Esmo Congress 2019: Focus on Breast Cancer

The ESMO Congress was held in Barcelona from September 27 to October 1, 2019. The conference recognized excellence in translational research and focused on clinically important findings and multidisciplinary topics. Following are highlights of breast cancer advances.

Neoadjuvant treatment for triple-negative breast cancer

In patients with early triple-negative breast cancer (TNBC), neoadjuvant pembrolizumab with chemotherapy followed by adjuvant pembrolizumab led to a higher pathologic complete response (pCR) rate than did neoadjuvant chemotherapy plus placebo.

Lead study author Peter Schmid, of the Centre for Experimental Cancer Medicine, Barts Cancer Institute-Queen Mary University of London, commented, “Now this is important, because large analyses have demonstrated that patients who achieve a pCR have a fantastic outlook and the recurrence risk is very low. Ninety to 95% of patients will not see any recurrence in that situation. However, patients who do not experience a PCR, we find residual tumor at the surgery. Even if we remove that residual tumor, unfortunately they have a relatively high risk of recurrence. Often around 40% to 50% in the first 3 to 5 years.”[2]

In the study, 784 patients with untreated, metastatic TNBC were randomized to receive pembrolizumab (200 mg every 3 weeks) and 390 were randomized to receive placebo. Both arms were treated with neoadjuvant chemotherapy before definitive surgery and adjuvant pembrolizumab.

In total, 602 patients could be assessed after a median follow-up of 15.5 months. In those receiving the pembrolizumab-chemotherapy regimen, the pCR rate was 64.8% compared with that of 51.2% for placebo plus chemotherapy. Of note, pCR was defined as ypT0/Tis ypN0.

A beneficial trend in event-free survival was also observed in those receiving neoadjuvant pembrolizumab arm compared with those in the placebo arm (hazard ratio [HR] 0.63; 95% CI, 0.43-0.93). On subgroup analysis, pCR was increased regardless of PD-L1 status.

The rate of grade 3 or more treatment-related adverse events was 78.0% in those in the pembrolizumab arm compared with that of those in the placebo arm. Moreover, mortality rates were 0.4% vs. 0.3% in these arms, respectively.[1,2,3]

HER2+ Advanced Breast Cancer and PD-L1 inhibitors

In patients with HER2+ advanced breast cancer who progressed following treatment with trastuzumab and a taxane, the programmed death ligand 1 (PD-L1) inhibitor atezolizumab plus trastuzumab emtansine (T-DM1) outperformed placebo plus T-DM1 in terms of overall survival (OS), according to the results of the phase 2 KATE2 trial.

Lead author Leisha Emens, of UPMC Hillman Cancer Center, Pittsburgh, stated, "Currently, there is a large effort to develop effective immunotherapy combinations that can enhance the activity of single agent PD-1 or PDL-1 blockade. HER2-positive breast cancer is unique in that there are a number of HER2-targeted agents that could potentially be combined with immune checkpoint blockade. The main ones include trastuzumab and trastuzumab emtansine, an antibody-drug conjugate. Both of those have, as a backbone, the trastuzumab antibody which in and of itself has immune-modulating activity. The antibody drug conjugate also has a chemotherapeutic agent conjugated directly to the antibody and that could also potentially have immune-modulating activity.”

She continued, “So, the rationale underlying KATE2, which is a phase II randomized trial that explored the clinical activity of adding atezolizumab to TDM1, is that combining these 2 agents maybe additive or even synergistic relative to the clinical activity of the single agents alone."[4]

In the current trial, patients were assigned 2:1 to receive either atezolizumab 1200 mg or placebo, with both cohorts receiving T-DM1 3.6 mg/kg intravenously every 3 weeks. Patients with PD-L1+ subtypes were determined via immune cell (IC) staining and included IC0 versus IC1/2/3 (<1% vs ≥ 1%, respectively).

In the atezolizumab plus T-DM1 arm, the median follow-up was 19.5 months compared with that of 18.2 months in the placebo arm. Although median overall survival was not attained, there were 52 measures of overall survival reported. One-year survival was similar in all patients, per the intention-to-treat population; whereas in PD-L1+ patients, 1-year OS was longer in the atezolizumab plus T-DM1 cohort. Compared with known safety profiles of each individual drug, the combined treatments had similar profiles. Pyrexia, however, was more common in those receiving atezolizumab plus T-DM1.

“Given the small number of OS events, the short follow-up and lack of statistical power, further study is necessary,” concluded the authors.[5]

Olaparib and durvalumab in breast cancer

Results presented from the phase 1/II MEDIOLA trial supported the combination treatment of olaparib and durvalumab in the treatment of patients with breast cancer.

The MEDIOLA trial assessed the efficacy and safety of olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer. In eligible patients, previous treatment with platinum was permitted, but previous treatment with PARP inhibitors or anti-PD1/PDL1 therapy was exclusionary. Treatment consisted of olaparib 300 mg twice-a-day for a 4-week run-in followed by olaparib 300 mg twice-a-day and durvalumab 1.5 g intravenous for 4 weeks. Primary endpoints were safety and disease control rate (DCR) at 12 weeks.[6]

In total, 30 patients were assessed for safety, and 34 patients were assessed for efficacy. Beating the target rate of 75%, the DCR at 12 weeks was 80% and the 28-week DCR was 50%.[7]

In other results, median progression-free survival (mPFS) in all patients was 8.2 months (95% CI, 4.6-11.8), median OS was 20.5 months (95% CI, 16.2-23.9), objective response rate (ORR) was 63.3% (95% CI, 43.9-80.1), and median duration of response (mDoR) was 9.2 months (95% CI, 5.5-20.3). The most common treatment-related adverse events of grade 3 or higher were anemia, neutropenia, and pancreatitis.

More specifically, in patients with hormone receptor (HR)-positive disease, mPFS was 9.9 months. The mPFS was 4.9 months in patients with triple-negative breast cancer.

“The data suggest that pts with fewer prior lines of chemotherapy (0/1) had higher ORR, longer mDoR, mPFS and mOS than those with 2 prior lines,” concluded the authors. “The chemo-free combination was well-tolerated, with safety consistent with the individual agent profiles. Confirmation of these results in early-line patients is warranted.”[6]

Abemaciclib and fulvestrant in breast cancer

In hormone-receptor (HR)-positive HER2-negative patients with advanced breast cancer resistant to endocrine therapy, adding the CD4/6 inhibitor abemaciclib to fulvestrant extended OS compared with fulvestrant and placebo, per the results of the MONARCH 2 trial.

In total, 669 patients were randomly assigned 2:1 to receive abemaciclib plus fulvestrant or placebo and fulvestrant, respectively. Fulvestrant was administered 500 mg twice daily, and abemaciclib was given 150 mg twice a day continuously.

The median OS in the abemaciclib-fulvestrant arm was 46.7 months compared with a median OS of 37.3 months in the placebo-fulvestrant arm (HR, 0.757; 95% CI, 0.606-0.945; P = .0137).

Principal investigator George W. Sledge Jr, of the Stanford University Medical Center concluded, “The addition of abemaciclib to fulvestrant provided a statistically significant OS improvement in patients with HR-positive, HER2-negative breast cancer who had progressed on prior endocrine therapy. “This OS benefit is consistent across subgroups, including patients with poor prognostic factors such as visceral metastasis and primary endocrine therapy resistance. Abemaciclib significantly delayed the receipt of subsequent chemotherapy in a subsequent analysis."[8,9]

FIVE KEY REFERENCES

2. ESMO. Adding Pembrolizumab to Neoadjuvant Chemotherapy Improves Outcome in Early TNBC. https://www.esmo.org/Oncology-News/Adding-Pembrolizumab-to-Neoadjuvant-Chemotherapy-Improves-Outcome-in-Early-TNBC. Accessed November 1, 2019.

3. Schmid P, Cortes Castan J, Bergh J, et al. KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo + chemo as neoadjuvant followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer (TNBC). Ann Oncol. 2019; 30(suppl 5):abstr 233TiP.

5. Emens LA, Esteva FJ, Beresford M, et al. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Ann Oncol . 2019; 30(suppl 5):abstr 3050.

6. Domchek S, Postel-Vinay S, Im S-A, et al. Phase II study of olaparib (O) and durvalumab (D) (MEDIOLA): Updated results in patients (pts) with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Ann Oncol. 2019; 30(suppl 5):abstr 11910.

8. Kaufman PA, Iwata H, Nikolinakos P, et al. Abemaciclib plus fulvestrant in patients (pts) with HR+/HER2- endocrine therapy naïve (EN) advanced breast cancer - an exploratory analysis of MONARCH 2. Ann Oncol. 2019; 30(suppl 5):abstr 253P.

References:

1. Interview. Cancer Network. Dr. Schmid Discusses the KEYNOTE-522 Trial. https://www.cancernetwork.com/esmo/dr-schmid-discusses-keynote-522-trial. Accessed November 1, 2019.

2. ESMO. Adding Pembrolizumab to Neoadjuvant Chemotherapy Improves Outcome in Early TNBC. https://www.esmo.org/Oncology-News/Adding-Pembrolizumab-to-Neoadjuvant-Chemotherapy-Improves-Outcome-in-Early-TNBC. Accessed November 1, 2019.

3. Schmid P, Cortes Castan J, Bergh J, et al. KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo + chemo as neoadjuvant followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer (TNBC). Ann Oncol. 2019; 30(suppl 5):abstr 233TiP.

4. Interview. Dr. Emens Discusses Overall Survival in HER2+ Breast Cancer. https://www.cancernetwork.com/esmo/dr-emens-discusses-overall-survival-her2-breast-cancer. Accessed November 1, 2019.

5. Emens LA, Esteva FJ, Beresford M, et al. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Ann Oncol. 2019; 30(suppl 5):abstr 3050.

6. Domchek S, Postel-Vinay S, Im S-A, et al. Phase II study of olaparib (O) and durvalumab (D) (MEDIOLA): Updated results in patients (pts) with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Ann Oncol. 2019; 30(suppl 5):abstr 11910.

7. Interview. OncLive. Olaparib/Durvalumab Combo Shows Promising Long-Term Activity in Germline BRCA+ Breast, Ovarian Cancer. https://www.onclive.com/web-exclusives/olaparibdurvalumab-combo-shows-promising-longterm-activity-in-germline-brca-breast-ovarian-cancer?p=2. Accessed November 5, 2019.

8. Kaufman PA, Iwata H, Nikolinakos P, et al. Abemaciclib plus fulvestrant in patients (pts) with HR+/HER2- endocrine therapy naïve (EN) advanced breast cancer - an exploratory analysis of MONARCH 2. Ann Oncol. 2019; 30(suppl 5):abstr 253P.

9. Interview. OncLive. Abemaciclib/Fulvestrant Improves Survival in HR+ Advanced Breast Cancer. https://www.onclive.com/conference-coverage/esmo-2019/abemaciclib-fulvestrant-improves-survival-in-hr-positive-advanced-breast-cancer. Accessed November 1, 2019.