Congress highlights

Meet the expert

Dr Aditya Bardia

Dr Aditya Bardia, a board-certified medical oncologist, is an attending physician at Massachusetts General Hospital (MGH), and Associate Professor, Harvard Medical School, Boston. As the Director of Breast Cancer Research Program at MGH, Dr Bardia is interested in advancing research to improve the outcomes with breast cancer. Dr Bardia has led the clinical development of the antibody–drug conjugate (ADC) sacituzumab govitecan, the first ADC approved for patients with metastatic triple-negative breast cancer. Dr Bardia has received several research awards including outstanding award for research excellence at Mayo Clinic, Young Investigator Award from ASCO, and Douglas Family Foundation prize for excellence in oncology research at MGH. Dr Bardia is the editor of the Precision Medicine Clinic section of The Oncologist, co-leader of the Molecular and Precision (MAP) Tumor board at MGH, and editorial board member of ASCO Molecular Oncology Tumor board.  

Disclosures

Consultant/Advisory board: AstraZeneca, Daiichi Sankyo, Foundation Medicine, Genentech, Gilead, Immunomedics, Lilly, Merck, Novartis, Pfizer, Phillips, Radius Health, Sanofi.

Contracted Research/Grant (to institution): AstraZeneca, Daiichi Sankyo, Lilly, Genentech, Gilead, Immunomedics, Merck, Novartis, Pfizer, Radius Health, Sanofi.

ASCO 2023 in review: Dr Gregory Vidal on CDK4/6 inhibitor use in early breast cancer

Hot topics at ASCO 2023 

CDK4/6 for the treatment of early HR+/HER2- breast cancer

One of highlights of the 2023 ASCO Annual Meeting was data suggesting cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors could boost survival in HR+/HER2– early breast cancer (EBC). The conference saw the publication of results from the NATALEE and monarchE trials, which suggest that the addition of ribociclib or abemaciclib, respectively, to endocrine treatment (ET) significantly improves survival in patients with EBC at high risk of recurrence.

NATALEE

The phase 3 NATALEE trial investigated whether adding adjuvant ribociclib for 3 years to ET for at least 5 years improved outcomes in a broad population of patients with stage II or III HR+/HER2− EBC at risk for recurrence, including patients with no nodal involvement (N0)¹.

Professor Dennis Slamon, from the University of California Los Angeles, USA, reported that at a median follow-up of 34 months, adjuvant ribociclib demonstrated significantly longer invasive disease-free survival (iDFS) compared with ET alone (hazard ratio [HR] = 0.748).

Three-year iDFS rates were 90.4% with ET plus ribociclib versus 87.1% with ET alone. This benefit was seen across stratification factors and subgroups. Overall survival (OS), recurrence-free survival (RFS) and distant disease-free survival (dDFS) consistently favoured ribociclib.

monarchE

In monarchE, presented by Dr Erika Hamilton from the Sarah Cannon Research Institute in Nashville, Tennessee, USA, patients were randomised to receive ET for up to 10 years with or without abemaciclib for 2 years². At a median follow-up of 42 months, there was a numerically favourable effect on both iDFS and dRFS in patients receiving abemaciclib plus ET versus ET alone.

The risk of an iDFS or dRFS event was reduced by 34% with the CKD4/6 inhibitor. Estimated 4-year DFS was 85.8% with abemaciclib plus ET compared with 79.4% with ET alone (6.4% difference). These benefits were seen across subgroups, including those with high and low Ki67.

Professor Nicholas Turner, from the Royal Marsden NHS Foundation Trust in the UK, who presented in the same session, stressed that the data from monarchE also demonstrate, for the first time, a further benefit from CKD4/6 inhibitors³.

“What’s really important about the latest data is that there is clear evidence of a carry-over benefit of 2 years of abemaciclib,” he said. “Over time the difference in HR for DFS was greater after 2 years versus during the 2 years, which was 2.8%.”

The data show that the HR was 0.78 at the end of the first year on abemaciclib, with a greater reduction at 1–2 years (HR = 0.67). In the first year off abemaciclib treatment, the HR improved to 0.62, and it improved further in the second year off treatment. The current follow-up is too short to assess OS.

Session discussant Professor Nadia Harbeck from LMU University Hospital in Munich, Germany, welcomed the new results but said the data also highlight a number of clinical challenges⁴.

“The good news for patients is that we now have two CDK4/6 inhibitors that increase the chance of cure [in HR+/HER2- EBC], but we still have a lot of work to do in identifying patients at high risk of recurrence, where CDK4/6 may be beneficial,” she said.

PENELOPE-B

New findings from the PENELOPE-B study of palbociclib with ET in HR+/HER2– EBC, presented by Professor Turner, suggest circulating tumour (ct)DNA analysis may be helpful in this regard.

Participants of the PENELOPE-B study who were endocrine naïve at the time of study entry were selected for ctDNA analysis⁵. Plasma samples were collected at baseline (after completion of neoadjuvant chemotherapy and surgery), prior to cycle 7 (approximately 6 months into ET with or without palbociclib) and at end of treatment. The samples were sequenced and up to 50 mutations were tracked.

Of 1250 participants, 129 were endocrine naïve at trial entry, and 78 had a baseline ctDNA sample analysed.

Detection of ctDNA at baseline (n=7) was strongly associated with worse iDFS (HR = 8.8). Detection of ctDNA at cycle 7 (n = 4) showed an even stronger association, with an HR of 25.5.

Of the patients with baseline ctDNA detection, two had undetectable ctDNA at cycle 7 and remained progression free at 30 months, although one later relapsed. The three patients with detectable ctDNA at cycle 7 all relapsed within 25 months.

The study authors concluded that the detection of ctDNA following neoadjuvant chemotherapy and surgery is associated with a very high risk of early relapse and suggests limited efficacy of adjuvant ET.

Professor Harbeck cautioned that the numbers involved in the analysis are too small to draw conclusions, but said the trial does show that “ctDNA dynamics matter”.

She said the new data presented at ASCO 2023 raise a number of clinical questions that need to be addressed, including the potential effects that using CDK4/6 inhibitors in the EBC setting will have on the management of metastatic breast cancer and the sequencing of treatment, and the possibility that CDK4/6 inhibitors could replace chemotherapy in the first-line treatment of EBC.

More research is needed, said Harbeck, including longer-term follow-up data from monarchE and NATALEE. At some point a pooled analysis will also be needed, she added. Furthermore, she called for adequately powered prospective studies to understand the predictive value of ctDNA detection and clearance to optimise outcomes.

References

1. Slamon DJ, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: Primary results from the phase III NATALEE trial. Abstract #LBA500. Oral abstract session. Breast cancer – local/regional/adjuvant. June 2, 2023. 2023 ASCO Annual Meeting. 2–6 June, 2023. https://meetings.asco.org/abstracts-presentations/218407
2. Hamilton EP, et al. Efficacy and safety results by age in monarchE: Adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC). Abstract #501. Oral abstract session. Breast cancer – local/regional/adjuvant. June 2, 2023. 2023 ASCO Annual Meeting. 2–6 June, 2023. https://meetings.asco.org/abstracts-presentations/218406 
3. Turner N. Using CDK4/6 inhibitors in early stage and advanced HR+ breast cancer. Educational session: Managing a long and winding road: ER-positive breast cancer. June 2, 2023. 2023 ASCO Annual Meeting. 2–6 June, 2023. https://meetings.asco.org/abstracts-presentations/215139/slides
4. Herbeck N. Cyclin through the inhibitors. Oral abstract session. Breast cancer –local/regional/adjuvant. June 2, 2023. 2023 ASCO Annual Meeting. 2–6 June, 2023. https://meetings.asco.org/abstracts-presentations/221624/slides
5. Turner NC, et al. Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: Analysis from the PENELOPE-B trial. Abstract #502. Oral abstract session. Breast cancer – local/regional/adjuvant. June 2, 2023. 2023 ASCO Annual Meeting. 2–6 June, 2023. https://meetings.asco.org/abstracts-presentations/220878

Are all CDK4/6 inhibitors equal?

In a debate on CDK4/6 inhibitors (CDK4/6i) Dr Debra Patt discussed the similarities between these important treatment options¹. Dr Patt took the ‘Pro’ position that CDK4/6is are similar.

CDK4/6is combined with endocrine therapy are the standard of care for HR+/HER2– advanced breast cancer (ABC) in multiple national and international guidelines¹. Dr Patt presented data compiled from numerous Phase III first-line CDK4/6i trials in HR+/HER2– advanced breast cancer, all showing benefits in progression-free survival (PFS), overall survival (OS) and quality of life (QoL).

PALOMA-2

The PALOMA-2 study included postmenopausal women without prior treatment for advanced disease. Patients received endocrine therapy (ET) letrozole (LET) plus either palbociclib (PAL) (n = 444) or placebo (n = 222). The primary endpoint of PFS was 27.6 (PAL+LET) versus 14.5 months with LET alone (hazard ratio [HR] 0.563). The secondary outcome of OS was 53.9 (PAL+LET) versus 51.2 months with LET alone (HR 0.96; 95% confidence interval [CI], 0.78–1.18).

MONALEESA-2

The MONALEESA-2 trial also included previously untreated postmenopausal women. Patients received LET plus either ribociclib (RIBO) (n = 334) or placebo (n = 334). The PFS was 25.3 (RIBO+LET) versus 16 months with LET alone (HR 0.568). OS was 63.9 (RIBO+LET) versus 51.4 months with LET alone (HR 0.76; 95% CI, 0.63–0.93).

MONARCH-3

In the MONARCH-3 trial, patients received nonsteroidal aromatase inhibitors (NSAI) plus either abemaciclib (ABE) or placebo. The PFS was 28.2 (ABE+NSAI) versus 14.8 months with NSAI alone (HR 0.54). Interim OS was 67.1 (ABE+NSAI) versus 54.5 months with NSAI alone (HR 0.75; 95% CI, 0.58–0.97). The addition of ABE to NSAI benefitted all subgroups, even those with poorer prognoses. Also, it delayed the initiation of first chemotherapy (CT), which is clinically meaningful to patients due to the added toxicity of CT. In a study evaluating central nervous system activity, the intracranial clinical benefit rate (iCBR) of abemaciclib was 24%.

MONALEESA-7

The MONALEESA-7 trial included pre-and perimenopausal women who had previously received prior chemotherapy. Patients received ET with either ribociclib or placebo. The PFS was 23.8 (RIB+ET) versus 13 months with ET alone (HR 0.553). In updated OS with a median of 53.5 months follow-up, the RIB+ET group showed significantly longer OS than ET alone.

Palbociclib, ribociclib and abemeciclib show similar pharmacokinetics but variable pharmacodynamics. Adverse event profiles also differ between CDK4/6 inhibitors². Abeciclib caused higher rates of grade 3 diarrhoea, while ribociclib showed a higher incidence of liver function test abnormalities and QTc prolongation. Ribociclib should therefore be avoided in patients with cardiac morbidities or other risk factors for QTc prolongation.

Taking the ‘Con’ side of the debate that all CDK4/6is are not the same, Dr Ruth O’Regan commented that these different toxicity profiles may influence treatment choices and show that they are not all comparable³.

Whether or not all CDK4/6 inhibitors are the same is still up for debate

Adjuvant therapies in HR+/HER2– breast cancer

In the MonarchE trial, adjuvant ABE+ET showed significant and clinically meaningful improvements for patients with HR+/HER2-, node-positive high-risk early breast cancer. Dr Stephen Johnston presented efficacy results from a pre-specified overall survival interim analysis two years after the primary outcome analysis⁴. All patients had finished abemaciclib treatment at a median follow-up period of 42 months, with a sustained benefit in invasive disease-free survival (iDFS) and distant relapse-free survival (DRFS). In the intent-to-treat population, the improvement in iDFS at 4 years increased from 79.4% with ET alone to 85.8% with added abemaciclib.

Similar abemaciclib treatment effects were seen in high-risk early BC patients, with a Ki-67 index of ≥20%, even though Ki-67 was associated with a worse prognosis. An iDFS and DRFS benefit was seen at 4 years, well after the completion of abemaciclib therapy. Immature OS data in Ki-67 high patients indicated that ABE may also improve OS.

CDK4/6 inhibitors are increasingly used in first-line care of hormone-positive breast cancers, in addition to endocrine therapy (ET). However, some physicians also treat tumours aggressively with chemotherapy, as the general opinion is that combination therapy will provide faster response times. Dr Yen-Shen Lu presented data from the RIGHT Choice Phase II trial⁵. Premenopausal women with aggressive HR+/HER2– ABC (n = 222) were treated with either first-line adjuvant ribociclib plus ET or physicians’ choice combination chemotherapy. While the overall response rate was similar between the two regimens, patients treated with ribociclib plus ET had PFS of 24 months, compared to 12.3 months in patients treated with chemotherapy. Adverse events leading to discontinuation were 7.1% in the RIBO+ET group but 23.0% in the combination chemotherapy group.

Favourable PFS, OS and safety data of abemaciclib plus fulvestrant, compared with fulvestrant alone from the MONARCH 2 trial, has been previously reported. Dr Antonio Llombart-Cussac presented a spotlight poster with pre-specified final OS data was at SABCS 2022⁶. Overall survival was 45.8 months in the ABE arm and 37.2 months in the placebo arm (HR 0.784). While OS benefit was generally consistent across subgroups, a more pronounced benefit was noted in subgroups associated with a poorer prognosis, such as visceral disease (HR 0.643), primary resistance to ET (HR 0.634) or negative progesterone receptor status (HR 0.623). The addition of abemaciclib to fulvestrant also deferred the initiation of chemotherapy (HR 0.674), with a substantial difference in yearly chemotherapy-free survival rates (5-year: 32.4% vs 14.7%), which is an important consideration for patients with ABC.

In the adjuvant setting, the value of adding palbociclib to ET has not been confirmed⁷. The PALLAS trial included HR+/HER2– patients who received ET with or without palbociclib. At a median follow-up of 23.7 months, no significant difference was observed in either 3-year iDFS or DRFS. Similar results were seen in the PENELOPE B trial testing palbociclib plus ET after neoadjuvant chemotherapy (NACT)⁸. HR+/HER2– patients without a pathological complete response (pCR) after taxane-containing NACT and at high-risk of relapse received ET with or without palbociclib. After a median follow-up of 42.8 months (92% complete), PAL did not improve iDFS versus placebo added to ET.

CDK4/6 inhibitor resistance in breast cancer patients

Resistance to CDK4/6 inhibitors is heterogeneous. Approximately 10% of patients who progress on CDK4/6 inhibitors acquire a loss of function mutations of the tumour suppressor protein RB1. Multiple resistance mechanisms can coexist within one patient, and ctDNA profiling post-CDK4/6i therapy is required⁹.

In commenting on several presentations, Dr Fabrice Andre identified acquired gene alterations between baseline and end-of-treatment (EOT) in pooled samples from the MONALEESA-2, -3, and -7 studies that may impact resistance to RIBO+ET¹⁰. ESR1, RB1, ATM, FAT1, and FAT3 were higher at EOT vs baseline in patients treated with RIBO+ET, while ESR1 and GATA3 alterations were higher at EOT vs baseline in patients treated with placebo+ET.

References

1. Patt D. Pro: CDK 4/6 inhibitors are similar. Presented at the SABCS 2022, 8 December. San Antoinio. Debate: Are All CDK4/6 Inhibitors the Same or Different?
2. Ettl J. Management of adverse events due to cyclin-dependent kinase 4/6 inhibitors. Breast Care. 2019;14(2):86-92.
3. O’Regan R. Con: All CDK4/6 inhibitors are not the same. Presented at the SABCS 2022, 8 December. San Antoinio. Debate: Are All CDK4/6 Inhibitors the Same or Different?
4. Johnston S. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes. Presented at the SABCS 2022, 6 December. San Antoinio. GS1-09.
5. Lu Y-S. Primary results from the randomized Phase II RIGHT Choice trial of premenopausal patients with aggressive HR+/HER2− advanced breast cancer treated with ribociclib + endocrine therapy vs physician’s choice combination chemotherapy. Presented at the SABCS 2022, 6 December. San Antoinio. GS1-10.
6. Llombart-Cussac A. Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer. Presented at the SABCS 2022, 9 December. San Antoinio. PD13-11.
7. Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, et al. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293.
8. Loibl S, Marmé F, Martin M, Untch M, Bonnefoi H, Kim SB, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol. 2021;39(14):1518-1530.
9. Hanker A. CDK4/6 inhibitor resistance: Biological mechanisms and novel approaches. Presented at the SABCS 2022, 8 December. San Antoinio. Forum 4: Demystifying CDKs in Breast Cancer: Beyond CDK4/6.
10. Andre F. Developing a 2nd line therapy free of cytotoxics in patients with HR+/Her2- mBC. Presented at the SABCS 2022, 8 December. San Antoinio. GS3-05.

Hot topics at ASCO 2022

Receptor status in breast cancer, traditionally classified as positive or negative, is assessed to determine patients’ eligibility for targeted therapies, such as endocrine therapy or human epidermal growth factor receptor 2 (HER2) inhibition^1,2. Breast cancers deemed HER2−, however, are not necessarily devoid of these receptors. Indeed, more than half of metastatic HER2− breast cancers express low levels of HER2³. Until recently, low HER2 expression was not considered clinically relevant and these cancers have been designated as HER2− because they are typically unresponsive to standard anti-HER2 therapy³.

DESTINY-Breast04 trial

We’re now witnessing a paradigm shift with the recognition of ‘HER2-low’ as a viable target for the new antibody-conjugate drugs trastuzumab deruxtecan (T-DXd) and trastuzumab duocarmine^4,5. This year, T-DXd was approved by the US Food and Drug Administration (FDA)⁶ and the European Medicines Agency (EMA)⁷ for treatment of HER2+ metastatic breast cancer. T-DXd is currently being evaluated in two phase 3 clinical trials for treatment of HER2-low metastatic breast cancer. The much-anticipated results of the first trial, DESTINY-Breast04⁸, were unveiled at ASCO 2022.

DESTINY-Breast04 was a randomised, multicentre, open-label, phase 3 trial that evaluated efficacy and safety of T-DXd, compared with treatment of physician’s choice (TPC), in patients with HER2-low metastatic breast cancer. Patients who had been treated previously with one or two lines of chemotherapy in the metastatic setting were recruited to the study. TPC included capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel⁸. At 18.4 months follow up, progression-free survival (PFS) was significantly greater in patients on T-DXd than those on TPC (9.9 months vs 5.1 months; hazard ratio [HR] 0.50; 95% confidence intervals [CI] 0.40, 0.63; P<0.0001). T-DXd also increased overall survival (23.4 months vs 16.8 months; HR 0.64; 95% CI 0.49, 0.84; P=0.0010). This amounts to an impressive 50% reduction in the risk of disease progression and a 36% reduction in the risk of death⁸. 

Updates on CDK4/6 inhibitors in HR+/HER2− breast cancer

Two interest-generating updates on cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors for HR+/HER2– came from results of the MAINTAIN and PALOMA-2 trials.

MAINTAIN

Observational data suggest a potential benefit of continuing CDK4/6 inhibition and switching endocrine therapy at progression of metastatic breast cancer. MAINTAIN was a small, randomised, multicentre phase 2 trial to evaluate the efficacy of fulvestrant or exemestane with or without ribociclib (300 mg, 3 weeks on/1 week off) in patients with HR+/HER2− metastatic breast cancer who had progressed while on treatment with any CDK4/6 inhibitor plus any endocrine therapy (n = 120)⁹. Patients who progressed while on fulvestrant were switched to exemestane and those previously on exemestane received fulvestrant. For patients who had not received prior treatment with fulvestrant or exemestane, the choice of endocrine therapy was at the discretion of the investigators, but fulvestrant was encouraged.

A significant improvement in progression-free survival (PFS), the primary endpoint of the trial, was seen in patients who received fulvestrant or exemestane plus ribociclib, compared with those on placebo (median PFS 5.33 months vs 2.76 months; HR 0.56; CI 2.66, 3.25 months; P=0.004). This result corresponds to a 43% reduction in the risk of disease progression or death. PFS rates at 6 and 12 months were considerably higher in the ribociclib group than in the placebo group (42% vs 24% and 25% vs 7%, respectively). While these results are encouraging, however, they are unlikely to change practice, given the small size of the trial.

PALOMA-2

Somewhat disappointing, but nevertheless interesting, were the results of the phase 3 PALOMA-2 trial for palbociclib. PALOMA 2 was a randomised, double-blind trial that evaluated palbociclib plus letrazole as first-line therapy in patients with HR+/HER2− advanced breast cancer¹⁰. Patients who had not received prior systemic therapy for advanced disease (n = 666) were randomised to receive palbociclib (125 mg/day, 3 weeks on/1 week off) plus letrazole (2.5 mg/day) or placebo plus letrazole.

The study met its primary endpoint of a significant improvement in PFS in the palbociclib group, compared with the placebo group (median PFS 27.6 months vs 14.5 months; HR 0.56; 95% CI 0.46, 0.69; P<0.0001). Overall survival data, however, were not available until later and were presented at ASCO 2022. In contrast to the encouraging PFS data, palbociclib did not confer benefit for overall survival. After a median follow-up of 90 months, an intent-to-treat analysis showed that median overall survival was 53.9 months for palbociclib and 51.2 months for placebo. The difference was not statistically significant¹⁰.

New treatment options for HR+ breast cancer

AMEERA trials

Patients with hormone receptor positive (HR+)/HER2− early breast cancer who are unable to tolerate endocrine therapy with aromatase inhibitors have few alternative options. The oral selective oestrogen receptor degrader (SERD) amcenestrant is currently under investigation as a potential therapeutic option for these patients¹¹.

SERDs exert a powerful inhibitory effect on the oestrogen signalling pathway through a dual mechanism of action on oestrogen receptors: they are potent oestrogen receptor antagonists as well as oestrogen receptor degraders¹². This class includes the parenterally administered fulvestrant, which was the first SERD to be developed and approved for treatment of HR+ metastatic breast cancer^12,13. Amcenestrant belongs to a new generation of SERDs with oral bioavailability. Results of AMEERA-1, a phase 1/2 clinical trial, presented at ASCO 2021, showed that amcenestrant as monotherapy or in combination with palbociclib had antitumour activity together with a favourable safety profile in postmenopausal women with HR+/HER2− metastatic breast cancer¹⁴. At ASCO 2022, the launch of AMEERA-6 was announced in a poster presentation¹¹.

AMEERA-6 is a large, prospective, randomised, international, double-blind, double-dummy phase 3 trial to evaluate efficacy and safety of amcenestrant in patients with HR+ early breast cancer who are unable to tolerate aromatase inhibitor therapy¹¹. Patients are eligible to participate in the trial if they have received a minimum of 6 months adjuvant treatment with aromatase inhibitors and have discontinued treatment within 30 months because of toxicity. So far, 3738 patients with HR+ early breast cancer, irrespective of HER2 status, have been recruited and will be randomised to receive either amcenestrant (200 mg/day) or tamoxifen (20 mg/day). Treatment duration is planned for 5 years and patients will be followed up for 10 years from randomisation. The primary endpoint is invasive breast cancer-free survival. Secondary endpoints include invasive disease-free survival and distant relapse-free survival. We look forward to updates on AMEERA-6 at ASCO 2023.

References

1. Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol. 2020;38(12):1346-1366.
2. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105-2122.
3. Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020;38(17):1951-1962.
4. Gampenrieder SP, Rinnerthaler G, Tinchon C, Petzer A, Balic M, Heibl S, et al. Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res. 2021;23(1):112.
5. Miglietta F, Griguolo G, Bottosso M, Giarratano T, Lo Mele M, Fassan M, et al. HER2-low-positive breast cancer: evolution from primary tumor to residual disease after neoadjuvant treatment. npj Breast Cancer. 2022;8(1):66.
6. FDA. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer | FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer.
7. European Medicines Agency. Enhertu: Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_en.pdf.
8. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40(17_suppl):LBA3-LBA3.
9. Kalinsky K, Accordino MK, Chiuzan C, Mundi PS, Trivedi MS, Novik Y, et al. 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. J Clin Oncol. 2022;40(17_suppl):LBA1004-LBA1004.
10. Finn RS, Rugo HS, Dieras VC, Harbeck N, Im S-A, Gelmon KA, et al. 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. J Clin Oncol. 2022;40(17_suppl):LBA1003-LBA1003.
11. Meyskens T, Metzger O, Poncet C, Goulioti T, Xenophontos E, Carey LA, et al. Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6). J Clin Oncol. 2022;40(16_suppl):TPS607-TPS607.
12. Hernando C, Ortega-Morillo B, Tapia M, Moragón S, Martínez MT, Eroles P, et al. Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective. Int J Mol Sci. 2021;22(15):7812.
13. Bross PF, Cohen MH, Williams GA, Pazdur R. FDA drug approval summaries: fulvestrant. Oncologist. 2002;7(6):477-480.
14. Chandarlapaty S, Linden HM, Neven P, Petrakova K, Bardia A, Kabos P, et al. AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). J Clin Oncol. 2021;39(15_suppl):1058-1058.

ESMO Breast 2022

Professor Nadia Harbeck, Director of the Breast Center at LMN University Hospital in Munich, Germany, attended ESMO Breast 2022 and shares her thoughts on the important developments for breast cancer treatment.

Professor Nadia Harbeck Introduction

ESMO Breast Cancer 2022 Main Takeaways

CDK4/6 inhibitor new data and clinical implications

CDK4/6 inhibitor approvals in Europe and the US

American Society of Clinical Oncology 2021

This year, a unique and unmissable opportunity to interact with one of the largest oncology audiences in the world occurred in June, with the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

This five-day virtual event, garnering a record-breaking 44,000+ attendees from 138 countries, gave key insights into cutting-edge research and practice-changing science in a range of oncology fields.

Below, we’ve summarised some of the exciting innovations that came out of the 2,500 presentations and 5,300 abstracts presented at ASCO this year, including recent data from the Penelope-B, Monarch-E, PALOMA-3, and MONALEESA-3 trials as well as research into investigational CDK4/6 inhibitor treatments.

Hot topics from ASCO 2021

Following ASCO 2021, Professor Nadia Harbeck, the Head of the Breast Cancer Centre at LMU University in Munich, Germany, shared her views on the thought-provoking discussions and exciting updates presented at the congress.

Exciting updates included results from ADAPTlate, a phase III trial that aimed to evaluate whether abemaciclib + endocrine therapy (ET) is superior to ET alone for patients at high risk for late disease recurrence, who have previously received locoregional therapy and are under adjuvant ET¹.

Translational research carried out in this study also aimed to assess the potential mechanisms of resistance to ET as well as CDK4/6 targeted therapy¹.

Professor Harbeck also discusses the phase III OlympiA trial. This trial investigated olaparib, a PARP inhibitor, as an adjuvant treatment in patients with germline BRCA mutant (gBRCAm) high-risk HER2-negative early breast cancer (EBC), who have previously completed primary local treatment and (neo)adjuvant chemotherapy¹.

Early breast cancer

One of the important topics discussed at ASCO 2021 was the use of CDK4/6 inhibitors in EBC. Watch below to see a summary of the exciting new developments from subgroup analyses of the Penelope-B and Monarch-E trials with Professor Harbeck.

Palbociclib in premenopausal women

In the PENELOPE-B subgroup analysis, no difference was found in the invasive disease-free survival (IDFS) between palbociclib (80.6%) and placebo (78.3%) in premenopausal women (HR 0.948; CI, 0.693–1.30)².

Safety results on combinations of tamoxifen, palbociclib, gonadotropin-releasing hormone analogues (GnRH), and aromatase inhibitors (AI) were also reported. Overall, the addition of palbociclib to tamoxifen with or without GnRH did not increase side effects compared to treatment with AI+GnRH².

Luminal A vs Luminal B

In the PENELOPE-B subgroup analysis, gene expressions were measured in tumours from PENELOPE-B patients. Luminal B patients were found to be older with a higher post-neoadjuvant Ki-67, risk status (CPS-EG), and grade. However, no correlation was found for the region of participating sites³.

Patients with luminal B tumours were found to have an estimated 3-year IDFS of 71.9% with palbociclib compared to 44.8% with placebo (HR 0.50; CI 0.24–1.05). Patients with luminal A tumours had a similarly higher 3-year IDFS of 83.9% with palbociclib compared to 79.5% with placebo (HR 0.93; CI, 0.68–1.28)³.

High risk early breast cancer

Another subgroup analysis from the Monarch-E trial explored the IDFS and distant relapse-free survival (DRFS) of patients with HR+, HER2-, high-risk EBC who had received neoadjuvant chemotherapy². The results showed that 2-year IDFS was significantly improved (P=0.0002) with abemaciclib plus adjuvant ET (87.2%) compared to ET alone (80.6%)⁴.

Metastatic breast cancer

Informative updates were also presented in the metastatic cancer setting, with new developments in the long-term overall survival in the PALOMA-3 and MONALEESA-3 studies. Join Professor Harbeck below to gain an overview of the updates from trials that featured at ASCO 2021.

Overall survival: A long term follow-up

An updated analysis from the PALOMA-3 trial investigated overall survival (OS) with palbociclib + fulvestrant in women with HR+, HER2– advanced breast cancer⁵.

The results showed that improvements in OS can still be seen in follow-ups at 5-years, with an OS rate of 23.3% with palbociclib + fulvestrant and 16.8% with placebo + fulvestrant (HR 0.806, P=0.0221). This benefit was observed in most subgroups among patients who were endocrine resistant or had prior chemotherapy. There were also no new safety signals identified⁵.

Overall survival in the first and second-line setting

Looking at the first and second line setting, an exploratory analysis of MONALEESA-3 assessed the long-term OS benefits of ribociclib after an extended median follow-up of 16.9 months⁶.

The extended follow-up showed that ribociclib with fulvestrant continued to provide more than 1 year overall survival benefit, at 53.7 months, compared with fulvestrant plus placebo, at 41.5 months (HR 0.73; 95% CI, 0.59–0.90)⁶.

The median OS of ribociclib plus fulvestrant was not reached in the first-line compared to fulvestrant plus placebo at 51.8 months (HR 0.64; CI, 0.46–0.88). However, in second-line subgroups ribociclib plus fulvestrant produced a 6 month longer median OS, at 39.7 months, compared to placebo plus fulvestrant, at 33.7 months. (HR 0.78; CI, 0.59–1.04)⁶.

The study also found that the time to second objective disease progression, time to chemotherapy, and CT-free survival were also more favourable in the ribociclib plus fulvestrant group than in fulvestrant plus placebo group⁶.

Investigational treatments

Among the important posters and abstracts that emerged from ASCO 2021 were new innovations in investigational treatments for breast cancer. Watch below to learn about investigational treatments that are just over the horizon with Professor Harbeck.

The DAWNA-1 trial

A notable update were the initial results from the DAWNA-1 trial on dalpiciclib, an investigational CDK4/6 inhibitor. DAWNA-1 is a randomised, double-blind, phase III trial of dalpiciclib, for pre-treated HR+/HER2- advanced or metastatic breast cancer patients who have relapsed or progressed on previous ET⁶.

Presented by Binghe Xu from China, the study found that progression-free survival (PFS) was more than doubled at 15.7 months in the dalpiciclib-fulvestrant treatment arm compared to 7.2 months in the placebo-fulvestrant arm (P<0.0001). The median PFS based on an independent review committee (IRC) assessment was also higher with dalpiciclib-fulvestrant at 13.6 months compared to placebo-fulvestrant at 7.7 months (P<0.0001)⁶.

The PRESERVE 2 trial

A new trial on the horizon is an ongoing international phase III, randomised, double-blind trial of trilaciclib. The PRESERVE 2 trial aims to evaluate the efficacy of trilaciclib administered prior to gemcitabine in patients with metastatic triple-negative breast cancer⁷.

Trilaciclib is an intravenous, highly potent and selective, reversible CDK4/6 inhibitor that protects haematopoietic stem cells and progenitor cells during chemotherapy and may directly enhance antitumor immunity⁷.

A previous randomised phase II trial of trilaciclib, administered prior to gemcitabine and carboplatin versus carboplatin alone in advanced metastatic triple-negative breast cancer, produced a substantial improvement in median OS (19.8 m vs 12.6 m, HR 0.37, CI 0.21–0.63). However, the primary endpoint of myeloprotection was not met⁷.

This cutting-edge research in the early and metastatic breast cancer settings has the potential to change the future of clinical practice. However, a lot of questions still remain in the field of CDK4/6 inhibitors and beyond.

References

1. Gluz O, Scheffen I, Degenhardt T, Marschner NW, Christgen M, Kreipe HH, et al. ADAPTlate: A randomized, controlled, open-label, phase III trial on adjuvant dynamic marker—Adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. TPS598.
2. Marme F, Martin M, Untch M, Bonnefoi HR, Kim SB, Bear HD, et al. Palbociclib combined with endocrine treatment in breast cancer patients with high relapse risk after neoadjuvant chemotherapy: Subgroup analyses of premenopausal patients in PENELOPE-B. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 518.
3. Denkert C, Marme F, Martin M, Untch M, Bonnefoi HR, Witkiewicz AK, et al. Subgroup of post-neoadjuvant luminal-B tumors assessed by HTG in PENELOPE-B investigating palbociclib in high risk HER2-/HR+ breast cancer with residual disease. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 519.
4. Martin M, Hegg R, Kim S, Schenker M, Grecea D, Saenz JAG, et al. Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC). 2021. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 517.
5. Cristofanilli M, Rugo HS, Im SA, Slamon DJ, Harbeck N, Bondarenko I, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 1000.
6. Slamon DJ, Neven P, Chia SKL, Jerusalem GHM, Laurentiis M De, Im SA, et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. 1001.
7. Goel S, O’Shaughnessy J, Tan AR, Krastev BM, Rugo HS, Aftimos PG, et al. Trial in progress: A phase 3, randomized, double-blind trial of trilaciclib versus placebo in patients receiving first- or second-line gemcitabine and carboplatin for locally advanced unresectable or metastatic triple-negative breast cancer (PRESERVE 2). Presented at the American Society of Clinical Oncology (ASCO) congress 2021, 4–8 June 2021, Virtual. TPS1107.

Introduction

The annual San Antonio Breast Cancer Symposium (SABCS) was held virtually for the very first time in December 2020 and presented the latest state-of-the-art information on breast cancer. This year, SABCS 2020 comprised of a five–day program attended by a broad international audience and included the first results from the PENELOPE-B trial and the final invasive disease-free survival (IDFS) analysis of monarchE. Results from the prospective multicenter RISAS trial and correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA Phase III studies were also presented amongst other topics.

Professor Harbeck from the Breast Centre at LMU in Munich, Germany shares her thoughts on the most important data and discussions to emerge from SABCS 2020.

Key trial updates and new data from the ADAPT and ASCENT trials presented at SABCS 2020

Amongst the most important data that emerged from SABCS 2020 were from Dr Nadia Harbeck who presented data from the ADAPT trial (NCT01779206)¹ and showed that certain patients with luminal EBC and up to 3 involved lymph nodes can be treated with adjuvant endocrine therapy (ET) according to the primary outcome analysis. The patients in the analysis had luminal EBC and were candidates for adjuvant chemotherapy. All patients received preoperative standard ET followed by adjuvant therapy alone. The patients were split into groups by recurrence score (0 to 11 and 12 to 25) and ki67 expression level, and both showed a response to preoperative ET, determined by a 10% or lower ki67 expression level.

The 5–year IDFS rate for patients with recurrence scores of 0 to 11 was also non-inferior to patients with recurrence scores of 12 to 25 (93.9% vs 92.6%, respectively), as was the 5–year distant disease-free survival (dDFS) rate (96.3% vs 95.6%, respectively) and 5–year overall survival (OS) rate (98/8% vs 97.3%, respectively). The 5–year dDFS did not differ by age or nodal subgroups either and a conclusion was reached that, irrespective of age, patients with 0 to 3 involved lymph nodes and a recurrence score of 0 to 11 as well as patients with a limited nodal burden and a recurrence score of 12 to 25 (and endocrine response after short perioperative ET) can be treated by ET alone.

In the metastatic breast cancer setting, Dr Sara Hurvitz discussed additional results from the phase III ASCENT trial (NCT02574455)² which showed favourable outcomes with sacituzumab govitecan in patients with triple-negative breast cancer regardless of their biomarker status. Sacituzumab govitecan extended the OS and improved the overall response and clinical benefit rates compared to the treatment of choice. Sacituzumab govitecan showed an OS with a median of 12.1 months (95% CI, 10.7–14.0) versus 6.7 months (95% CI, 5.8–7.7) for chemotherapy, with a hazard ratio (HR) of 0.48 (95% CI 0.38-0.59; p<0.0001). Moreover, the KEYNOTE355 trial updates highlighted a benefit in previously untreated patients with inoperable or metastatic triple-negative breast cancer after adding pembrolizumab to chemotherapy. For the overall study population, the addition of pembrolizumab to chemotherapy reduced the risk of disease progression by 18% (HR, 0.82; 95% CI, 0.69–0.97), and a reduced risk of disease progression in patients who received pembrolizumab was also observed.

The monarchE and MONALEESA-7 trial updates presented the most exciting data on CDK4/6 inhibitors at SABCS 2020

Professor Harbeck provides an expert opinion on the most exciting discussion points at SABCS 2020 related to CDK4/6 inhibition in breast cancer.

Updates from the monarchE trial (NCT03155997)¹ were key at SABCS 2020. Compared to ET alone, the CDK4/6 inhibitor, abemaciclib, plus ET was shown to improve IDFS in patients with high-risk, node-positive, early-stage HR+/HER2- BC. Those who received abemaciclib had a 28.7% reduced risk of invasive disease (P=0.0009).

In the monarchE trial, the 2–year IDFS rate was 92.3% in those who received abemaciclib and 89.3% in those who received abemaciclib plus ET, and the 2–year distant relapse-free survival rate was also improved in the abemaciclib cohort (93.8% vs 90.8%), with the benefit of abemaciclib being consistent in all subgroups and the safety data being consistent with the known safety profile of the drug. In addition to the results discussed above, the monarchE study was also the first study to look at patients based on their ki-67 status with a defined cut-off and to use it for validation as a prognostic factor. Amongst the patients with a high ki-67 status, the patients who received abemaciclib showed a 30.9% decreased risk of invasive disease compared to those who received ET alone (P=0.0111). More so, the 2–year IDFS rates were higher in patients who received abemaciclib (91.6% vs 87.1%).

An updated analysis of the phase 3 MONALEESA-7 trial (NCT02278120)⁴ showed a significant survival benefit with the CDK4/6 inhibitor, ribociclib, in treating HR+/HER2- breast cancer. A median follow-up of 53.5 months (range, 46.9–66.4) was reported and a median OS with ribociclib plus ET of 58.7 months vs 48.0 months with placebo/ET (HR, 0.763; 95% CI, 0.608–0.956) that translates to a 24% relative reduction in the risk of death with the CDK4/6 inhibitor. 

The use of the recurrence score in guiding treatment decisions

Professor Harbeck from the Breast Centre at LMU in Munich, Germany gives an overview of the impact of the findings on treating early breast cancer patients.

Besides the results from the monarchE trial and their impact discussed above, the data from the ADAPT study highlight the role of Oncotype DX Breast Recurrence Score test in shaping clinical practice. 5–year outcomes of the trial presented at SABCS 2020 confirmed the value of the test to help guide treatment decisions in breast cancer patients with a high clinical risk. More so, a new meta-analysis of data from more than 10,000 patients with node-negative disease supports the Oncotype DX Breast Recurrence Score test as the standard of care genomic test in early stage, invasive breast cancer. The latest data from the RxPONDER trial also highlight the unique value of the Recurrence Score in providing important information to improve the quality of treatment decisions in node-positive and node-negative early breast cancer patients.

References

1. ADAPT - Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer (ADAPT). Available at: https://clinicaltrials.gov/ct2/show/NCT01779206.
2. ASCENT-Study of Sacituzumab Govitecan in Refractory/Relapsed Triple-Negative Breast Cancer (ASCENT). Available at: https://clinicaltrials.gov/ct2/show/NCT02574455.
3. Endocrine Therapy With or Without Abemaciclib (LY2835219) Following Surgery in Participants With Breast Cancer (monarchE). Available at: https://clinicaltrials.gov/ct2/show/NCT03155997.
4. Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer (MONALEESA-7). Available at: https://clinicaltrials.gov/ct2/show/NCT02278120.