Episode Notes

The record number of oncologists, scientists, patient advocates, and everyone in between were eager to attend the American Society of Clinical Oncology (ASCO) 2022 annual meeting and  descended upon Chicago, Illinois early in the month of June to hear the latest research findings in cancer care. About 31,000 of them were able to rest from the Zoom fatigue and put their physical stamina to the test trekking the vast McCormick Place, sections of which were transformed into field hospital wards when the pandemic hit in 2020. 

I have no doubt the by now you have heard that some of the research highlights presented this year are “practice-changing.” In fact, a plenary presentation for Destiny-Breast04  clinical trial received a rarely given standing ovation. In breast cancer, was is worthy of a standing ovation? What practice is it changing? We are eager to  hear the answer to these questions and a lot more in the report back from ASCO

Just like the conference itself, the report back from ASCO has become an annual event and a tradition at SHARE.  Shortly after the conference my  co-producer of the Our MBC Life podcast Natalia Green and I welcomed Dr Niel Iyengar to SHARE to talk about the main highlights in Metastatic Breast Cancer from 2022 ASCO. We are thrilled to be able to bring it to you as a  bonus podcast episode.

It would be negligent to not comment on the most thrilling event during this exhilarating conference, which was the reveal of the trastuzumab deruxtecan (Enhertu) data from the DESTINY-Breast04 trial in HER2-low metastatic breast cancer, presented by Dr. Shanu Modi of MSKCC. With a near doubling of median progression-free survival (mPFS) (5.1 to 9.9 months) in all patients, irrespective of hormone receptor (HR) status, it was clear that this was game changing data. The announcement elicited even more excitement as the overall survival (OS) and HR- cohort data was revealed. Median overall survival (mOS) in the overall Enhertu treated population was 23.4 months (compared to 16.8 months) and even more surprising was the 18.2-month OS in the HR-/HER2-low subgroup (previously defined as triple negative breast cancer, or TNBC) compared to the dismal 8.3 months with chemo. Not only will this data immediately impact the treatment paradigm, but it will also shake up how we segment breast cancer patients by defining a new sub-segment of HER2-low disease (which comprises ~50% of all breast cancers). This also raises the question, do we need better diagnostic tools to stratify these patients based on HER2 quantification? The answer is yes, as current immunohistochemistry (IHC) methods were shown to miss patients who could potentially benefit from Enhertu. Add Enhertu into into the toolbox along with PARP, HER2, CDK4/6 inhibitors, and checkpoint inhibitors, and the future is looking a bit brighter for all breast cancer patients. “It is no surprise that following the presentation the entire plenary hall erupted in a standing ovation to celebrate not the presenter, not the data itself, but the implications for individuals who suffer and will suffer from the crippling diagnosis of metastatic breast cancer,” as Karson Kump wrote in the Health Advances Blog

Subjects and Terms Included in This Episode

Novel Therapies Mentioned in the Episode

More on CDK4/6 inhibitors

The MANTAIN study gave us a first legistimate answer to the question  that everyone has been asking - “Is there a difference in the 3 cdk4/6 inhibition therapies? Should they be sequenced?”  Considering the data from the MAINTAIN trial when patients received ribociclib with a new endocrine therapy partner after progression under  any CDK4/6 inhibitor administered together with endocrine therapy, the answer seems to be yes, and patients should be offered ribociclib after progressing on a different cdk4/6 inhibitor, like ibrance for example.

This ASCO heard a presentation of the long awaited survival data on palbociclib, more commonly known as ibrance, to an AI  in the first-line treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer.  The era of CDK4/6 inhibitors began at ASCO 7 years ago  with the presentation of the primary endpoint, PFS from the same PALOMA-2 study. It confirmed efficacy of palbociclib,  and almost doubled progression-free survival  by addition of palbociclib to mono endocrine therapy letrazoole versus endocrine therapy  alone (24.8 versus 14.5 months). Both the data from the MONALEESA-2 study (25.3 months) and the data from the MONARCH 3 study (28.8 months) confirmed the clear advantage in PFS with the addition of CDK4/6 inhibitors in HR-positive breast cancer in the metastatic setting. This therapy is now the standard of care in metastatic HR-positive HER2-negative breast cancer.

Positive OS data are already available for the MONALEESA-2 in postmenopausal women, as well as the MONALEESA-7 in premenopausal women and the MONALEESA-3 in combination with fulvestrant. In the second-line setting MONARCH 2 also reported positive OS data, while MONARCH 3 results on OS are still pending. Although CDK4/6 inhibitors as class improved overall survival (OS) of HR+/HER2– metastatic breast cancer patients, in the PALOMA-2 study, after 7.5 years of follow-up, results did not reach key secondary endpoint – OS  and failed to show the overall survival benefit.There could be few reasons for this finding. One of the reasons could be significant dropout from the study, as even one third of patients were missing survival data – 13% of patients in the palbociclib arm and 21% in the placebo arm. The OS analysis was adjusted by exclusion of the patients missing survival data, which most most likely has provoked some bias. Further on, the PALOMA-2 study has included quite diverse patient population. 20% of the patients on the trial were less than  12 months out after they were treated for early stage diagnosis before they progressed to stage 4 that might indicate extremely aggressive and difficult to treat type of breast cancer. When the OS was analyzed solely in the subgroup of patients with disease free interval longer than 12 months, OS in the palbociclib group was 64 months compared to 44.6 months in the placebo group, which is comparable to the OS data from the MONALEESA-2 study, which confirmed significant OS prolongation  by addition of CDK4/6 inhibitor ribociclib to the aromatase inhibitor. Two essential questions now arise for clinical practice: (1) How should the doctors deal with the patients who are currently on palbociclib? (2) Which of the 3 available CDK4/6 inhibitors should be offered to new patients?

To answer the first question: There is currently no data that indicates patients on palbociclib should be switched to another CDK inhibitor. If the patient tolerates the drug well, she should continue treatment (never change a winning team).

Concerning the second question: The already positive OS data on ribociclib and the OS data from the PALOMA-2 data now presented at ASCO must be taken into account in everyday clinical practice.Ribociclib resulted in the strongest OS data available so far, which is a fact that cannot be neglected. PALOMA-2 OS data of over 50 months for everyone and over 60 months in clearly endocrine-sensitive patients, positions palbociclib as full-fledged CDK4/6 inhibitor in the first-line treatment of endocrine-sensitive postmenopausal population, especially due its favorable toxicity profile, which makes it the optimal choice in old and fragile patients with lots of comorbidities.

Abstracts Presented at ASCO and Mentioned in the Episode

• DESTINY-Breast 04 LBA3 Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): A randomized, phase 3 study (NCT03734029)

• Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03.(NCT03529110)

• LBA1001 Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer

• LBA1003 Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2.

• A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial.

• NRG-BR002: A phase IIR/III trial of standard of care systemic therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) for newly oligometastatic breast cancer (NCT02364557)

Meet the Guest of this Episode