Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer

This article is featured in Selected Articles from This Issue, p. 4991

Tumors that express hormonal receptors (HR) and amplified human epidermal growth factor receptor 2 (HER2) comprise 11% of all breast cancer cases (1), with a higher frequency among young patients. In patients with young onset breast cancer (diagnosed at ≤45 years), HR+/HER2+ disease comprises 20% of cases and equals or exceeds the frequency of triple-negative disease (2). Visceral and CNS metastases are common in HR+/HER2+ metastatic breast cancer (MBC), and the associated morbidity and mortality is substantial.

In HR+/HER2+ disease, efficacy of antihormonal and HER2-targeted agents is diminished due to cross-talk of the pathways: HER2 expression drives resistance to antihormonal agents, whereas HR signaling allows for tumor survival despite HER2 blockade (2–5). Dual targeting of HR and HER2 has documented efficacy in preclinical models (6), however, clinical results have been variable (7–10). Current guidelines for HER2+ MBC rely on sequential HER2 targeting: first using anti-HER2 antibodies with chemotherapy and, in later lines, tyrosine kinase inhibitors (TKI) with chemotherapy, or anti-HER2 antibody–drug conjugates as single agents (11). Recently, two studies showed favorable results with chemotherapy-free regimens targeting HR and HER2 in the first (9) or third line (10) MBC setting, whereas older trials had modest results (7, 8). Although highly effective, the current recommended chemotherapy-based combinations or antibody–drug conjugates are associated with multiple side effects, and all have the need for infusion time (12–14). Therefore, there is an unmet need for effective oral targeted regimens for HR+/HER2+ disease, with the potential of delaying chemotherapy to later treatment lines, similar to HR+/HER2− breast cancer.

Signaling from both HR and HER2 results in the increased transcription of CCND1 gene encoding cyclin D1 (15). Upon a mitogenic stimulus, cyclin D1 complexes with cyclin-dependent kinases (CDK) 4 and 6, inducing cell-cycle progression (Fig. 1). The cyclin D1–CDK4/6 complex is a primary driver of resistance to drugs targeting both HR and HER2 (2, 5, 16, 17), and many preclinical studies demonstrated synergy of CDK4/6 inhibitors with antihormonal and HER2-targeted agents (2, 16–19).

We hypothesized that triple targeting of HER2, CDK4/6, and hormonal signaling will be clinically effective in HR+/HER2+ MBC. Considering that an all-oral regimen would be appealing to patients, we chose to combine the CDK4/6 inhibitor palbociclib and aromatase inhibitor letrozole with the HER2 TKI tucatinib. Tucatinib is an oral, potent, HER2-specific TKI approved for the treatment of HER2+ MBC in the second- or third-line setting (20). Tucatinib is active in combination with capecitabine and trastuzumab (21, 22), has preliminary evidence of efficacy with the antibody–drug conjugate T-DM1 (23), and high CNS activity (22, 23).

We previously showed that tucatinib in combination with palbociclib and antihormonal agents had high efficacy in vitro and in vivo (2), and moreover, that the two drugs in the combination may overcome resistance to the third agent (2), suggesting that triple targeted combination would more effectively block emergence of resistance on therapy. Recently, the preclinical rationale for investigating tucatinib and CDK4/6 inhibitor combinations has been further strengthened (19). On the basis of the signaling rationale (16) and our preclinical data (2), we proposed a regimen of three oral targeted agents—tucatinib, palbociclib, and letrozole (TLP), to block HR and HER2 pathways, and their key intersection at cell-cycle checkpoints mediating drug resistance (5, 16). In addition, we aimed to investigate a patient-centered, chemotherapy-free regimen to reduce toxicities and eliminate the need for infusion time. Here we present results of a phase Ib/II clinical trial of tucatinib, letrozole, and palbociclib (TLP combination, NCT03054363) in patients with HR+/HER2+ MBC.

This was a phase Ib/II trial to determine the safety, tolerability, and antitumor activity of tucatinib, palbociclib, and letrozole in HR+/HER2+ MBC. The study was conducted in accordance with ethical guidelines (Belmont Report and US Common Rule) and approved by the institutional review boards of all participating sites. All patients provided written informed consent before enrollment. The trial protocol is available in Appendix S1.

The primary objective of the phase Ib part was to evaluate the safety and tolerability of the TLP combination by NCI CTCAE version 4.03. The secondary objective was to evaluate the pharmacokinetic (PK) properties of tucatinib and palbociclib. Phase Ib participants were treated on a 28-day cycle with tucatinib 300 mg orally twice a day, palbociclib 125 mg orally daily taken for 21 days on followed by 7 days off, and letrozole 2.5 mg orally daily. All premenopausal women received mandatory ovarian function suppression. Dose-limiting toxicity (DLT) was defined as any grade≥3 nonhematologic adverse event (AE), grade 3 neutropenia with fever, grade 3 thrombocytopenia with bleeding, or any hematologic toxicity grade≥4. DLT required dose reduction of the attributed medication, per investigator determination. Dose reductions of tucatinib and/or palbociclib, and discontinuation of either palbociclib or letrozole (but not both) were allowed. All AEs and serious AEs (SAE) were collected from signing of consent through 30 days after the end of treatments.

The primary objective of phase II was to assess the efficacy of the TLP combination by median progression-free survival (mPFS), defined as the time from the start of treatment to the first documented disease progression or death due to any cause, whichever occurred first. Secondary objectives were to determine overall response rate (ORR), clinical benefit rate (CBR), and median duration of response (mDOR), to evaluate safety of the combination therapy, and to obtain additional PKs of tucatinib and palbociclib. Phase II participants were treated with tucatinib 300 mg orally twice a day, palbociclib 75 mg daily for 21 days on followed by 7 days off, and letrozole 2.5 mg orally daily. Tumor response was assessed by radiographic evaluations every two cycles up to and including cycle 6, and every three cycles thereafter, applying RECIST 1.1 criteria, and/or RANO-BM criteria for patients with brain metastases (24, 25). Patients with isolated CNS progression were allowed to remain on study if systemic disease was controlled. They underwent local therapy to the progressive CNS lesion(s) and continued therapy until a second progressive event occurred.

Patients were ages ≥18 with HR+/HER2+ MBC previously treated with at least 2 HER2-targeted agents in the adjuvant or metastatic setting. HR and HER2 positivity were assessed locally. HR positivity was defined as ≥1% of positive cells by IHC, and HER2 positivity was defined by fluorescent in situ hybridization and/or 3+ staining by IHC according to ASCO/CAP guidelines (26, 27). Measurable or evaluable disease was required. Additional inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status ≤1, estimated life expectancy ≥6 months, adequate organ function, and normal left ventricular ejection fraction (LVEF). Key exclusion criteria were treatment with prior EGFR or HER2 TKIs or CDK4/6 inhibitors, ≥2 lines of endocrine therapy for MBC, and significant cardiovascular disease. Patients with locally treated and stable or locally untreated asymptomatic CNS metastases not requiring immediate local therapy were included. Patients with locally treated progressing brain metastases were excluded from the study.

Concentrations of palbociclib, tucatinib, and its metabolite ONT-993 were measured on cycle 1 day 15 and cycle 2 day 1 in all phase Ib patients. Additional PKs were collected on day 9 of cycles 1 and 2 in the first 9 patients enrolled in phase II part (Appendix S1, p. 80–81).

The phase Ib primary endpoint was safety and tolerability of the combination therapy as evaluated by NCI CTCAE version 4.03. Interim safety analyses were performed after the first 10 and then 20 subjects were accrued. Safety was considered clinically meaningfully altered if ≥60% of subjects experienced DLTs secondary to palbociclib, ≥20% of subjects had toxicity secondary to tucatinib, or ≥50% of subjects had DLTs attributable to both drugs. If the proportion of patients with DLTs crossed safety boundaries, doses of tucatinib, palbociclib, or both medications would be decreased. Letrozole dose was kept constant for all study subjects. We expected letrozole toxicities of grade ≥3 to occur at a frequency of 4% to 6% (28), be non-life-threatening and not affecting the study safety. Final safety analysis included all patients who received at least 1 dose of study drugs. Demographics, baseline characteristics, DLTs, AEs, and laboratory toxicities were summarized using descriptive statistics.

The primary efficacy endpoint for phase II was mPFS defined as the time from the start of treatment until progressive disease (PD) or death and determined by the Kaplan–Meier method. For subjects who did not have a documented date of progression or death, PFS was censored at the date of the last adequate assessment. For patients with CNS metastases who had an event of isolated CNS progression, underwent local therapy, and remained on study per protocol, PFS was calculated as the time from the start of treatment until the first CNS progression. Evaluable patients received at least two cycles of treatment and one radiographic tumor assessment. Because the study evaluated standard doses of tucatinib, palbociclib, and letrozole, the outcomes of all evaluable patients from phase Ib and phase II were combined in the efficacy analysis. Objective responses were evaluated in patients with measurable disease by RECIST and/or RANO-BM. CBR was assessed in patients with measurable lesions and defined as proportion of patients who experienced complete response (CR), partial response (PR), or stable disease (SD) for ≥6 months. Statistical analysis was performed in PRISM 7.0 (GraphPad) or SAS 9.4.

The study was designed to detect a 50% improvement in mPFS compared with the historical control: TH3resa trial (NCT01419197), which demonstrated mPFS of 6.2 months in the T-DM1 treatment group (29). At the time of our study planning, the best available historical control of a HER2-targeted regimen that did not contain traditional chemotherapy, was widely used clinically, effective in the third line setting, and with reported activity in CNS disease was T-DM1. TH3resa included patients with HER2+ breast cancer regardless of HR status, however, the outcomes were similar in HR+ and HR− cohorts (29). Therefore, mPFS in the overall cohort was used as our historical comparator. The sample size of 40 patients would achieve a statistical power of 82% with a one-sided type I error of 0.1 to detect 50% improvement in mPFS (from 6.2 months to 9.3 months).

Data generated during this clinical trial are available upon request through the global clinical research data sharing platform Vivli: https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/

Between November 2017 and April 2020, 42 patients from 6 U.S. sites were enrolled, 20 into phase Ib and 22 into phase II (Fig. 2). Patients were female ages 22 to 81 years (mean age 52). They received a median of two lines of therapy in the metastatic setting (range 0–5 lines); 30 (71.4%) had visceral disease and 15 (37.5%) had CNS disease (Table 1). All 42 patients received prior trastuzumab and pertuzumab, 19 (45.2%) had T-DM1, 1 had margetuximab, and 1 had fam-trastuzumab deruxtecan (Table 1). Forty patients were evaluable for efficacy. Here we report the mature data as of November 2, 2021, with median follow up of 33.6 months estimated by reverse Kaplan–Meyer method. At this time, 32 patients discontinued study for PD, 4 patients for other reasons, and 4 patients continued treatment on study (Fig. 2). Racial / ethnic characteristics and representativeness of study participants are reflected in Supplementary Table S1.

Final phase Ib safety analysis was conducted on January 4, 2019. Among the 20 phase Ib patients, 1 (5%) had a dose reduction of tucatinib, and 9 (45%) had a dose reduction of palbociclib for DLTs. Two patients (10%) discontinued palbociclib because of DLTs (neutropenia) and continued tucatinib and letrozole. One patient (5%) discontinued letrozole for toxicity, and continued tucatinib and palbociclib. The pre-defined safety boundaries (Appendix S1, p. 52) were not crossed. Phase Ib PKs showed that concentrations of tucatinib, its metabolite ONT-993, and palbociclib within 6 hours post-dose corresponded to previously published parameters (Supplementary Fig. S1A–S1C; refs. 30, 31). However, ONT-380–012 study results that became available at the time of phase Ib safety analysis demonstrated that tucatinib is a strong CYP3A4 inhibitor (32). Considering that palbociclib is a CYP3A4 substrate, it was decided to proceed to phase II with the palbociclib dose of 75 mg orally daily 21 days on, 7 days off, as appropriate in combination with a strong CYP3A4 inhibitor per FDA prescribing information.

Enrollment in phase II resumed on February 15, 2019. Thirteen patients on treatment at the time of phase II initiation had their palbociclib dose changed to 75 mg daily 21 days on, 7 days off, and 22 patients were enrolled in phase II at that dose of palbociclib. Among 35 patients treated on study after the palbociclib dose change, 5 (14%) had dose reduction of tucatinib, 6 (17%) discontinued palbociclib and continued tucatinib and letrozole, and 2 (6%) discontinued letrozole and continued tucatinib and palbociclib. One patient (3%) discontinued all three drugs and came off study due to asymptomatic grade 4 liver function test (LFT) elevation.

Additional PKs at late time-points were collected from 9 patients enrolled in phase II. For the first 9 days of study, to reach the steady state of palbociclib, these patients took palbociclib and letrozole only, and then initiated tucatinib. palbociclib PKs were sampled in the absence and presence of tucatinib, with each patient serving as their own control. The PKs were sampled at 10 to 19 hours to account for the fact that it may take up to 12 hours post-dose to achieve maximum concentration of palbociclib. Late PKs showed a drug–drug interaction: in the presence of tucatinib, geometric mean increase (%CV) in palbociclib AUC_{10–19 hours} was 1.7-fold (31% CV; Supplementary Fig. S1D). There were no changes to tucatinib PKs. Therefore, in combination with tucatinib, a reduced dose of palbociclib at 75 mg daily was appropriate and matched the exposure of palbociclib 125 mg daily.

All patients (N = 42) were included in a final safety analysis (Table 2). The most commonly reported treatment-emergent AEs (all grades, regardless of attribution) were neutropenia (78.6%), diarrhea (76.2%) fatigue (66.7%), and nausea (64.3%). Most common grade 3 and 4 toxicities were neutropenia (64.3% overall, which reduced to 50% after the 75 mg starting dose of palbociclib was employed), diarrhea (19%), fatigue (14%), and thrombocytopenia (9.5%). Side effects were expected and manageable. Neutropenia and thrombocytopenia were attributed to palbociclib and managed with dose reductions or discontinuation of palbociclib per protocol. As expected from the PK data, patients enrolled at the 75 mg palbociclib dose had fewer grade ≥3 AEs compared with patients enrolled at 125 mg of palbociclib daily (Supplementary Fig. S2). Diarrhea, nausea, and fatigue were manageable with supportive care.

During the study, there were 19 SAEs occurring in 16 patients (38%; Supplementary Table S2). SAEs in 9 patients (21%) were related to the study medications per investigator assessment: 1 SAE was attributed to tucatinib (colitis), 2 were attributed to palbociclib (complicated urinary tract infections), and 6 were attributed to a combination of tucatinib and palbociclib (LFT elevation, pneumonia, sepsis, hyponatremia, upper respiratory tract infection, and dehydration).

The following were AEs of special interest: decrease in LVEF or symptomatic congestive heart failure, liver toxicity meeting Hy's law definition, and cerebral edema not attributable to disease progression. Of these, 1 patient experienced asymptomatic G2 decrease in LVEF that improved with supportive medications without changes in the study drug doses. There was a case of grade 4 LFT elevation not meeting Hy's law criteria that resolved without sequala after discontinuation of all study drugs. There were no cases of cerebral edema, and no grade 5 events during treatment on study.

In all evaluable patients (N = 40), mPFS was 8.4 months, with a 95% confidence interval (CI) of 6.6 to 10.8 months (Fig. 3A). This mPFS did not reach the prespecified threshold to achieve a 50% improvement over historical control (TH3resa trial; ref. 29). In patients without CNS metastases, the mPFS was 10.0 months (95% CI, 7.2–14.9 months), whereas in the CNS cohort mPFS was 8.2 months (95% CI, 5.4–20.1 months). The median duration of time on study was 8.5 months for the overall cohort, 5.9 months for CNS cohort, and 8.7 months for non-CNS cohort, with four durable responders at or past 24 months continuing treatment on study at the time of data cut off (Fig. 3B). Four patients experienced isolated CNS progression, underwent local therapy for the progressive CNS lesions, and continued treatment on study for an additional 2 to 13 months; 2 of these patients remained on treatment at the time of data cutoff.

This trial was not powered to observe the differences in outcome correlated to prior therapies; prior therapy data interpretation should be done with caution. With that consideration, we observed in our CNS cohort that patients with prior T-DM1 exposure appeared to have shorter duration of time on study than those without prior T-DM1 exposure. In the CNS cohort, 6 out of 9 (66.7%) T-DM1 naive patients stayed on study for ≥6 months in comparison with 1 of 6 (16.7%) of T-DM1 treated patients; median duration of time on study in these subgroups was 11.1 months versus 5.2 months, respectively (Fig. 3B). This was not observed in the non-CNS cohort. Given the benefit of tucatinib in patients treated with T-DM1 on HER2CLIMB (22), we attribute this to a small sample size in our study.

Twenty-seven of 40 patients (67.5%) had measurable lesions and their percent change from baseline is shown in Fig. 4. In patients with measurable lesions, CBR was 70.4%: 12 of 27 patients (44.5%) had PR and 7 (25.9%) had SD for ≥6 months. Five patients (18.5%) had SD for <6 months and only 3 had PD as their best response (11.1%). ORR was 44.5% with mDOR of 13.9 months.

The study enrolled 15 patients with CNS disease (Supplementary Table S3). Among 14 patients with evaluable CNS metastases, 12 had nonmeasurable (previously treated) metastases and 2 had untreated metastases; 1 non-evaluable patient had surgically resected metastasis and was without CNS disease for 24 months on study. At the time of data cut off, 2 patients with CNS disease were continuing treatment on study at 24 and 32 months. Among 13 patients with CNS disease who came off study, 11 had PD (2 had systemic PD, 5 had CNS PD, 4 had combined systemic/CNS PD), and 2 came off study for reasons other than PD. In 12 patients with nonmeasurable CNS disease, 1 achieved CNS CR after 4 months on study, 5 had CNS SD for ≥6 months, and 6 had CNS SD for <6 months. Among 2 patients with CNS disease untreated with local therapy, 1 had nonmeasurable dural lesion with CNS SD for 5 months, and 1 had measurable cerebellar lesion with CNS SD for 8 months.

Given the mandated change of palbociclib to a fixed dose of 75 mg daily for phase II, we performed an exploratory analysis of the mPFS in patients treated with 125 mg starting dose (phase Ib) and 75 mg fixed dose (phase II) to see if any differences were notable (Supplementary Fig. S3). Patients treated with the 75 mg fixed dose of palbociclib had numerically better mPFS compared with the 125 mg (10.5 months vs. 8.2 months, respectively), which was not statistically significant (log-rank test P = 0.9).

The results of this phase Ib/II clinical trial demonstrated that the TLP regimen is clinically effective with mPFS of 8.4 months and CBR of 70.5% in the overall patient cohort. The mPFS was 10 months in the non-CNS cohort and 8.2 months among patients with CNS disease. Our overall patient cohort did not reach the prespecified mPFS of 9.6 months to achieve a 50% improvement over the historical control (PFS of 6.2 months from the TH3resa trial of T-DM1; ref. 29). Reasons why the goal was not met may include differences in the study populations enrolled and the prior T-DM1 exposure in our study population. TH3resa included patients with ≥2 prior HER2-targeted agents, visceral disease, and previously treated stable CNS disease whereas our study permitted locally untreated CNS disease. TH3resa had 10.3% of patients with CNS involvement and this study had a total of 37.5% of patients with CNS disease. In addition, 45.2% of our patients had prior T-DM1, compared with T-DM1-naive TH3resa patients. Thus, it was perhaps overly ambitious to expect a 50% mPFS improvement using the TH3resa results as our historical control.

We propose these results as still clinically meaningful when considered in the context of the current HER2 targeted treatment options and the benefit seen in the CNS metastasis patients for a non-chemotherapy-based regimen. The overall mPFS of 8.4 months is on par with both the mPFS of 7.8 months from the HER2CLIMB trial (22) of chemotherapy-based regimen of tucatinib, capecitabine, and trastuzumab, and the results of NALA trial (33) that showed mPFS of 5.6 months in the neratinib and capecitabine cohort. HER2CLIMB (22) and NALA (33) studies were not used as a historical control, because at the time when the TLP trial was conceptualized the results of these studies were not available. In our CNS cohort, mPFS was not statistically different compared with non-CNS patients, and there was durable benefit with 26.6% of CNS metastatic patients remaining on study for more than 1 year, demonstrating notable CNS activity of the TLP combination. Finally, we saw that continuing TLP therapy after first CNS progression is beneficial in carefully adjudicated cases.

Overall, the TLP combination was safe and tolerable. AEs were as expected and manageable with standard supportive therapy and dose reductions of study medications. A substantial proportion of patients with grade ≥3 neutropenia in the overall patient population is attributed to the palbociclib dosed of 125 mg daily for the first 20 study participants before the drug–drug interaction was discovered, as we confirmed a 1.7-fold increased AUC of palbociclib by tucatinib. The subsequent phase II dose reduction of palbociclib to 75 mg daily was appropriate and matched the exposure of palbociclib 125 mg daily. This resulted in an improved safety profile without apparent difference in efficacy of the regimen. In our study, 9.8% of patients had ≥G3 thrombocytopenia. This is higher than previously reported with palbociclib therapy (28, 34), and it could reflect either tucatinib and palbociclib interaction, or the fact that we allowed enrollment of patients with a baseline platelet count as low as 75,000 per mm³ compared with ≥100,000 per mm³ in the other studies of palbociclib. The frequency of ≥G3 LFT abnormalities in our study (4.8%) is comparable with those reported in HER2CLIMB (6%–8%; ref. 22).

The options for expanded targeting of multiple pathways driving cancer progression in HER2+ breast cancer with non-chemotherapy-based regimens are rapidly increasing. Other studies have explored targeted combinations for HR+/HER2+ MBC. The PERTAIN phase II trial (NCT01491737) showed efficacy of dual HER2 blockade with trastuzumab and pertuzumab in combination with an aromatase inhibitor as a front-line treatment in selected HR+/HER2+ metastatic patients (9). PERTAIN demonstrated that “smart” targeting can be successful in HR+/HER2+ disease, as pertuzumab and trastuzumab bind to different epitopes on HER2, providing a more complete suppression of HER2 signaling and inhibiting HER2–HR crosstalk more efficiently, thereby enhancing the antitumor activity of the regimen (9).

The PATRICIA phase II trial (NCT02448420) evaluated palbociclib and trastuzumab with or without endocrine therapy in patients with HER2+ MBC after 2 to 4 prior anti-HER2 regimens (10). In this study, 28 patients with HR+/HER2+ disease received concomitant letrozole; the mPFS of this group was 5.1 months. The PATRICIA trial is notable for correlative work showing that luminal disease defined by the PAM50 test was associated with longer PFS compared with nonluminal disease (mPFS 10.6 months vs. 4.2 months, P = 0.003; ref. 10).

Two neo-adjuvant studies have explored palbociclib with HER2-targeted antibodies and anti-hormonal agents in HR+/HER2+ disease. NA-PHER2 (NCT02530424) demonstrated that neoadjuvant palbociclib, fulvestrant, trastuzumab, and pertuzumab for 20 weeks yield objective responses in 29 of 30 patients (97%). At surgery, 8 of 30 patients (27%) had a pathologic complete response (pCR) in breast and axillary nodes (35). The PALTAN trial (NCT02907918) that combined palbociclib with letrozole and trastuzumab showed a low pCR rate of only 7.7%. The study was stopped for futility, although the regimen was well tolerated (36).

In the context of these recent advances, our study achieved a mPFS of 8.4 months in the overall study population where patients had a median of two lines of prior therapy for MBC, 71.4% of patients had visceral metastases, 35.7% of participants had CNS disease comprised of both stable previously locally treated and asymptomatic locally untreated metastasis. Durable responses were noted, with mDOR of 13.9 months, 60% of patients on treatment for more than 6 months, 25% for ≥1 year, and 10% for ≥2 years. An analysis of correlative samples is ongoing to identify factors predicting for durable response. At present, it is unknown if dual HER2 targeting would potentially add to these results in the clinical setting. Recent important preclinical evidence has demonstrated that dual HER2 blockade with tucatinib and trastuzumab may have greater efficacy when compared with tucatinib alone (19). At present, the TLP regimen presented herein provides clinical evidence for the efficacy of triple targeting the HR and HER2 pathways with their key intersection at cell-cycle checkpoints mediating drug resistance. Likewise, consideration to other multidrug, multipathway, nonchemotherapy drug combinations would also be warranted with the emerging data for CDK4/6 inhibitors (37), SERDs, and other potential tucatinib partners based on the results of our study and those reviewed. We propose the next steps for clinical trials are to study this regimen or others similar to it in the neo-adjuvant setting, and in an earlier line of treatment for metastatic disease, either as a primary regimen, or as a maintenance targeted therapy. A currently accruing trial (NCT005319873) in the neoadjuvant space investigating ribociclib with tucatinib and trastuzumab (with the addition of fulvestrant for the HR+ group) will add valuable information on expanded drug interaction, safety, and efficacy data.

In summary, an all-oral chemotherapy-free regimen of tucatinib, palbociclib, and letrozole demonstrated clinically meaningful efficacy with acceptable safety, and warrants further testing.

Although further studies are needed to determine how the TLP combination would fit in the current treatment paradigm, our study demonstrated that TLP could possibly be an effective regimen for patients with metastatic HR+/HER2+ breast cancer who would like to avoid chemotherapy.

E. Shagisultanova reports grants and nonfinancial support from Pfizer, Inc. and nonfinancial and other support from Seagen during the conduct of the study as well as nonfinancial and other support from Novartis and Seagen outside the submitted work; in addition, E. Shagisultanova reports participation in Novartis Advisory Board, with advisory board fees in 2019. U. Brown-Glabberman reports personal fees from SeaGen, Menarini, Sanofi Aventis, and Gilead outside the submitted work. P. Chalasani reports other support from University of Arizona during the conduct of the study as well as grants from Pfizer and personal fees from TerSera Therapeutics, AstraZeneca, Eli Lilly, Novartis, and Gilead Sciences outside the submitted work. A.J. Brenner reports other support from Criterium during the conduct of the study as well as other support from Plus Therapeutics, grants from Gilead, and personal fees from Seagen outside the submitted work. A. Stopeck reports grants from Criterium, Inc. CRO during the conduct of the study as well as other support from Regeneron, G1 Therapeutics, EQRx International, and Boehringer Ingelheim; personal fees from Amgen, AstraZeneca, Sandoz, Stemline, Biotheranostics, Beigene, and Macrogenics; and grants and personal fees from Exact Sciences and Hibercell outside the submitted work. T. Mcspadden reports grants and other support from Pfizer and other support from Seagen during the conduct of the study. P. Kabos reports grants from Eli Lilly, Genentech, Sanofi, Menarini, and AstraZeneca outside the submitted work. V.F. Borges reports other support from Seagen and grants from Pfizer during the conduct of the study as well as other support from AstraZeneca and Gilead outside the submitted work. No disclosures were reported by the other authors.

E. Shagisultanova: Conceptualization, formal analysis, funding acquisition, investigation, writing–original draft, writing–review and editing. W. Gradishar: Investigation, writing–review and editing. U. Brown-Glabberman: Investigation, writing–review and editing. P. Chalasani: Investigation, writing–review and editing. A.J. Brenner: Investigation, writing–review and editing. A. Stopeck: Investigation, writing–review and editing. H. Parris: Formal analysis, validation, writing–original draft, writing–review and editing. D. Gao: Formal analysis, validation, writing–original draft, writing–review and editing. T. McSpadden: Data curation, writing–review and editing. J. Mayordomo: Investigation, writing–review and editing. J.R. Diamond: Investigation, writing–review and editing. P. Kabos: Conceptualization, resources, investigation, writing–review and editing. V.F. Borges: Conceptualization, resources, supervision, funding acquisition, investigation, writing–original draft, writing–review and editing.

This study has been funded by Pfizer ASPIRE grant to E. Shagisultanova, with additional support from Seagen for clinical trial; NIH KL2TR001080 and 1K08CA241071 career development awards to E. Shagisultanova, Robert F. and Patricia Young Connor Endowed Chair in Young Women's Breast Cancer to V.F. Borges, University of Colorado Cancer Center support grant P3CA046934. We thank all the patients who participated in the study, as well as the medical teams of all participating centers for their dedicated effort. In addition, we thank the Academic Breast Cancer Consortium (ABRCC) for feedback on study design and support in the study conduct. We acknowledge Veronica Wessels for the manuscript proofreading, and Heather Fairchild for creating Fig. 1 signaling diagram.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.