Recurrent Metastatic Breast Cancer Research Articles

Pembrolizumab (Keytruda)


 CADTH recommends that Keytruda be reimbursed by public drug plans, in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) who have not received prior chemotherapy for metastatic disease and whose tumours express programmed death-ligand 1 (PD‐L1) (combined positive score [CPS] ≥ 10) as determined by a validated test if certain conditions are met.
 Keytruda should only be covered for adult patients with centrally confirmed TNBC who have PD-L1–positive tumours (CPS ≥ 10), have not received treatment for locally recurrent or metastatic TNBC, and are in relatively good health (i.e., have a good performance status, as determined by a specialist). Patients with unstable central nervous system (CNS) metastases or those who have clinical contraindications to immunotherapy are not eligible for reimbursement.
 Keytruda should only be reimbursed if prescribed in combination with chemotherapy and given by a clinician who is experienced in treating breast cancer and the cost of Keytruda is reduced.

Frequency of Hepatic Metastatic Disease in Patients with Stage IV Breast Cancer Is Similar for Steatotic and Non-Steatotic Livers.

Breast cancer is the most common non-cutaneous malignancy and the second leading cause of cancer mortality in the United States. Breast cancer is a heterogeneous disease; diagnosis at an early stage renders it potentially curable, whereas advanced metastatic disease carries a worse prognosis. To investigate whether hepatic steatosis (HS) is associated with liver metastases in patients with newly diagnosed stage IV female breast cancer patients (either de novo metastatic breast cancer or recurrent metastatic breast cancer) using non-contrast computed tomography (CT) as a marker of HS. Retrospective analysis. We retrospectively identified 168 patients with stage IV breast cancer with suitable imaging from a prospectively maintained oncologic database. Three radiologists manually defined hepatic regions of interest on non-contrast CT images, and attenuation data were extracted. HS was defined as a mean attenuation <48 Hounsfield units. The frequency of hepatic metastatic disease was calculated for patient with and without HS. Relationships between HS and various patient (age, body mass index, race) and tumor (hormone receptor status, HER2 status, tumor grade) characteristics were also analyzed. There were 4 patients with liver metastasis in the HS group (41 patients) versus 20 patients with liver metastases in the non-HS group (127 patients). The difference in frequencies of liver metastases among patients with (9.8%) versus without (15.7%) hepatic steatosis (odds ratio = 1.72 [0.53-7.39]) was not statistically significant (P = .45). Body mass index was significantly higher (P = .01) among patients with hepatic steatosis (32.2 ± 7.3 vs 28.8 ± 7.1 kg/m2). Otherwise, there were no significant differences between patients with versus without HS with respect to regarding age, race, hormone receptor status, HER2 status, or tumor grade. The frequency of hepatic metastatic disease in patients with stage IV breast cancer is similar for steatotic and non-steatotic livers.

Comment on "The lingering mysteries of metastatic recurrence in breast cancer".

Comment on "The lingering mysteries of metastatic recurrence in breast cancer".

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1

ObjectiveIn the KEYNOTE-355 (KN355) trial, pembrolizumab in combination with chemotherapy demonstrated superior efficacy and manageable safety compared with chemotherapy alone in patients with previously untreated locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1 positive (Combined Positive Score [CPS]≥ 10) tumours. This study aimed to evaluate the clinical benefits and risks of pembrolizumab measured by quality-adjusted survival in the trial population. MethodsThe study used data from the final analysis of KN355. The Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare treatments of pembrolizumab plus chemotherapy versus chemotherapy alone. Patients’ survival time was partitioned into three health states — toxicity before disease progression (TOX), time without symptoms or toxicity before disease progression (TWiST), and relapse (REL). Utilities for these health states were estimated using EuroQol-5 Dimensions, 3 Levels (EQ-5D-3L) data collected in KN355. Q-TWiST was derived as the utility-weighted sum of the mean health state durations. ResultsPatients randomised to pembrolizumab plus chemotherapy had 3.7 months greater Q-TWiST (relative gain of 18%; P = 0.003) compared to those randomised to chemotherapy at the median follow-up of 44 months, and 4.3 months greater Q-TWiST (relative gain of 20%; P = 0.004) at the maximum follow-up of 52 months. The Q-TWiST gain increased with longer follow-up time. ConclusionsPembrolizumab plus chemotherapy was associated with statistically significant and clinically important improvement in Q-TWiST compared to chemotherapy in previously untreated PD-L1–positive mTNBC.

Does the Timing of Eribulin Treatment for Advanced or Metastatic Breast Cancer Matter? Evidence from a Real-World Setting

Background: This study aimed to examine the effectiveness and safety of eribulin used as an early-line (EL, i.e., first-/second-line) versus late-line (LL, i.e., third-line and beyond) chemotherapy for recurrent advanced or metastatic breast cancer (A/MBC) patients. Methods: This study conducted a retrospective observation of A/MBC patients initiating eribulin between January 1, 2015, and June 30, 2019, using medical database at a university-affiliated teaching hospital in Taiwan. Patients were assigned into either the EL or LL group based on the timing of respective eribulin treatments and were observed for at least 6 months up to December 2019 for progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), disease response, and occurrence of adverse events. The Kaplan-Meier and Cox proportional hazard regression survival analyses were performed. Results: Of 127 patients, 23.6% (n = 30) and 76.4% (n = 97) were assigned to the EL and LL groups, respectively, between which no difference in patient characteristics was noted. Median PFS and TTF were 6.5 months and 5.0 months for the EL and 4.2 months and 3.4 months for the LL, respectively. Median OS could not be estimated in the EL group and was 20.5 months in the LL group. Eribulin as an EL treatment was the only factor associated with longer TTF and OS, whereas the number of metastatic sites was additionally associated with PFS in the multivariate analysis. No complete response was reported in either group, but a partial response was obtained in 6.7% in the EL group and 3.1% in the LL group. The common adverse events between two groups were similar, including leukopenia (80.0%), neutropenia (76.7%), and anemia (60.0%). Conclusions: The eribulin used as an EL of chemotherapy was effective for A/MBC patients with known toxicities in this study, while eribulin as the LL chemotherapy showed consistent results with previous reports.

236P Subgroup analysis by disease history and prior treatments of patients (pts) with HER2-positive (HER2+) metastatic breast cancer (MBC) from DESTINY-Breast03, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1)

T-DXd showed superior progression-free survival (PFS) vs T-DM1 (HR, 0.28; 95% CI, 0.22-0.37), with manageable safety, in pts with HER2+ MBC in DESTINY-Breast03 (NCT03529110; Cortes 2022). We present additional patient subgroups by disease history and prior treatment. Pts with HER2+ MBC whose disease had progressed on or after trastuzumab and a taxane were randomized 1:1 to receive T-DXd or T-DM1. An exploratory analysis was conducted of subgroups based on presence of de novo (stage IV disease at initial diagnosis) or recurrent (diagnosed at early stage, developed metastatic disease later) MBC, early progression (disease progression within 6 months [mo] after [neo]adjuvant therapy [12 mo for pertuzumab-containing regimens]), and number and type of prior treatments. PFS (by BICR, data cutoff May 21, 2021) benefit was observed with T-DXd vs T-DM1 for both pts with de novo (HR, 0.35) and recurrent (HR, 0.28) MBC (table). Confirmed objective response rates were consistent between de novo (T-DXd, 79.6% [95% CI, 69.9-87.2] vs T-DM1, 33.7% [24.7-43.6]) and recurrent (T-DXd, 79.8% [72.9-85.6] vs T-DM1, 34.6% [27.2-42.5]) MBC. Within the subgroup of pts with recurrent MBC, there were 35 early progressors (T-DXd, n = 15; T-DM1, n = 20); in a sensitivity analysis, PFS (HR, 0.19; 95% CI, 0.05-0.71) was consistent with the primary analysis. PFS benefit for T-DXd vs T-DM1 was observed regardless of the number of prior lines of anti-HER2 therapy (HR, 0.33 for 1 prior line and HR, 0.23 for ≥2 lines). The safety profile of the subgroups was consistent with the primary analysis.Table: 236PPFS by Disease History, Prior TherapyT-DXdMedian PFS (95% CI), moT-DM1Median PFS (95% CI), moT-DXd vs T-DM1nnHR (95% CI)All pts261NE (18.5-NE)2636.8 (5.6-8.2)0.28 (0.22-0.37)De novo MBC9322.4 (15.0-NE)1045.8 (4.2-8.1)0.35 (0.23-0.53)Recurrent MBC168NE (18.5-NE)1597.0 (5.4-9.7)0.28 (0.20-0.39)Setting of prior systemic therapy in pts with 1 line in metastatic setting excluding hormone therapyMetastatic115NE (15.6-NE)1037.0 (5.4-9.8)0.34 (0.23-0.51)(Neo)adjuvant (early progressors)15NE (12.4-NE)208.2 (5.4-NE)0.19 (0.05-0.71)Lines of prior anti-HER2 therapy1193NE (18.5-NE)1978.0 (5.7-9.7)0.33 (0.24-0.45)≥26622.2 (16.8-NE)634.2 (2.8-5.7)0.23 (0.13-0.38) Open table in a new tab In this exploratory analysis, a benefit of T-DXd vs T-DM1 was observed irrespective of disease history and prior treatment, consistent with the results of the overall primary analysis. T-DXd had a manageable safety profile.

Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer. In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review. Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%). SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.

Clinical subtype, treatment response, and survival in De Novo and recurrent metastatic breast cancer.

This study evaluated whether patients with de novo metastatic breast cancer (MBC) have superior outcomes compared to those with recurrent MBC in a contemporary treatment era and examined factors related to outcome differentials. Using an institutional database, we examined patient and tumor characteristics, treatment response, and outcome among 232 patients with de novo and 612 patients with recurrent MBC diagnosed between 2011 and 2017. De novo MBC had 9-month (m) longer overall survival (OS) than recurrent MBC (36.4 vs 27.4m, p < 0.001). Contributions to this difference included nearly twofold more HER2-positive (29.3% vs 15.2%) and significantly fewer triple-negative breast cancers (20.3% vs 32.4%, both p < 0.001) in de novo compared with recurrent MBC cohorts. Stratified by clinical subtype, progression-free survival (PFS) on first-line therapy was significantly longer in de novo MBC in all but the triple-negative subtype, 25.5 vs 11.6m (p < 0.001) among 390 patients with hormone receptor-positive, HER2-negative, 11.4 vs 5.4m (p = 0.002) among 142 patients with HER2-positive, and 4.0 vs 3.0m (p = 0.121) among 162 with triple-negative MBC. In multivariable analysis, de novo status remained independently associated with improved OS (hazard ratio 0.63, 95% CI 0.49-0.80), regardless of subtype and other features. Patients with de novo MBC have better outcomes than those with recurrent MBC. Differences in clinical subtype and response to therapy in the metastatic setting contribute to, but do not fully explain, this difference. Longer PFS to first-line therapy in de novo MBC suggests biologic differences compared to recurrent MBC, which may be intrinsic or due to acquired resistance from treatment for prior localized breast cancer in recurrent disease.

Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer

BackgroundIn an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1–staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported.MethodsWe randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator’s choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine–carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed.ResultsA total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab–chemotherapy group, and 281 to the placebo–chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab–chemotherapy group and 16.1 months in the placebo–chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P=0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P=0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab–chemotherapy group and in 66.9% in the placebo–chemotherapy group, including death in 0.4% of the patients in the pembrolizumab–chemotherapy group and in no patients in the placebo–chemotherapy group.ConclusionsAmong patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.)

EE159 Cost Effectiveness of Pembrolizumab Combined with Chemotherapy Vs. Chemotherapy As First-Line Treatment for Metastatic TNBC That Expresses PD-L1 in the United States

This analysis aimed to evaluate the cost effectiveness of pembrolizumab in combination with chemotherapy (paclitaxel, nab-paclitaxel or gemcitabine+carboplatin) vs chemotherapy as first-line treatment in patients with locally recurrent unresectable or metastatic triple negative breast cancer (mTNBC) whose tumors express programmed death ligand-1 (PD-L1) (combined positive score (CPS) ≥10), from a US third-party public healthcare payer perspective.

Real-world practice patterns in the diagnosis of recurrent metastatic breast cancer in Washington state.

e13640 Background: Evidence-based, national guidelines for the diagnosis of recurrent metastatic breast cancer (MBC) recommend confirmation of recurrence with biopsy and reassessment of biomarker status. Real world practice patterns may demonstrate disparities in adherence to guidelines with implications for patients and health systems. Methods: We utilized the Hutchinson Institute for Cancer Outcomes Research (HICOR) data repository that links Washington State cancer registry data to enrollment and claims from the major insurance payers in the state. We identified women &gt; 18 years old diagnosed with recurrent MBC between 2008 and 2017 with evidence of enrollment in a commercial plan (Premera or Regence), Medicare, or Medicaid. Recurrence in Stage I-III patients was detected through identification of ICD 9/10 codes for metastatic disease or resumption of breast cancer systemic therapy (after minimum of 4 months from completion of early breast cancer therapy). Using claims, we identified receipt of and factors associated with biopsy, biomarker re-assessment, and treatment administered at recurrence. Results: We identified 715 patients with recurrent MBC (any ER or HER2 status) with median age of 62 (range 52-73). The majority of the cohort were Caucasian (89%) with the rest comprising of Asian, Black, American Indian, and Hispanic patients. Based on the Rural Urban Commuting Area (RUCA) classification, patients predominantly lived in metropolitan neighborhoods (97%). Approximately 13% of patients lived in areas of high deprivation (area of deprivation index, ADI, 8-10). Patients had either Commercial (53.1%), Medicaid (4.2%), Medicare (29.7%) or multiple (13.0%) insurance. Patients were primarily treated at high volume centers (70.9%), though 23% of patients were seen at low volume centers (&lt;25 breast cancer patients/year). Of the patients with recurrent MBC, 49.5% received a biopsy to confirm metastatic diagnosis. Similarly, 48.7% of recurrent MBC patients underwent biomarker reassessment. Patients with highest co-morbidity index (&gt;2) were more likely to undergo biopsy confirmation (20.3% vs 13.0%, p = 0.02). Biopsy was more often performed in patients receiving care at a high-volume center compared to low-volume center (74.3% vs 18.6%, p = 0.03). First line treatment selection was directly associated with receipt of biopsy and biomarker testing. Hormone therapy only was more common in patients who did not undergo biopsy (62.3% vs 37.7%, p &lt;0.001) or biomarker reassessment (62.7% vs 37.3%, p &lt;0.001). Conclusions: Our study shows there is variation across Washington state in biopsy and biomarker assessment in the diagnosis of recurrent metastatic breast cancer. Nearly half of cases had metastatic biopsy omitted. Our findings demonstrate downstream implications for treatment selection and support the need for quality initiatives to improve adherence to guidelines.

KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2- locally recurrent inoperable or metastatic breast cancer.

TPS1118 Background: HR+/HER2− advanced breast cancer that progresses on endocrine therapy is treated with chemotherapy (chemo). The phase 1b KEYNOTE-028 trial showed durable activity with pembrolizumab (pembro) monotherapy in previously treated HR+/HER2−, PD-L1–positive (combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study of pembro + chemo vs placebo (pbo) + chemo in centrally assessed PD-L1–positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer (mBC) after progression on prior endocrine therapy. Methods: ∼800 patients (pts) with HR+/HER2− locally recurrent inoperable or mBC who are candidates for chemo (no prior chemo for metastatic disease) with PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line with CDK4/6 inhibitor treatment for mBC in pts who had a relapse within 24 mo of primary surgery. Pts without prior CDK4/6 inhibitor treatment may enroll if they had progressed within 6 mo of starting endocrine therapy for metastatic disease and had previously relapsed within 24 mo of primary tumor surgery while on adjuvant endocrine therapy. Pts are randomized 1:1 to receive pembro 200 mg IV or pbo Q3W, each in combination with investigator’s choice of chemo: paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or capecitabine 1000 mg/m2 PO BID on days 1–14 Q3W. Randomization is stratified by tumor PD-L1 (CPS 1–9 vs ≥10), presence of visceral metastases (yes vs no), and chemo on-study (taxanes vs liposomal doxorubicin vs capecitabine). Treatment is continued until disease progression, unacceptable toxicity, withdrawal, or, for pembro/pbo, completion of 35 cycles (̃2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed Q9W for 54 wk and then Q12W thereafter. AEs occurring from randomization until 30 d after treatment discontinuation (90 d for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by BICR and OS in pts with PD-L1 CPS ≥10 and ≥1 tumors, separately. Enrollment is ongoing at 204 international sites. Clinical trial information: NCT04895358.

Improved sensitivity in identification of first recurrences of metastatic breast cancer with a combination of cell and cell-free liquid biopsy analysis.

e13003 Background: Liquid biopsy analysis detecting circulating tumor cells (CTC) or circulating tumor DNA (ctDNA) is a non-invasive approach that may provide clinically actionable information for patients’ (pts) treatment decisions when conventional biopsy is otherwise inaccessible or infeasible. Here we report a liquid biopsy method including CTC characterization &amp; ctDNA alterations in pts symptomatic of first metastatic recurrence with a history of primary breast cancer (BC). Methods: Blood samples from 34 symptomatic BC pts were collected for cell &amp; cell-free DNA analysis before undergoing contemporaneous tissue biopsy &amp; initiating treatment for metastatic BC (MBC). Blood was also collected from 25 blood donors (HD) with no known cancer history. After plasma isolation, nucleated cells were plated, &amp; slides were bio-banked. Immunofluorescent staining &amp; subsequent imaging were performed on replicate slides. CTCs were identified using Epic Sciences digital imaging &amp; machine learning algorithms trained to identify breast cancer cells. Single-cell (sc) isolation for genomic quantification of large-scale transitions (scLST) was used to further characterize individual CTCs. cfDNA from bio-banked plasma was analyzed to detect Class IA alterations in ctDNA. Results: Within this cohort of 34 patients, CTCs &amp; ctDNA alterations were detected in 80% &amp; 58%, respectively while no CTCs &amp; ctDNA were detected in the HD cohort suggesting high specificity (100% &amp; 100%). In this study, 26 pts were confirmed MBC (M1-BC) by tissue biopsy, 3 pts were non-MBC by tissue biopsy but still diagnosed as metastatic (Mx-BC), &amp; 5 pts were confirmed non-MBC (M0-BC). To benchmark the cellular (CTCs &amp; scLST+CTCs) &amp; genomic (ctDNA) individual platforms, we designed thresholds of CTCs &gt; 4, scLST+CTC+, &amp; ctDNA+ that optimally identified M1-BC pts with high specificity (100%, 100%, &amp; 100%) but low sensitivity (46%, 46%, &amp; 50%). CTCs &gt; 4 &amp; scLST+CTC+ cutoffs had low concordance with the presence of ctDNA alterations, suggesting these platforms provide independent &amp; complementary value when identifying MBC. To test this hypothesis, we designed combination models [CTC &gt; 4][ctDNA+] &amp; [scLST+CTC+][ctDNA+] that significantly improved sensitivity (75% &amp; 67%) over individual platforms while maintaining high specificity (100% &amp; 100%) when identifying the first recurrence of metastasis in BC pts. Conclusions: To our knowledge, this is the first report showing the additive &amp; complementary value of models combining cellular &amp; genomic liquid biopsy platforms for the detection of the first MBC recurrence. Our data suggest the clinical utility of combined CTC &amp; ctDNA platforms for the identification of MBC when tissue biopsy is inaccessible or infeasible.

Phase 1b/2 study of GX-I7 plus pembrolizumab in patients with refractory or recurrent (R/R) metastatic triple-negative breast cancer (mTNBC): The KEYNOTE-899 Study.

1081 Background: GX-I7 (efineptakin alfa) is a hybrid Fc-fused long-acting recombinant human IL-7 which plays an essential role in the development and homeostasis of T-cells. GX-I7 can potentially enhance the anti-tumor effect of pembrolizumab via induction of T-cell activity. Here, we report results of phase 1b/2 study of GX-I7 plus pembrolizumab in patients with R/R mTNBC. Methods: Eligible patients had R/R mTNBC that failed up to 3rd lines of chemotherapy in the metastatic setting. Phase 1b patients received GX-I7 in 5 dose levels ranging from 360 µg/kg to 1,440 µg/kg every 9 (Q9W) or 12 (Q12W) weeks plus pembrolizumab 200 mg Q3W (n=51). Phase 2 is an expansion cohort where 33 patients were treated with the recommended phase 2 dose (RP2D). The primary objective was to determine the RP2D for phase 1b and to assess the objective response rate (ORR) for phase 2. Results: The study included 84 patients (phase 1b, n=51; phase 2, n=33) and 53.6% (45/84) of patients have received 2nd to 3rd lines of previous therapy. In phase 1b, one dose-limiting toxicity (DLT; grade 3 skin rash) was reported in the 1,440 µg/kg cohort and GX-I7 1,200 µg/kg Q9W was selected as RP2D. The ORRs were 15.7% [95% confidence interval (CI): 7.0 – 28.6] for phase 1b (n=51) and 21.2% [95% CI: 9.0 – 38.9] for phase 2 (n=33). Median PFS was 2.4 months (95% CI: 2.1 – 2.7) at the median follow-up of 10.4 months for all patients combined (n=84). GX-I7 induced up to 3.6-fold (range 1.2 – 8.1) increase in absolute lymphocyte counts (including CD4+ and CD8+ T cell) in all dose levels. The most common treatment-related adverse events (AEs) of any grade were injection site reaction (50.0%), ALT increased (39.3%), pyrexia (38.1%) and rash (35.7%). The additional correlative study data will be presented. Conclusions: GX-I7 in combination with pembrolizumab demonstrated a manageable safety profile with promising anti-tumor activity in patients with R/R metastatic TNBC. Clinical trial information: NCT03752723. [Table: see text]

Overall survival of patients with metastatic breast cancer in Sweden: a nationwide study

BackgroundBreast cancer is the most common cancer among women in Sweden. Whereas survival for the overall breast cancer population is well-documented, survival of patients with metastatic breast cancer (MBC) is harder to quantify due to the lack of reliable data on disease recurrence in national cancer registers.MethodsThis study used machine learning to classify the total MBC population in Sweden diagnosed between 2009 and 2016 using national registers, with the aim to estimate overall survival (OS).ResultsThe total population consisted of 13,832 patients—2528 (18.3%) had de novo MBC whereas 11,304 (81.7%) were classed as having a recurrent MBC. Median OS for patients with MBC was found to be 29.8 months 95% confidence interval (CI) [28.9, 30.6]. Hormone-receptor (HR)-positive MBC had a median OS of 37.0 months 95% CI [35.9, 38.3] compared to 9.9 months 95% CI [9.1, 11.0] for patients with HR-negative MBC.ConclusionThis study covered the entire MBC population in Sweden during the study time and may serve as a baseline for assessing the effect of new treatment strategies in MBC introduced after the study period.

159P Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic TNBC that expresses PD-L1

Pembrolizumab in combination with chemotherapy showed significantly longer progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone and manageable safety as first-line treatment in patients with locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1-positive (Combined Positive Score [CPS]≥ 10) tumors in the KEYNOTE-355 (KN355) trial. The objective of this analysis was to gain insights on the clinical benefits and risks of pembrolizumab in terms of quality-adjusted survival among patients in the trial.

Association between age at initial diagnosis and post-metastasis mortality among women with recurrent metastatic breast cancer in China

BackgroundLittle is known about whether age at initial diagnosis influences the prognosis of recurrent metastatic breast cancer (rMBC). Here, we analyzed the association between age at initial diagnosis and rMBC mortality in China.MethodsA total of 1636 women diagnosed with rMBC between 1989 and 2020 at West China Hospital, Sichuan University were included in this study. The age at initial diagnosis was categorized as young (≤ 40 years), middle-aged (41–64 years) and elderly (≥ 65 years). Post-metastasis mortality was the primary outcome and its associated factors were analyzed by Cox proportional hazards models.ResultsDuring a median follow-up of 5.2 years after initial diagnosis of breast cancer, 620 deaths were identified. Compared with middle-aged patients, elderly patients had a 70% increased risk of post-metastasis mortality (95%CI, 1.24–2.33) after adjusting for demographics, tumor characteristics and treatment modes. Similarly, elderly patients were associated with a 75% increased risk of post-metastasis mortality (95%CI, 1.19–2.59) compared with young patients. Subgroup analyses also showed similar trends.ConclusionOur findings suggest that in breast cancer, elderly patients at initial diagnosis face a higher risk of post-metastasis mortality.

Abstract OT1-18-06: KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer

Abstract Background: For patients with HR+/HER2− advanced breast cancer who experience disease progression on endocrine therapy, cytotoxic chemotherapy (chemo) regimens are standard of care. Adding immunotherapy to chemo may improve patient outcomes. The anti-PD-1 antibody pembrolizumab (pembro) has demonstrated efficacy in patients with triple-negative breast cancer, including those with metastatic disease (KEYNOTE-355) and with early-stage disease (KEYNOTE-522). The phase 1b KEYNOTE-028 trial showed durable activity with pembro monotherapy among patients with previously treated HR+/HER2−, PD-L1-positive (ie, combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study comparing pembro plus chemo vs placebo plus chemo in patients with PD-L1-positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer who progressed on prior endocrine therapy. Methods: Approximately 800 patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer who are candidates for chemo (no prior chemo for metastatic disease) and who have a PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line plus CDK4/6 inhibitor treatment with relapse within 24 months of surgery in the adjuvant setting. Patients without CDK4/6 inhibitor treatment may enroll if they have progression within 6 months of starting endocrine therapy for metastatic disease and within 24 months of surgery while on adjuvant endocrine therapy. Patients are randomized 1:1 to receive pembro 200 mg IV or placebo Q3W, each in combination with investigator’s choice of 1 of 4 chemo regimens: paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or capecitabine 1000 mg/m2 PO BID on days 1-14 Q3W. Randomization is stratified by tumor PD-L1 expression (CPS 1-9 vs ≥10), visceral metastases (yes vs no), and chemo (taxanes vs liposomal doxorubicin vs capecitabine). Participants, investigators, and study personnel are blinded to treatment assignment and tumor PD-L1 status. Treatment is continued until radiographic disease progression, unacceptable toxicity, withdrawal, or, for pembro/placebo, completion of 35 administrations (~2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed every 9 weeks through the first 54 weeks and then every 12 weeks thereafter to detect evidence of progression. AEs occurring from randomization until 30 days after treatment discontinuation (90 days for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review in patients with PD-L1 CPS ≥10 and ≥1 tumors, separately. A key secondary endpoint is OS; additional secondary endpoints are investigator-assessed PFS, ORR, disease control rate, duration of response, and health-related quality of life using EORTC QLQ-C30 (each assessed in patients with PD-L1 CPS ≥10 and ≥1 tumors), as well as safety in the overall population. The family-wise type-I error rate is controlled at 0.025 (one-sided) across the PFS and OS endpoints. PFS and OS will be estimated using the Kaplan-Meier method. Treatment differences will be assessed using a stratified log-rank test, and HRs and 95% CIs will be determined using a stratified Cox proportional hazards model. Enrollment is ongoing. Citation Format: Peter Schmid, Carlos Baccan, Zifang Guo, Kostas Tryfonidis, Hope S. Rugo. KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-06.

Abstract P1-18-09: Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program

Abstract Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or &amp;gt; 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p &amp;lt; 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to &amp;gt;48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-09.

Abstract GS1-02: Final results of KEYNOTE-355: Randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract Background: In the phase 3 KEYNOTE-355 trial (NCT02819518), pembrolizumab (pembro) combined with chemotherapy (chemo) showed statistically significant improvements in OS and PFS compared to placebo + chemo in patients with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 with a combined positive score (CPS) ≥10. There were no statistically significant differences between treatment groups in the CPS ≥1 population, and statistical significance was not tested in the ITT population due to the prespecified testing strategy. Here, we compare outcomes in subgroups of patients by additional CPS cut-offs to the primary results of KEYNOTE-355. Methods: 847 patients with measurable disease per RECIST v1.1, ECOG PS 0-1, and ≥6 month disease-free interval were randomized 2:1 to pembro + chemo (nab-paclitaxel 100 mg/m2 days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 days 1, 8, and 15 every 28 days; or gemcitabine 1000 mg/m2 + carboplatin AUC 2 days 1 and 8 every 21 days) or placebo + chemo for up to 35 administrations of pembro/placebo or until progression/intolerable toxicity. Patients were stratified by chemo type (taxane or gemcitabine-carboplatin), PD-L1 status (CPS ≥1 or &amp;lt;1), and prior neoadjuvant/adjuvant treatment with same-class chemo (yes or no). Dual primary endpoints were OS and PFS (RECIST v1.1, blinded independent central review) in patients with PD-L1-positive tumors (CPS ≥10 and ≥1) and in the ITT population. Hazard ratios (HRs) and 95% CIs in the additional CPS subgroups were based on an unstratified Cox model. Results: At the time of the final analysis (data cutoff, June 15, 2021), the median time from randomization to data cutoff was 44 months. Baseline characteristics of the CPS 1-9, 10-19, and ≥20 subgroups were generally similar to those of the ITT population. In the primary analyses, the HRs (95% CI) for OS were 0.73 (0.55-0.95) in the CPS ≥10 subgroup, 0.86 (0.72-1.04) in the CPS ≥1 subgroup, and 0.89 (0.76-1.05) in the ITT population; HRs (95% CI) for PFS were 0.66 (0.50-0.88), 0.75 (0.62-0.91), and 0.82 (0.70-0.98), respectively. Efficacy data are presented for the additional CPS subgroups in the Table. For OS, results in the CPS 1-9 subgroup showed comparable efficacy for pembro + chemo and placebo + chemo; however, results in the CPS 10-19 and CPS ≥20 subgroups showed a similar treatment benefit with the addition of pembro. Results for PFS were generally consistent with those observed for OS. Conclusions: These results provide support that CPS ≥10 is a reasonable cut-off to define the population of patients with metastatic TNBC expected to derive treatment benefit from pembro + chemo. Table. Efficacy in additional subgroups of patients by PD-L1 CPSCPS subgroupTreatmentMedian OS, mo (95% CI)OS HR (95% CI)*Median PFS, mo (95% CI)PFS HR (95% CI)*1-9†Pembro + Chemo. n = 20513.9. (12.2-16.6)1.09 (0.85-1.40)5.7. (5.4-7.4)0.85 (0.65-1.11)Placebo + Chemo n = 10815.5. (12.4-17.6)5.6. (5.3-7.6)10-19†Pembro + Chemo. n = 8020.3. (15.2-29.0)0.71 (0.46-1.09)9.9. (7.4-11.8)0.70 (0.44-1.09)Placebo + Chemo n = 3917.6. (10.3-25.8)7.6. (5.3-9.7)≥20‡Pembro + Chemo. n = 14024.0 (19.0-28.3)0.72 (0.51-1.01)9.2 (7.6-11.8)0.62 (0.44-0.88)Placebo + Chemo n = 6415.6. (12.3-20.8)5.4 (3.9-7.2)*Analyses based on an unstratified Cox model. †Post-hoc analyses. ‡Prespecified exploratory analyses. Citation Format: Javier Cortes, David W. Cescon, Hope S. Rugo, Zbigniew Nowecki, Seock-Ah Im, Mastura Md Yusof, Carlos Gallardo, Oleg Lipatov, Carlos Henrique Barrios, Jose Perez-Garcia, Hiroji Iwata, Norikazu Masuda, Marco Torregroza Otero, Erhan Gokmen, Sherene Loi, Zifang Guo, Xuan Zhou, Vassiliki Karantza, Wilbur Pan, Peter Schmid. Final results of KEYNOTE-355: Randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-02.