Palbociclib in Combination with either Aromatase Inhibitors or Fulvestrant for Patients with Advanced HR+/HER2− Breast Cancer in Germany: Final Results of the Phase 2 Multicohort INGE-B Trial

CDK4/6 inhibitors have advanced to standard-of-care treatment for patients with advanced hormone receptor-positive/human epithelial growth factor receptor 2-negative (HR+/HER2−) BC over the past decade [1]. In conjunction with cyclin D1, the proto-oncogenes CDK4 and 6 regulate cell cycle progression from G1 to S-Phase. Alterations in the CDK4/6 pathway are key oncogenic drivers in BC and mediate resistance to endocrine therapy (ET) [2]. According to European guidelines, ET is the preferred option for HR+ BC, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance [3]. Current German guidelines recommend the combination of a CDK inhibitor with ET for these patients [4]. Palbociclib (PAL) is an orally bioavailable, selective CDK4/6 inhibitor. Based on the pivotal trials PALOMA-1 [5], PALOMA-2 [6], and PALOMA-3 [7], investigating the combination of PAL with letrozole or fulvestrant, extended EMA approval was granted for the combination of PAL with any aromatase inhibitor (AI) or with fulvestrant after prior ET for metastatic BC.

The phase 2 trial PALOMA-1 tested the combination of PAL with letrozole versus letrozole alone for postmenopausal women with ER+/HER2− advanced or metastatic breast cancer (ABC) in first palliative treatment line (1L) [5]. The combination treatment improved median progression-free survival (PFS) to a medically relevant extent (20.2 vs. 10.2 months, HR 0.49) [5]. In the phase 3 study PALOMA-2 (N = 666), the combination of PAL and letrozole showed significant PFS improvement compared to letrozole monotherapy as 1L treatment of HR+/HER2− ABC. Median PFS was increased from 14.5 months (letrozole alone) to 24.8 months (PAL plus letrozole; HR 0.58) [6]. However, no difference in overall survival (OS) between PAL and letrozole compared to letrozole alone was observed in this first-line setting (53.9 vs. 51.2 months, HR 0.96) [8].

In PALOMA-3, the combination of PAL with fulvestrant significantly improved the median PFS from 3.8 to 9.2 months (HR 0.42) compared to fulvestrant alone in patients with HR+/HER2− mBC after prior ET [9]. Median OS of 34.8 months in the PAL plus fulvestrant cohort compared with 28.0 months in the placebo with fulvestrant alone (HR 0.81), was not significantly different, yet revealed a trend toward improved OS with PAL plus fulvestrant versus fulvestrant alone [10].

The key objective of the prospective, multicenter phase 2 trial INGE-B was to generate efficacy and safety data on the combination of PAL with letrozole (1L) or with fulvestrant (first and later line) in Germany in accordance with the PALOMA trials [5‒7] and to generate so far lacking data on efficacy and safety of the combination of PAL with anastrozole or exemestane in 1L and with letrozole in later-line treatment.

INGE-B (EudraCT No: 2015-001603-32) was a prospective, open-label, single-arm, multicohort, multicenter phase 2 clinical trial conducted in Germany with the aim of investigating efficacy and safety data in patients with HR-positive, HER2-negative loco-regionally recurrent or metastatic breast cancer receiving a combination of PAL with letrozole (1L) or with fulvestrant (first and later line after prior ET) in accordance with the PALOMA trials [5‒7]. In addition, the study set out to generate so far lacking trial data on the combination of PAL with anastrozole or exemestane in 1L and the combination of PAL with letrozole in later-line treatment. The study was approved by the Responsible Ethics Committee (Bayerische Landesärztekammer, Referenznummer 16001) and written informed consent was obtained from each patient prior to enrollment. The study was conducted and analyzed in accordance with the ethical standards of the National Research Committee and the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards and is registered at ClinicalTrials.gov (NCT02894398).

Adult patients with histologically confirmed HR+/HER2− ABC with at least one measurable lesion as per RECIST v1.1 or bone-only disease, ECOG performance status 0–2 and adequate organ and bone marrow function could be enrolled in the INGE-B study. Pre-/perimenopausal women had to receive a luteinizing hormone-releasing hormone (LHRH) agonist/ovarian ablation. All patients scheduled for first- or later-line treatment with fulvestrant had prior endocrine failure. Key exclusion criteria were prior treatment with any CDK4/6 inhibitor, prior adjuvant therapy with the respective endocrine combination partner within 12 months before study entry, symptomatic, visceral metastases, and brain metastases. For patients scheduled for later-line treatment, the following exclusion criteria applied in addition: prior palliative therapy with the respective endocrine combination partner and more than one prior palliative chemotherapy.

Patients received 125 mg PAL orally once a day for 21 consecutive days of each 28-day cycle followed by 7 days off PAL treatment (3/1 schedule). Depending on the endocrine combination partner selected by the treating physician, the patients were assigned to 6 treatment cohorts (PAL + letrozole, anastrozole, exemestane, or fulvestrant in first line and PAL + letrozole or fulvestrant in second or later line). The respective combination partners were administered according to product labeling and in compliance with their local prescribing information. The regular treatment with PAL was administered until either ET was stopped, or until disease progression or inacceptable toxicity occurred. Dose modifications and interruptions of PAL and the endocrine partners were recommended based on individual safety and tolerability and in accordance with current Summary of Product Characteristics.

Imaging (CT/MRI) was done at screening and was then scheduled every 12 weeks (±2 weeks). Imaging and bone scans continued to be performed until disease progression, beginning of a subsequent anticancer therapy, or withdrawal from the trial, whichever came first. Tumor response was evaluated by the investigators. For measurable disease, tumor response was also calculated centrally according to RECIST v1.1.

Safety and tolerability were monitored by cardiac assessments at screening and at EOT, assessing routine laboratory parameters, physical examination and vital signs throughout the treatment with PAL until 30 days after EOT. Adverse events (AEs) were reported until PD or start of new anticancer treatment, whatever came first. Note, that AE reporting was continued beyond EOT if PAL was discontinued due to reasons other than PD. Health-related QoL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire, the Brief Fatigue Inventory (BFI), and the Hospital Anxiety and Depression Scale (HADS-D), every 12 weeks until PD (or start of next anticancer therapy, whatever came first).

The primary study endpoint was the clinical benefit rate (CBR) for patients with measurable disease, as assessed by central calculation per RECIST v1.1. CBR was defined as the rate of complete response (CR), partial response (PR), or stable disease (SD) for a duration of at least 24 weeks (≥24 weeks). Secondary endpoints included overall response rate, disease control rate, PFS, OS, 1- and 2-year PFS and OS rates, safety, treatment adherence and assessment of health-related quality of life, fatigue, anxiety, and depression using the validated questionnaires FACT-B, BFI, and HADS-D. Data were analyzed with descriptive statistics.

All time to event endpoints were estimated using the Kaplan-Meier method [11]. PFS was defined as interval between start of 1L treatment until first progression or death from any cause. Patients without such an event were censored at start of 2L treatment. Patients without an event who did not start 2L treatment were censored at their respective date of last tumor evaluation or day of last study drug administration plus one. OS was defined as interval between start of 1L treatment until death from any cause. Patients alive or lost to follow-up at database lock were censored at the last date known to be alive. All analyses were performed using R version 4.3.2 (2023-10-31) “Eye Holes” (Platform: x86_64-pc-linux-gnu (64-bit)).

From September 2016 to December 2018, a total of 388 patients with ABC were enrolled in 64 study sites in Germany, of whom 351 were treated and assigned to the 1L cohorts: cohort 1: PAL plus letrozole (PAL+LET 1L; N = 62), cohort 2: PAL plus anastrozole (PAL+ANA 1L; N = 60), cohort 3: PAL plus exemestane (PAL+EXE 1L; N = 58), and cohort 4: PAL plus fulvestrant (PAL+FUL 1L; N = 50), or second- or later-line cohorts: cohort 5: PAL plus letrozole (PAL+LET 2L; N = 60) and cohort 6: PAL plus fulvestrant (PAL+FUL 2L; N = 61) (Fig. 1). For the analyses of demographic, disease-related, and survival data, 10 patients were excluded as they had been treated in later line: PAL+ANA; N = 7 and PAL+EXE; N = 3 (Fig. 1).

Table 1 presents baseline patient and clinical characteristics of 341 patients included in this analysis. As the allocation of patients to distinct cohorts was determined by physicians’ preference and not by randomization, differences in prognostic relevant demographics and tumor characteristics were observed. Median age for patients treated in 1L was 67.3 years (PAL+LET 1L), 63.3 years (PAL+ANA 1L), 63.8 years (PAL+EXE 1L), 69.8 years (PAL+FUL 1L), and for patients treated in later line, it was 60.9 years (PAL+LET 2L) and 68.4 years (PAL+FUL 2L). Over 90% of patients in each cohort had an ECOG performance of 0 or 1 at inclusion. 64.5% of patients receiving letrozole 1L were initially diagnosed with early breast cancer, 49.1% in the anastrozole, 66.7% in the exemestane and 88% in the fulvestrant 1L cohorts. In 2L treatment arms, 73.3% (letrozole) and 54.1% (fulvestrant) of patients were initially diagnosed with M0 disease. For patients treated in 1L, 79% presented with measurable disease in the letrozole cohort, 60.4%, 77.8%, and 68.0% in the anastrozole, exemestane, and fulvestrant cohort, respectively (Table 1). For later-line cohorts, 85.0% and 72.1% presented with measurable disease in the letrozole and fulvestrant cohort, respectively. Bone-only disease was present in 24.2% in the letrozole, 41.5% in the anastrozole, 22.2% in the exemestane and 36.0% in the fulvestrant 1L cohort, and 16.7%, and 36.0% in the letrozole and fulvestrant 2L cohorts, respectively.

Endocrine pretreatment was received by 37.7% of patients in the 1L PAL+ANA cohort, 59.7% in the PAL+LET cohort, 64.8% in the PAL+EXE cohort, and 94.0% of patients in the PAL+FUL cohort, respectively. The proportion of prior (neo)adjuvant chemotherapy (CTx) was lowest with 30.2% in the anastrozole and highest with 66.0% in the fulvestrant cohort. Prior CTx in the letrozole and exemestane cohorts was 46.8%, and 50.0%, respectively. In the 2L cohorts (PAL+LET 2L and PAL+FUL 2L), prior ET was documented for almost all patients (95.0% and 100%), while 75.0% and 62.3% of patients had received prior (neo)adjuvant or palliative chemotherapy (Table 1).

The primary endpoint CBR was 63.7% in patients with measurable disease treated with 1L PAL. For the 1L cohorts, CBR was 71.4% (PAL+LET), 56.2% (PAL+ANA), 64.3% (PAL+EXE), and 58.8% (PAL+FUL). The CBR among all patients treated in 1L was 72.1%, for patients treated with PAL in combination with letrozole it was 71.0%, 79.2% with anastrozole, 74.1% with exemestane, and 64.0% with fulvestrant. In second or later line, the CBR in patients with measurable disease was 45.1% (PAL+LET) and 40.9% (PAL+FUL). CBR was 49.6% among all patients treated in 2L and 48.3% and 50.8% in patients receiving a combination with PAL, letrozole, or fulvestrant, respectively.

Median PFS in all patients treated in 1L was 20.1 months (95% CI 14.6–24.0), 18.0 months (95% CI 11.2–24.3) in the PAL+LET cohort, 23.3 months (95% CI 13.7–38.7) in the PAL+ANA cohort, 22.6 months (95% CI 16.0–26.9) in the PAL+EXE cohort, and 13.7 months (95% CI 8.0–30.4) in the PAL+FUL cohort. In all patients treated in 2L, median PFS was 8.7 months (95% CI 5.8–11.0); with PAL+LET 2L 8.7 months (95% CI 4.1–19.4), and PAL+FUL 2L 8.2 months (95% CI 5.6–10.9). Median OS in all patients treated in 1L was 40.9 months (95% CI 35.1–49.2); with 54.6 months (95% CI 40.3–NA) in the PAL+ANA cohort, 49.2 months (95% CI 40.3–NA) in the PAL+FUL cohort, 40.0 months (95% CI 32.9–58.8) in the PAL+LET cohort and 34 months (95% CI 27.1–41.0) in the PAL+EXE cohort (Table 2; Fig. 2a). For all patients treated in second or later line, median OS was 33.0 months (95% CI 21.1–39.3), while it was 34.7 months (95% CI 20.7–41.7) in the PAL+LET 2L and 26.9 months (95% CI 15.6–37.2) in the PAL+FUL 2L cohort (Table 2; Fig. 2b).

Treatment-emergent adverse events (TEAEs) of any grade were reported by 224 1L patients (97.4%) and 115 later-line patients (95.0%). A total of 152 patients (66.1%) in the 1L cohorts and 78 patients (64.5%) in the 2L cohorts experienced grade 3/4 AEs (Tables 3, 4). The most common TEAE was neutropenia in 1L cohorts (any grade: 45.2%; grade 3/4: 33.4%) and later-line cohorts (any grade: 42.1%; grade 3/4: 34.7%). The relative frequencies of TEAEs were similar in the individual cohorts. The TEAEs that occurred in at least 10% of all patients are summarized in online supplementary Table S1 (for all online suppl. material, see https://doi.org/10.1159/000542459).

During the course of the study, 56.1% patients in the safety analysis set (SAF) died (197/351). In the 1L cohorts, death occurred in 49.2% of the patients (117/238); in second- or later-line cohorts, death was documented in 66.1% (80/121) of the patients. Overall, breast cancer-related deaths occurred in 135 patients (38.5%) in the SAF.

We report here the results of a phase 2 trial on efficacy and safety of PAL in combination with letrozole, anastrozole, exemestane and fulvestrant in first-line treatment as well as PAL in combination with letrozole or fulvestrant in second- or later-line treatment. Our data confirm the results of the three registrational trials that evaluated PAL in combination with letrozole (1L) or with fulvestrant (first and later line): PALOMA-1 [5], PALOMA-2 [6], and PALOMA-3 [7]. Additionally, INGE-B offered evidence for the efficacy and safety of PAL with anastrozole or exemestane in 1L, and with letrozole in later lines, which had not been confirmed before.

Comparing the results of the INGE-B trial with the pivotal PALOMA-2 trial, the CBR in 1L cohorts among all patients treated with the combination of PAL and an AI was 71.0% (95% CI 58.1–81.8) in the letrozole cohort, 74.1% (95% CI 60.3–85.0) in the exemestane cohort, and 79.2% (95% CI 65.9–89.2) in the anastrozole cohort. These results are in line with the reported CBR rate for patients treated with PAL and letrozole of 84.9% (95% CI 81.2–88.1) in PALOMA-2 [6]. Similarly, in patients with measurable disease, the CBRs in the INGE-B trial for 1L PAL plus letrozole of 71.4% (95% CI 56.7–83.4) was also in line with the 84.3% (95% CI 80.0–88.0) in patients with measurable disease treated with PAL and letrozole in PALOMA-2 [6], whereas CBR was lower in the anastrozole cohort 56.2% (95% CI 37.7–73.6) and in the exemestane cohort 64.3% (95% CI 48.0–78.4). For the treatment combination of PAL and fulvestrant, the CBR among all patients was 64.0% (95% CI 49.2–77.1) (1L) and 50.8% (95% CI 37.7–63.9) (later line) and therefore comparable with the reported CBR of 67% (95% CI 61.3–71.5) in PALOMA-3 [7].

The reported median PFS in patients treated 1L with PAL plus letrozole was 20.2 months (95% CI 13.8–27.5) in PALOMA-1 [5], and 24.8 months (95% CI 22.1–NA) in PALOMA-2 [6], and therefore in line with the 1L PFS of PAL in combination with AI in the INGE-B trial: 18.0 months (95% CI 11.2–24.3) for the PAL plus letrozole cohort, 23.3 months (95% CI 13.7–38.7) for the anastrozole cohort and 22.6 months (95% CI 16.0–26.9) for the exemestane cohort, respectively. These findings demonstrate good efficacy of 1L treatment with PAL in combination with AI, especially for the two AIs not represented in the pivotal clinical trials. Notably, real-world data on 1L PAL plus AI revealed a PFS of 19.3 months (95% CI 17.5–20.7) [12]. In combination with fulvestrant, median PFS was 13.7 months (95% CI 8.0–30.4) for patients treated 1L and 8.2 months (95% CI 5.6–10.9) for patients treated later line in the INGE-B trial compared to a median PFS of 9.5 months (95% CI 9.2–11) in the PALOMA-3 trial, underlining good efficacy of PAL plus fulvestrant in patients with progressive disease after previous ET [7].

Although the PALOMA-2 study met its primary endpoint of improving PFS significantly [6], the addition of PAL to letrozole in 1L treatment of HR+/HER2− ABC failed to demonstrate OS benefit 53.9 months (95% CI 49.8–60.8) compared to 51.2 months (95% CI 43.7–58.9) [8]. Median OS in 1L cohorts among all patients treated with the combination of PAL and AI in INGE-B was 34.0 months (95% CI 27.1–41.0) in the exemestane cohort, 40.0 months (95% CI 32.9–58.8) in the letrozole cohort, and 54.6 months (95% CI 40.3–NA) in the anastrozole cohort. The presented OS in the anastrozole and letrozole cohorts are in line with the data from PALOMA-2, as well as the reported OS of 49.1 months (95% CI 45.2–57.7) in the real-world analysis P-REALITY X [12], whereas a shorter OS was seen in the exemestane cohort. This might be explained by differences in patients and disease characteristics between patients observed in the PALOMA-2 trial and the exemestane cohort of INGE-B. In PALOMA-2, patients presented more often with ECOG 0 at start of first palliative treatment line compared to those treated with exemestane as endocrine combination partner in INGE-B (57.9% vs. 52%). With regard to disease stage at initial diagnosis, patients treated with PAL + letrozole in the PALOMA-2 trial presented more often with initially metastatic disease compared to patients in the exemestane cohort of INGE-B (37.6% vs. 29.6%, respectively). Consequently, patients enrolled in the exemestane cohort have more often received prior ET compared to patients observed in the PALOMA trial (65% vs. 56%). Particularly, AIs were used more frequently as endocrine pre-therapies (cumulative by substance class) in the exemestane cohort of INGE-B (37.0%) compared to PALOMA patients (27.5%). Taken together, regarding relevant prognostic factors, patients treated with PAL + exemestane in the INGE-B trial presented with unfavorable patient and disease characteristics compared to those treated with letrozole as endocrine combination partner in the PALOMA-2 trial, which might explain the observed differences in OS.

Although most international guidelines recommend upfront use of CDKi in the palliative setting, not all patients in clinical routine receive this treatment for unknown reasons. In the SONIA phase 3 trial, presented at ASCO 2023, the sequence of PAL + ET followed by endocrine monotherapy did not prolong PFS2 compared to endocrine monotherapy followed by PAL + ET and led to a greater overall incidence of toxicity due to longer exposure to CDKi [13]. Therefore, sequence of endocrine monotherapies followed by second-line CDKi + ET might be a good option for a subset of patients. Our data show good efficacy and tolerability of PAL in combination with either letrozole or fulvestrant in second- or later-line treatment of HR+/HER2− ABC. However, further research is still needed to better define the optimal use and the optimal sequence of PAL as well as CDKi in general in palliative treatment of HR+/HER2− metastatic breast cancer.

The phase 2 INGE-B trial prospectively confirmed the good efficacy and tolerability of PAL in combination with letrozole (1L) or with fulvestrant (first and later line) in accordance with the PALOMA trials. In addition, INGE-B for the first time demonstrated good efficacy and safety for the combination of PAL with anastrozole and exemestane in 1L and with letrozole in later line. These data further support the use of 1L PAL in combination with AI or fulvestrant, and later-line treatment with PAL in combination with letrozole or fulvestrant in women with HR+/HER2− ABC. No new safety concerns of PAL plus AI or fulvestrant were identified.

The authors thank Dr. Jörg Hartkamp (iOMEDICO) for help with preparation of the manuscript.

The study was conducted and analyzed in accordance with the ethical standards of the National Research Committee and the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was reviewed and approved by the Responsible Ethics Committee [Bayerische Landesärztekammer], reference number 16001. Written informed consent was obtained from each patient prior to enrollment. The study is registered at ClinicalTrials.gov (NCT02894398).

K.P., C.S., L.M., C.B., J.M., A.S., R.L., T.K., H.U.S., G.B., and K.G. declare no conflict of interest concerning the topic of this publication. N.M. is chief executive officer and shareholder of iOMEDICO AG. The institutions of M.W., M.Z., L.M., C.B., C.S., M.U., J.M., D.L., A.W., S.D., V.H., A.S., R.L., and T.K. received remuneration for the documentation of patient data. M.W.: consulting fees: Novartis, Daiichi Sankyo, Lilly, BMS, AstraZeneca; honoraria for lectures/presentations, travel support, participation on a data safety monitoring board, or advisory board: Novartis, Daiichi Sankyo, Lilly, BMS, AstraZeneca, Gilead, Stemline, AbbVie, and Pierre Fabre. M.Z.: honoraria for lectures/presentations: AbbVie, MSD, Takeda, Vifor, Roche, Lilly; participation on a data safety monitoring board, or advisory board: AbbVie, AstraZeneca, BMS, Celgene, Eisai, Gilead, Hexal, Janssen, Lilly, Novartis, Pfizer, Roche, and Vifor. M.U.: honoraria for lectures/presentations: AstraZeneca, Daiichi Sankyo, Lilly, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi Aventis, and Menarini Stemline; participation on a data safety monitoring board or advisory board: AstraZeneca, Daiichi Sankyo, Lilly, MSD Merck, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Gilead, Roche, Sanofi Aventis Seagen, Menarini Stemline, and CD Pharma. D.L.: consulting fees, honoraria for lectures/presentations, payment for expert testimony, and travel fees: AstraZeneca, Pfizer, Novartis, Eli Lilly, Amgen, Loreal, GSK, onkowissen, high5MD, Daiichi Sankyo, Novartis, and Gilead; leadership or fiduciary role in DGHO from 2012 to 2019. A.W.: advisory boards: MSD, Roche, Novartis, Pfizer, Seagen, Lilly, Menarini Stemline, and P. Fabre; participation on a data safety monitoring board: iOMEDICO; honoraria for lectures/presentations: Roche, Eisai, Novartis, Pfizer, Lilly, iOMEDICO, Interplan, MSD, MCI, RCC, and Menarini Stemline. S.D.: travel support: BeiGene (DGHO 2024); participation on a data safety monitoring board or advisory board: AbbVie, BeiGene, and Servier; stock ownership: iOMEDICO. V.H.: consulting fees: Novartis, Roche, Pfizer, BMS, and Boehringer Ingelheim; honoraria for lectures/presentations: Roche, Amgen, Pfizer, Celgene, BMS, Boehringer Ingelheim, Novartis, AstraZeneca, Lilly, and mteacademy; travel support: Roche, Pfizer, JansenCilag, iOMEDICO, Gilead, Celgene, and Daiichi Sankyo; and stock ownership: BMS, JNJ.

The INGE-B study was managed and analyzed by iOMEDICO and has received continuous financial support from Pfizer Pharma GmbH, Germany (Grant No. WI200513). Pfizer had no role in study design, data collection and analysis, interpretation of results, decision to publish, or preparation of the manuscript.

M.W., M.Z., L.M., C.B., C.S., M.U., J.M., D.L., A.W., S.D., V.H., A.S., R.L., and T.K.: investigation, resources, and writing – review and editing; K.P., conceptualization, methodology, validation, funding acquisition, and writing – review and editing; H.U.S., data curation, formal analysis, visualization, and writing – review and editing; G.B., project administration and writing – review and editing; C.V., conceptualization, methodology, validation, and writing – review and editing; N.M., conceptualization, funding acquisition, and writing – review and editing; and K.G., conceptualization, methodology, validation, and writing – original draft.

The patient-level data supporting the findings of the study are not openly available due to data privacy protection regulations. Inquiries regarding the data used for this study can be directed to the corresponding author.