Leading Research From ESMO 2020 Further the Potential of Targeted Agents in Breast Cancer

Breast cancer data reported during the 2020 European Society Medical Oncology (ESMO) Virtual Congress revealed major advances in the treatment paradigm. The agents included in these trials challenged that standard-of-care.

The biggest updates presented at ESMO were in the setting of hormone receptor (HR)–positive, HER2-negative advanced breast cancer. There were also some reports of efficacy with agents in triple-negative breast cancer and early breast cancer.

Alpelisib Plus Fulvestrant in SOLAR-1

Updated results from the use of alpelisib (Piqray) in combination fulvestrant in the phase 3 SOLAR-1 trial were presented at ESMO by Fabrice Andre, MD, PhD, director of research at Gustave Roussy in France. First, Andre provided a recap of the primary analysis data.¹

“We previously reported in 2019 in the New England Journal of Medicine that alpelisib improves progression-free survival from 5 to 11 months in patients with PIK3CA mutations. There was no benefit observed in patients without PIK3CA mutations,” Andre told Targeted Oncology, in an interview.

“At ESMO we reported a secondary endpoint, overall survival. What was observed is that there was a difference in the median overall survival of 8 months between patients who did not receive alpelisib in patients who received alpelisib,” Andre added.

The addition of alpelisib specifically prolonged overall survival (OS) in patients with HR-positive, HER2-negative, PIK3CA-mutant advanced breast cancer by 7.9 months as compared with chemotherapy alone. The median OS with alpelisib/fulvestrant was 39.3 months (95% CI, 34.1-44.9) compared with 31.4 months (95% CI, 26.8-41.3) in the placebo-plus-fulvestrant arm (HR, 0.86; 95% CI, 0.64-1.15; one-sided P ≤.0161).

Considering stratification measures in SOLAR-1, subanalyses of patients with lung and/or liver metastases, as well as patients with PIK3CA mutations in plasma circulating-tumor DNA
(ctDNA) were separately assessed. The OS result favored alpelisib plus fulvestrant in patients with lung and/or liver metastases. The median OS was 37.2 months (95% CI, 28.7-43.6) with added alpelisib versus 22.8 months (95% CI, 19.0-26.8) with fulvestrant alone (HR, 0.68; 95% CI, 0.46-1.00).

Patients with PIK3CA mutations in their plasma ctDNA also fared better in terms of OS with alpelisib/fulvestrant compared with placebo/fulvestrant with a median OS of 34.4 months (95% CI, 28.7-44.9) versus 25.2 months (95% CI, 20.7-29.6), respectively. The HR for risk of death in this subgroup was 0.74 (95% CI, 0.51-1.08).

The combination of alpelisib plus fulvestrant was overall beneficial for patients with HR-positive, HER2-negative advanced breast cancer, although the OS result did not meet the prespecified O’Brien-Fleming boundary. Notably, there was a progression-free survival (PFS) benefit observed with patients, which Andre determined was supported by a numeric increase in OS.

Abemaciclib With or Without Tamoxifen in nextMonarch

The CDK4/6 inhibitor abemaciclib (Verzenio) was administered alone or in combination with tamoxifen as treatment of patients with HR-positive, HER2-negative metastatic breast cancer in the phase 3 nextMONARCH clinical trial. It was hypothesized with this study that, unlike other CDK4/6 inhibitors, abemaciclib monotherapy at 150 mg over 200 mg could improve survival on its own.²

To validate the theory, the study included 3 arms. In arm A, patients received abemaciclib 150 mg in combination with tamoxifen 20 mg. Arm B received abemaciclib 150 mg only, and arm C received abemaciclib 200 mg plus prophylactic loperamide.

The trial did show a promising OS improvement in the combination arm, despite not being powered for this result.

“We have seen a lot of data in the first- and second-line space with CDK4/6 inhibitors, with ribociclib [Kisqali], palbociclib [Ibrance], and abemaciclib. Abemaciclib is a bit different because it’s the only CDK4/6 inhibitor that has a single-agent approval,” Erika Hamilton, MD, told Targeted Oncology in an interview.

“What we saw in nextMONARCH was that the progression-free survival and overall survival was quite similar to what was previously published, a 7.9-months difference that was not statistically significant. But we did see an overall survival benefit in [the combination arm] when abemaciclib was given in combination with tamoxifen.”

The OS observed with abemaciclib plus tamoxifen was 24.2 months compared with 20.8 months among patients treated with single-agent abemaciclib at 150 mg and 17.0 months among those who received abemaciclib 200 mg. The difference between the arm A and arm C was calculated with a HR of 0.62 (95% CI, 0.40-0.97; P = .0341). The HR for the difference between arm B versus arm C was 0.96 (95% CI, 0.64-1.44; P = .8321).

It was noted during Hamilton’s ESMO presentation that abemaciclib/tamoxifen also improved PFS at 9.07 months compared with 7.43 months with 200-mg abemaciclib alone (HR, 0.81; 95% CI, 0.56-1.16; P = .2493). Single-agent abemaciclib 150 mg had a median PFS of 7.23 months compared with the 200-mg dose (HR, 1.06; 95% CI, 0.74-1.53; P = .7400).

The survival results from nextMONARCH were said to have confirmed the benefit of abemaciclib that was previously observed in phase 2 MONARCH-1 clinical trial of abemaciclib alone in patients with refractory HR-positive, HER2-negative metastatic breast cancer (NCT02102490).

Abemaciclib With Endocrine Therapy in MonarchE

In the randomized, open-label phase 3 MonarchE trial (NCT03155997), abemaciclib in combination with endocrine therapy improved invasive disease-free survival (iDFS) compared with endocrine therapy alone in patients with HR-positive, HER2-negative early breast cancer, demonstrating the benefit of CDK4/6 inhibitors in other settings.³

“The primary end point was invasive disease-free survival [in which we] saw significantly fewer events in those patients treated with abemaciclib compared to those who had endocrine therapy alone. It resulted in a 25% reduction in the risk of recurrence with a hazard ratio of 0.747 and this was statistically significant,” Stephen R. D. Johnston, MD, PhD, FRCP, professor of breast cancer medicine and consultant medical oncologist, at the Royal Marsden, NHS Foundation Trust, told Targeted Oncology in an interview.

The HR Johnston mentioned was based on 136 iDFS events in the abemaciclib combination arm versus 187 in the endocrine therapy-only arm (95% CI, 0.598-0.932; 2-sided P = .096). At 2 years, the iDFS rate was 92.2% in the abemaciclib/endocrine therapy group versus 88.7% in the endocrine therapy-only group for an absolute difference of –3.5 percentage points. The benefit was carried over into subgroups populations, most notably among patients who had received prior neoadjuvant chemotherapy and those who were premenopausal.

A key secondary end point in this study was distant relapse-free survival (RFS), which did not include patients with local recurrence or second primary cancers. The data observed in this analysis were consistent with the primary end point showing 106 events in the abemaciclib combination arm versus 152 in the endocrine therapy arm (HR, 0.717; 95% CI, 0.559-0.920; 2-sided P = .0085). This resulted in a 28.3% reduction in the risk of distant recurrence. The 2-year distant RFS rate was 93.6% with abemaciclib/endocrine therapy versus 90.3% with endocrine therapy alone for an absolute difference of –3.3 percentage points.

The results overall imply that the addition of abemaciclib to the standard treatment of HR-positive, HER2-negative early breast cancer can prevent recurrence in these patients.

Sacituzumab Govitecan in ASCENT

The anticipated primary analysis results from the phase 3 ASCENT trial of sacituzumab govitecan (Trodelvy) in patients with metastatic triple-negative breast cancer (NCT02574455) were presented during ESMO by Aditya Bardia, MD, MPH, medical oncologist at Massachusetts General Hospital, and assistant professor of medicine at Harvard Medical School. The results showed a significant improvement with sacituzumab govitecan over standard single-agent chemotherapy across all primary and secondary end points explored in the study.⁴

“The first results from the ASCENT trial were presented at ESMO 2020. The primary and point of the study was progression-free survival and the study met its primary end point,” Bardia told Targeted Oncology in an interview.

“Overall the study was positive. Patients who received sacituzumab govitecan had a 59% lower risk of disease progression as compared with those who received standard therapy,” Bardia added.

First, the median PFS achieved with sacituzumab govitecan was 5.6 months (95% CI, 4.3-6.3) versus only 1.7 months (95% CI, 1.5-2.6) with treatment of physician’s choice (HR, 0.41; 95% CI, 0.32-0.52; P <.0001) per blinded independent central review. The PFS benefit was consistent across the subgroup populations explored in the study.

The OS analysis also demonstrated favor for the sacituzumab govitecan arm, which had a median OS of 12.1 months (95% CI, 10.7-14.0) versus 6.7 months (95% CI, 5.8-7.7) in the physician’s choice arm (HR, 0.48; 95% CI, 0.38-0.59; P <.0001).

Finally, treatment with sacituzumab govitecan improved response from baseline in the ASCENT trial. The objective response rate (ORR) was 35% in the sacituzumab govitecan arm, which included complete responses (CRs) in 10 patients and partial responses (PRs) in 72 patients. In comparison, the physician’s choice arm had an ORR of only 5% with 2 CRs and 9 PRs. Response were also more durable in the patients who received sacituzumab govitecan with a median duration of response of 6.3 months (95% CI, 5.5-9.0) versus 3.6 months (95% CI, 2.8-not evaluable) with physician’s choice of therapy. The P value was .057.

Based on the primary ASCENT findings, Bardia et al concluded that the benefit of sacituzumab govitecan as treatment of metastatic triple-negative breast cancer is confirmed and should be considered a new standard-of-care treatment in this patient population.

Ribociclib in MONALEESA-3 and MONALEESA-7

Patients with HR-positive, HER2-negative advanced breast cancer were given treatment with ribociclib in both the MONALEESA-3 (NCT02422615) and MONALEESA-7 (NCT02278120) clinical trials. Among these patients, a subgroup had developed resistance to prior endocrine therapy.⁵

In MONALEESA-3 explored treatment with ribociclib in combination with fulvestrant in men and postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment. MONALEESA-7 studied ribociclib compared with placebo plus tamoxifen in premenopausal women with HR positive, HER2 negative advanced breast cancer.

Pooled findings for outcomes for this subgroup from both studies were presented during ESMO by Sara Hurvitz, MD, a medical oncologist at the Ronald Reagan UCLA Medical Center, at UCLA Health - Santa Monica Medical Center.5The combined results showed a more than doubling of PFS with the addition of ribociclib to endocrine therapy.

“What we showed in this exploratory analysis was that ribociclib was associated with 6-month improvement in overall survival compared with endocrine therapy alone. This underscores the activity of ribociclib in patients whose disease can be considered endocrine therapy-resistant,” Hurvitz told Targeted Oncology, in an interview.

In MONALEESA-3, the 6-month PFS rate observed was 67% with ribociclib/endocrine therapy compared with 46% with endocrine therapy alone. In MONALEESA-7, treatment with ribociclib plus endocrine therapy led to a 74% 6-month PFS rate compared with 46% in the endocrine therapy–only arm.

The Kaplan-Meier curves for PFS in MONALEESA-3 showed that the median PFS favored the ribociclib combination over endocrine therapy alone at 13.4 months versus 5.7 months, respectively (HR, 0.621; 95% CI, 0.367-1.049). The benefit was also observed in MONALEESA-7 at 14.5 months versus 5.6 months, respectively (HR, 0.562; 95% CI, 0.342-0.922).

The median OS observed with ribociclib/endocrine therapy in the MONALEESA-3 study was 37.5 months compared with 31.7 months in the endocrine therapy–alone arm (HR, 0.697; 95% CI, 0.365-1.330). In MONALEESA-7, the median OS was not yet reached in the ribociclib plus endocrine therapy arm versus 32.7 months with endocrine therapy alone (HR, 0.588; 95% CI, 0.304-1.136).

According to Hurvitz et al, these poster data demonstrate the consistent efficacy of ribociclib in patients with early breast cancer and endocrine therapy resistance.

_References:

_{1. Andre F, Ciruelos EM, Juric D, et al. Overall Survival (OS) Results From SOLAR-1, a Phase 3 Study of Alpelisib (ALP) + Fulvestrant (FUL) for Hormone Receptor-Positive (HR+), Human Epidermal Growth Factor Receptor 2-Negative (HER2–) Advanced Breast Cancer (ABC). Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract LBA18.}

_{2. Hamilton EP, Cortes J, Ozyikan O, et al. nextMONARCH: Final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2- metastatic breast cancer. Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract 2730.}

_{3. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib in high risk early breast cancer. Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract LBA5_PR.}

_{4. Bardia A, Tolaney SM, Loirat D, et al. ASCENT: A randomized phase 3 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract LBA17.}

_{5. Hurvitz SA, Lee SS, Jerusalem G, et al. Ribociclib (RIB) in patients (pts) with HR+/HER2_ advanced breast cancer (ABC) and resistance to prior endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials. Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract 329P.}