Patients with ER-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy

PALOMA-2 was an international, randomized, double-blind, parallel-group, multicenter study of IBRANCE plus letrozole versus placebo plus letrozole conducted in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. A total of 666 patients were randomized 2:1 to IBRANCE plus letrozole or placebo plus letrozole. Randomization was stratified by disease site (visceral versus non-visceral), disease-free interval (de novo metastatic versus ≤12 months from the end of adjuvant treatment to disease recurrence versus >12 months from the end of adjuvant treatment to disease recurrence), and nature of prior (neo)adjuvant anticancer therapies (prior hormonal therapies versus no prior hormonal therapy). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Patients received study treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST). Additional efficacy outcome measures were confirmed overall response rate (ORR) as assessed by the investigator according to RECIST Version 1.1 and overall survival (OS).

Patients enrolled in this study had a median age of 62 years (range 28 to 89). The majority of patients were White (78%), and most patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (98%). Forty-eight percent of patients had received chemotherapy and 56% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Thirty-seven percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (97%) had metastatic disease. Twenty-three percent of patients had bone only disease, and 49% of patients had visceral disease.

Major efficacy results from PALOMA-2 are summarized in Table 10 and Figure 1. Consistent results were observed across patient subgroups of disease-free interval (DFI), disease site, and prior therapy. The treatment effect of the combination on PFS was also supported by an independent review of radiographs. Based on the prespecified final OS analysis conducted after 435 events, OS was not statistically significant.

Figure 1. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-2 (Investigator Assessment, Intent-to-Treat Population)
	LET=letrozole; PAL=palbociclib; PBO=placebo.

Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy

PALOMA-3 was an international, randomized, double-blind, parallel-group, multicenter study of IBRANCE plus fulvestrant versus placebo plus fulvestrant conducted in women with HR-positive, HER2-negative advanced breast cancer, regardless of their menopausal status, whose disease progressed on or after prior endocrine therapy. A total of 521 pre/postmenopausal women were randomized 2:1 to IBRANCE plus fulvestrant or placebo plus fulvestrant and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal), and presence of visceral metastases. IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Pre/perimenopausal women were enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of PALOMA-3. Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed PFS evaluated according to RECIST 1.1.

Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients on study were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were postmenopausal. All patients had received prior systemic therapy, and 75% of patients had received a previous chemotherapy regimen. Twenty-five percent of patients had received no prior therapy in the metastatic disease setting, 60% had visceral metastases, and 23% had bone only disease.

The results from the investigator-assessed PFS and final OS from PALOMA-3 are summarized in Table 11. The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively. Consistent PFS results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. After a median follow-up time of 45 months, the final OS results were not statistically significant.

Figure 2. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-3 (Investigator Assessment, Intent-to-Treat Population)
	FUL=fulvestrant; PAL=palbociclib; PBO=placebo.

Figure 3. Kaplan-Meier Plot of Overall Survival (Intent-to-Treat Population) – PALOMA-3
	FUL=fulvestrant; PAL=palbociclib; PBO=placebo.

INAVO120: IBRANCE plus Inavolisib and Fulvestrant

Adults with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease

INAVO120 (NCT04191499) was a randomized (1:1), double-blind, placebo-controlled trial evaluating the efficacy of inavolisib in combination with IBRANCE and fulvestrant in adult patients with endocrine-resistant PIK3CA-mutated, HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-), locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease. Randomization was stratified by presence of visceral disease (yes or no), endocrine resistance (primary or secondary), and geographic region (North America/Western Europe, Asia, other).

Primary endocrine resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy (ET) and secondary endocrine resistance was defined as relapse while on adjuvant ET after at least 2 years or relapse within 12 months of completing adjuvant ET.

Patients were required to have a HbA1C <6% and fasting blood glucose <126 mg/dL. The study excluded patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment at the start of study treatment.

PIK3CA mutation status was prospectively determined in a central laboratory using the FoundationOne® Liquid CDx assay on plasma-derived circulating tumor DNA (ctDNA) or in local laboratories using various validated polymerase chain reaction (PCR) or next-generation sequencing (NGS) assays on tumor tissue or plasma. All patients were required to provide both a freshly collected pre-treatment blood sample and a tumor tissue sample for central evaluation and determination of PIK3CA mutation(s) status.

Patients received either inavolisib 9 mg (n=161) or placebo (n=164) orally once daily, in combination with IBRANCE 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days, and fulvestrant 500 mg administered intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle. Patients received treatment until disease progression or unacceptable toxicity. In addition, all pre/perimenopausal women and men received an LHRH agonist throughout therapy.

The baseline demographic and disease characteristics were: median age 54 years (range: 27 to 79 years); 98% female, of which 39% were pre/perimenopausal; 59% White, 38% Asian, 2.5% Unknown, 0.6% Black or African American; 6% Hispanic or Latino; and ECOG PS of 0 (63%) or 1 (36%). Tamoxifen (57%) and aromatase inhibitors (50%) were the most commonly used adjuvant endocrine therapies. Sixty-four percent of patients were considered to have secondary endocrine resistance. Eighty-three percent of patients had received prior chemotherapy (in the neo/adjuvant setting) and 1.2% of patients had been treated with a CDK4/6 inhibitor.

The major efficacy outcome measure was investigator (INV)-assessed PFS per RECIST version 1.1. Additional efficacy outcome measures included OS, INV-assessed ORR, and INV-assessed duration of response (DOR).

Efficacy results are summarized in Table 12 and Figure 4. INV-assessed PFS results were supported by consistent results from a blinded independent central review (BICR) assessment. At the time of the PFS analysis, OS data were not mature with 30% deaths in the overall population.

Figure 4. Kaplan-Meier Curve for Investigator-Assessed Progression-Free Survival in INAVO120