjuvant setting, but is also extrapolated from a survival benefit (OS) seen in the metastatic setting:

NCCN guidelines for breast cancer (Version 2.2016):

"Considering the unprecedented improvement in [overall survival] OS in the metastatic setting [432] and the significant improvement in pCR seen in the neoadjuvant setting, [314,316] the NCCN Panel considers it reasonable to incorporate pertuzumab into the above adjuvant regimens [in certain patients]. . . An ongoing study is evaluating pertuzumab and trastuzumab with standard chemotherapy regimens in the adjuvant setting. . ."

Reference 432 is a 2012 abstract, but a paper with OS results from the CLEOPATRA trial in the metastatic setting is now available: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1413513

Nevertheless, the NCCN's dual rationale does not appear to have been adopted by other groups (e.g., ASCO, ESMO).

Will NCCN's current position be borne out by the results of on-going trials in the adjuvant setting? Unknown. In ASCO's view, the role of pertuzumab in adjuvant therapy of HER2-positive breast cancer needs "further clarification", "because demonstration of survival benefit awaits completion of randomized trials," such as the APHINITY trial (NCT01358877; Adjuvant Pertuzumab and Herceptin in Initial Therapy in Breast Cancer).

NCCN guidelines do include some adjuvant uses of pertuzumab. However, not all guidelines appear to be in complete accord, we are awaiting the adjuvant APHINITY trial results, and insurance coverage and cost considerations may be barriers to access. Patients should consult their medical oncologists for current, case-specific expert advice.

All information above should be verified with a medical oncologist to ensure accuracy and currency.

BarredOwl

Another feature on pertuzumab mentioned the readout from "a large adjuvant trial" will be available in 2017, which may be the adjuvant Phase III APHINITY trial.

Above we noted that the accelerated approval in the neoadjuvant setting was based on improvements in pCR, the primary endpoint of the NeoSphere trial (see also, results from the neoadjuvant TRYPHAENA trial). In May-June 2016, some additional results from the NeoSphere trial at 5-year follow-up were published, with some important caveats:

Neoadjuvant NeoSphere: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00163-7/fulltext

"[S]econdary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only."

It seems that the trial was not statistically powered to detect differences in PFS and DFS between groups, and indeed the observed Confidence Intervals ("CIs") were large and overlapping ("Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs . . .") Elsewhere the results were said to show a trend, but were not statistically significant.

BarredOwl

Stephincanada, I just stumbled on this post. I am receiving Taxotere, Herceptin and Pergeta and I am stage 1, less than a cm IDC, no nodes. I am receiving Pergeta because my insurance is military and I am treated at a naval hospital. The military does not have the limitations like private insurance. My breast surgeon was shocked that I was getting Pergeta because she said it was only being used for latter stages cancers and before surgery.

Further to my first two posts above of August 5 and August 6, 2016 regarding the differing positions of NCCN and ASCO in this area, the ASCO committee was recently questioned about their stance on adjuvant pertuzumab in this letter:

Prat (2017): "Pertuzumab Use in the Adjuvant Setting: Why Not?"

http://ascopubs.org/doi/full/10.1200/JCO.2016.68.6212

(Free pdf available under PDF tab)

The reply indicates that the ASCO committee will continue to await the results of the APHINITY trial, commenting:

Denduluri (2017): Reply

http://ascopubs.org/doi/full/10.1200/JCO.2016.70.9758

(Free pdf available under PDF tab)

"The primary end points of this trial [APHINITY] include invasive disease-free survival as well as the frequency of heart failure with a decrease in left ventricular ejection fraction. These results will inform future [ASCO] guideline updates (NCT01358877)."

I note that kayb's clear explanations and perspective are missed.

BarredOwl

Roche just released that the APHINITY trial results were positive in the use of adjuvant Perjeta in combination with chemotherapy and Herceptin. This is wonderful news, but let's see what the data says when they present it at ASCO 2017- I'm so curious to see the numbers and what subsets had the most improvement in DFS. I don't see anything in the press release about OS.