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ESMO West 2023: Early Breast Cancer Updates with Dr Lower

Presentation by Dr Elyse E. Lower, MD, University of Cincinnati



At the 2023 ESMO West review conference presented by Total Health in Colorado Springs, Colorado, Dr Elyse Lower, Emerita Professor from the University of Cincinnati, presented updates in early breast cancer (EBC) treatment, as reported at this year’s European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain.  Her selected abstracts focused on two key therapeutic strategies in EBC, immunotherapy, which helps the body’s immune system to more efficiently recognize and kill cancer cells, and the cyclin-dependent kinase (CDK)4/6 inhibitors (CDKi), which have become an important component of adjuvant treatment for patients with hormone receptor positive (HR+), lymph node positive (LN+) EBC, who have a high risk for recurrence.

 

Immunotherapy in Early-Stage Breast Cancer

Dr Lower began with an overview of the use of immunotherapy in EBC, specifically with immune checkpoint inhibitors (ICIs).  She noted that breast cancers which are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 negative (HER2-) generally have better outcomes compared to HER2+ or triple negative breast cancers (TNBC), but a subgroup of these patients are classified as high risk, and may require neoadjuvant (pre-surgery) chemotherapy (NAC).  The goal of NAC is to achieve a pathologic complete response/remission (pCR) or shrinkage of the tumor, and achieving a pCR after NAC has been associated with better outcomes such as overall survival (OS).  Rates of pCR following NAC, however, range only between 0% and 18% and the addition of ICIs such as pembrolizumab to NAC, which targets the programmed death ligand 1 (PD-L1) pathway can improve pCR rates.  For example, in the I-SPY-2 Trial, addition of pembrolizumab to NAC improved pCR rates from 13.6% to 34.2% for patients with ER+/HER2- tumors.

 

With this background, Dr Lower noted recent results from the KEYNOTE-756 Trial, a phase III study that examined the use of neoadjuvant pembrolizumab + chemotherapy (Pembro+Chemo) as compared to placebo + chemotherapy (PBO+Chemo) followed by adjuvant (post-surgery) Pembro or PBO in addition to endocrine therapy for patients having high-risk early stage ER+/HER2- breast cancer.  The primary endpoint in the trial was pCR rate and event-free survival (EFS), with secondary endpoints including OS, and most of the patients (~90%) had LN+ disease.  The results showed a significant improvement in pCR rate (BOX 1), and a benefit of Pembro+Chemo was seen across all relevant subgroups of patients. The safety profile of the regimen was as expected, with no new safety signals.  The results for EFS are as yet immature, and will require further follow up.

 

Similarly, Dr Lower noted the results from the CheckMate7FL Trial (NCT04109066).  This was a randomized, phase III trial examining another ICI, nivolumab (Nivo) versus PBO in combination with NAC, followed by adjuvant endocrine therapy, again in patients with high-risk, ER+/HER2− primary breast cancer.  The primary endpoint was pCR, with a secondary endpoint of residual cancer burden (RCB) 0-1 status (meaning very minimal residual disease) for the overall population, and the subgroup of patients with positive PD-L1 expression in their tumors.  Notably, ~99% of patients in the trial had Grade 3 tumors, over 40% had stage III disease, ~80% had LN+ disease, and about 1/3 had positive PD-L1 expression (>1%).  The results again showed a significant benefit in pCR rate of adding the ICI to NAC (BOX 1).  There was also a 9.2% improvement with Nivo+Chemo over PBO+Chemo in the rate of patients achieving RCB 0-1 status (30.7% vs. 21.3%) in the overall population.  Notably, the benefit of Nivo in both pCR rate and RCB 0-1 rate was greater for patients having PD-L1 expression >1%.  The safety profile of the combination regimen was again consistent with the known safety profiles of the treatment components. 

   

 Box 1.  pCR Rates: ICI Immunotherapy + NAC in ER+/HER2-/High-Risk Early Breast Cancers

Trial (ICI)

ICI + Chemo

PBO + Chemo

P Value

KEYNOTE 756

(Pembro)

24.3%

15.6%

0.00005

CheckMate7FL

(Nivo)

24.5%

13.8%

0.0021

Dr Lower also reviewed the use of ICIs + NAC in the setting of triple negative breast cancers (TNBCs), which lack expression of both hormone receptors (estrogen and progesterone) and HER2.  For patients with TNBC, achieving a pCR has also been associated with improved survival and studies have shown the use of ICIs can improve pCR rates. She highlighted updated EFS results first from the 5-year follow up of the KEYNOTE 522 Trial, which examined the use of Pembro or PBO + Chemo, followed by Pembro or PBO, for patients with early stage TNBC.  Initial results from the trial showed significant improvement in both pCR rates and EFS, and reported at ESMO were EFS results after a median 63.1 months.  The results continued to show a significant benefit of Pembro over PBO, with a 9% absolute improvement in EFS (81.3% vs. 72.3%; HR=0.73).  The benefit of Pembro was also noted across all subgroups of patients, and, importantly, was seen regardless of whether patients achieved a pCR or not.  There was also an improvement in distant metastasis free survival with Pembro over PBO (84.4% vs. 76.8%; HR=0.64) and follow up for OS is ongoing.  The updated results establish neoadjuvant Pembro + Chemo followed by adjuvant Pembro as a standard of care for high risk early TNBC.

 

Also reported at ESMO 2023 were updated results from the NeoTRIP/Michelangelo Trial (NCT002620280), a Phase III open-label randomized trial which examined the use of another ICI, atezolizumab (Atezo) in combination with neoadjuvant Chemo (nab-paclitaxel/carboplatin) for women with operable TNBC.  Previous results showed the feasibility of the regimen, and that pCR rates were higher with Atezo, but not significantly so.  Dr Lower noted that the 5-year EFS results from the trial were negative, with no significant improvement with Atezo + Chemo versus Chemo alone (70.6% vs. 74.9%; P=0.76). In an exploratory analysis of biomarkers that might be predictive for Atezo benefit, it was found that achieving a pCR, earlier stage disease, and positive PD-L1 status were associated with better EFS, but were not predictive of a benefit of Atezo.  For example, the 5-year EFS rate was 90.3% for those achieving a pCR versus 55.7% for those not achieving a pCR (HR=0.19; P<0.0001).  Dr Lower noted that EFS results with Atezo in the NeoTRIP study differ from those seen with another ICI, durvalumab (Durva) in the GeparNuevo Trial (as well as the larger KEYNOTE 522 trial as reported above) both of which have now shown a benefit of ICI + Chemo in the setting of early TNBC (BOX 2).


Box 2. ICIs + NAC in Early TNBC

Trial (ICI)

# of Patients

Follow up Period

Survival Endpoint

ICI+NAC

PBO+NAC

Significant?

KEYNOTE 522

(Pembro)

1174

5

EFS

81.3%

72.3%

Yes

NeoTRIP

(Atezo)

280

5

EFS

70.6%

74.9%

No

GeparNuevo

(Durva)

174

3

DFS

85.6%

77.2%

Yes

DFS=Disease-free survival

 

Adjuvant CDK Inhibitors in EBC

Dr Lower then reviewed the use of the CDKi in EBC in the adjuvant (post-surgical) setting, noting that about 30% of patients with LN+ early breast cancer may be at high risk for recurrence, and previous results from the two major trials that have examined the use of CDKi in combination with adjuvant endocrine therapy.  In monarchE, patients received adjuvant abemaciclib (Abema) for two years in combination with aromatase inhibitors (AIs), and this treatment is now approved for use in patients with LN+, high risk early breast cancer.  In NATALEE, the CDKi ribociclib (Ribo) was administered for a total of three years, in combination with adjuvant AI, for patients with high risk Stage IIA, or Stage IIB or III disease.  Results for the primary endpoint in NATALEE, invasive disease-free survival (iDFS), showed a significant benefit of Ribo + AI versus AI alone.

 

Results for NATALEE reported at ESMO described findings from a prespecified analysis of iDFS at 27.7 months in both treatment arms across clinically relevant patient subgroups.  The results showed an iDFS benefit of Ribo+AI versus AI alone across all patient subgroups, that was generally consistent with that observed in the ITT population of NATALEE (90.4 vs. 87.1%; HR=0.748), suggesting that the benefit is not driven by any one subgroup of patients (BOX 3).  Notably, the control arm also confirmed a risk for recurrence in the patients with LN negative (N0) and Stage II disease.  The results confirm previous findings and support the use of Ribo + AI for stage II and III HR+/HER2− early breast cancer.

 

Box 3. Subgroup Analysis for 3-Year iDFS from the NATALEE Trial

Subgroup

Ribo+AI

AI Alone

HR

Anatomic stage

Stage II

Stage III

94%

87%

 

91%

84%

 

0.761

0.740

Nodal status

N0

N1-N3

94%

90%

 

89%

87%

 

0.630

0.771

Menopausal status

Premenopausal

Postmenopausal

91%

90%

 

89%

86%

 

0.722

0.781

Age

<65

>65

90%

90%

 

87%

86%

 

0.765

0.723

Results for the monarchE Trial reported at ESMO detailed findings from a preplanned interim analysis of OS, including 5-year efficacy outcomes.  Patients in the trial had high risk, LN+ HR+/HER2- disease and received 2 years of Abema in combination with endocrine therapy (ET) of physician’s choice.  The results showed a continued benefit of Abema + ET versus ET alone, with a 5-year iDFS rate of 83.6% and 76.0% respectively (HR=0.680; P<0.001), and a benefit across all patient subgroups.  The benefit in distant recurrence free survival was also sustained (86.0% vs. 79.2%; HR=0.675; P<0.001), and while patients continue to be followed for OS outcomes, there were fewer deaths with Abema + ET.  Another abstract which Dr Lower highlighted from monarchE examined the prognostic and predictive impact of ER/PR status, and Ki-67 index (a measure of tumor proliferation) for Abema + ET benefit. The results of this analysis showed a consistent benefit of Abema + ET regardless of Ki67 index, ER expression, or PR expression.  As patients with ER+/PR negative (PR-) tumors have worse prognosis compared to patients with ER+/PR positive tumors, it was also notable that a significant benefit of Abema + ET was seen regardless of PR status (BOX 4)


Box 4.  Impact of PR Status on iDFS Outcome in monarchE

Subgroup

Abema+ET

ET Alone

HR

P Value

ER+ and PR+

86.7%

81.5%

0.711

<0.0001

ER+ and PR-

80.0%

68.5%

0.583

0.0008

Summary

Summarizing, Dr Lower noted the efficacy of ICIs in combination with NAC for patients with high risk HR+/HER2- early breast cancer, as seen in the KEYNOTE 756 (Pembro) and CheckMate7FL (Nivo) trials, with significantly increased pCR rates for the ICI combinations versus NAC alone in both trials. She further noted the use of ICI + NAC in TNBC, with positive results seen in the KEYNOTE 522 Trial for Pembro.  While the benefit was greatest in the subgroup achieving pCR, there was also benefit seen across subgroups, including those without pCR, and patients continue to be followed for OS outcomes.  By comparison, there was no benefit of Atezo + NAC for EFS in the NeoTRIP study, and while EFS was greatest in those with a pCR and in those with high PD-L1 expression, this was not predictive for Atezo benefit.  She noted the superiority of Pembro over Atezo in TNBC patients and that, while pCR appears prognostic, it is not a predictive factor for ICI benefit. In addition, the role of PD-L1 biomarker assessment and/or positive PD-L1 status as it relates to ICI + NAC treatment is unclear, with some conflicting findings across studies.

 

For the CDKi in early breast cancer, Dr Lower noted the NATALEE results, which met the primary endpoint of the trial, and showed a consistent iDFS benefit with Ribo + AI across subgroups, as well as the monarchE results from ESMO, which showed sustained benefit of Abema + ET after 5 years follow up, and a consistent benefit regardless of ER, PR, and Ki67.  While acknowledging the differences between the trials, for example, in the duration of CDKi adjuvant therapy (2 years vs 3 years) and a lack of OS data at present, Dr Lower noted that adjuvant CDKi plus AI is an important option for high-risk, ER+, HER2- early breast cancer patients.

 

Speaker Disclosure Information: Dr Lower reported no disclosures for this presentation.

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