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ASCO 2018 BREAST CANCER TRACK

SPOTLIGHT ON BREAST CANCER

By: Anita Shree Jacob, MBBS and Stijn van den Borne, MSc | Last updated: 19th June 2018 | In: ASCO 2018 Annual Meeting, Breast Cancer, Chemotherapy, Conferences, Immunotherapy, Oncology, Targeted Therapies, Translational Research

Breast cancer has always been a front-runner when it comes to the development of novel therapeutic strategies. With the advent of newer targeted- and immunotherapies, oncologists have an increment of therapeutic options to offer their patients – therapies that inherently have lower toxicity risks or the ability to reduce the duration of treatment as well as novel combinations with older therapeutics. The American Society of Clinical Oncology’s (ASCO) 2018 Breast Cancer track offered an extensive look at the latest advancements and updates from on-going trials covering the various subtypes of breast cancer.

ASCO 2018 Breast Cancer Keywords

#ASCO18, ABC, abemaciclib, abscopal, AC, Afinitor, AKT, AKT1, alpelisib, anthracycline, Aromasin, AstraZeneca, AZ, AZD5363, BC, BRCA, BYL719, capecitabine, CCNE1, CDK2, CDK4/6, chemotherapy, CNS metastases, ctDNA, cyclophosphamide, docetaxel, doxorubicin, durvalumab, E2F1, Eli Lilly, epirubicin, ER-positive, ESR1, ESR1 Y537S, everolimus, EXE, exemestane, Faslodex, Femara, FGFR1, fulvestrant, GDC-0032, Genentech, GnRH, goserelin, HER2-negative, HER2-positive, HER2E, HR-positive, Imfinzi, ipatasertib, Keytruda, Ki67, Kisqali, LABC, letrozole, leuprorelin, MAPK, MBC, Merck, MSD, neoadjuvant, niraparib, nivolumab, Novartis, OfS, Opdivo, paclitaxel, PARP, PARPi, pCR, PD-L1, pembrolizumab, perimenopausal, pertuzumab, Pfizer, Pi3K, PI3Ki, PIK3CA, postmenopausal, PR-positive, premenopausal, PTEN, RAD001, RB1, ribociclib, RNA, Roche, TAC, talazoparib, tamoxifen, taselisib, taxane, TNBC, trastuzumab, triptorelin, tucatinib, utidelone, Verzenio

Management of HER2-positive breast cancer

The randomised Phase III PHEREXA (NCT01026142) trial investigated the addition of pertuzumab (PER) to trastuzumab (H) plus capecitabine (X) in 452 patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC).¹Urruticoechea A et al. J Clin Oncol 2018;36(suppl): Abstr 1013 All participants were pretreated with a taxane and had progressed during or after H-based therapy. The overall survival (OS) in the PER+H+X arm was 37.2 months vs 28.1 months in the H+X arm (HR=0.76; 95% CI, 0.60-0.98). The progression-free survival (PFS) was 11.8 vs 9.0 months (HR=0.83; 95% CI, 0.68-1.02; not significant [NS]), respectively. The investigators did not report any new safety signals, nor any evidence of late cardiac toxicity.

Two randomised Phase III trials presented at ASCO 2018, the PERSEPHONE (NCT00712140)² and the RESPECT (NCT01104935)³, investigated a less aggressive adjuvant treatment regimen for HER2-positive breast cancer.

The PERSEPHONE study found, within a pre-specified 3% non-inferiority-boundary, that 6 months of adjuvant H was as effective to the empirical 12 months of adjuvant H in early breast cancer (EBC) patients (N=4089). The 6-month adjuvant H-regimen reduced cardiac toxicities by half.²Earl HE et al. J Clin Oncol 2018;36(suppl): Abstr 506

The RESPECT study investigated whether H-monotherapy is as effective as H plus chemotherapy (CTx) in elderly (>70 years old) HER2-positive primary breast cancer patients (N=275).³Sawaki M et al. J Clin Oncol 2018;36(suppl): Abstr 510 Although not significant, the investigators reported that omitting CTx from H+CTx in elderly HER2-positive breast cancer patients was associated with a loss in survival-duration of approximately 1 month at 3 years post randomisation. H-monotherapy patients had less toxicity and reported a better quality-of-life (QoL) compared to patients receiving H+CTx.

HER2-positive/HR-positive disease

The Phase II PerELISA neoadjuvant study (NCT02411344) recruited 64 postmenopausal, operable HER2-positive/hormone receptor (HR)-positive patients to undergo 2 weeks of letrozole (L) therapy.⁴Guarneri V et al. J Clin Oncol 2018:36(suppl): Abstr 507 At two weeks, patients underwent re-biopsy to compare the Ki67-level expression (Ki67-LE) after L with baseline values. Patients with a reduction in Ki67-LE of ≥20% were deemed Ki67-responders and continued L with the addition of PER and H. Ki67-non responders were those with a Ki67-LE reduction <20%. These patients received paclitaxel (T) plus PER and H. The primary objective was breast and axillary pathological complete response (pCR). The Simon’s Two-Step design required at least 8 patients in 43 Ki67 responders to have a pCR, which was met as 44 patients (69%) had a Ki67-response on L and 9 cases (20.5%) had a pCR after completion of L+PER+H and surgery. The pCR rate in the HER2E subtype was 45.5% vs 13.8% in other subtypes (P=0.042). Patients with a Ki67 response after short-term L therapy have an opportunity to continue treatment with a CTx-free regimen.

Controlling brain metastasis

Finally, the ASCO 2018 HER2-positive breast cancer track included a pooled analysis of two Phase I studies in 117 (total) patients receiving the novel HER2-directed small molecule inhibitor tucatinib.⁵Murthy RK et al. J Clin Oncol 2018;36(suppl): Abstr 1015 The analysis revealed a difference in median time to isolated brain-progression between patients (N=11) who continued tucatinib post initial brain metastases (BM) progression (12.3 months) and patients (N=14) who discontinued tucatinib upon initial BM progression (6.3 months). In patients continuing treatment post-BM progression, a median time of 8.3 months to any second event was observed. This study contributes toward the ongoing HER2CLIMB trials (NCT01983501 and NCT02025192).

Strategies in managing hormone receptor-positive breast cancer patients

In postmenopausal women

The standard of care (SOC) in postmenopausal HR-positive breast cancer are adjuvant aromatase inhibitors (AIs). However, AI-treatment is known to cause osteoporosis and subsequent fractures. The Phase III placebo (PBO)-controlled D-CARE study (NCT01077154) evaluated the inclusion of denosumab (Dmab) to SOC (neo)adjuvant therapy in postmenopausal women (N=4509) with EBC.⁶Coleman RE et al. J Clin Oncol 2018;36(suppl): Abstr 501 After a median follow-up of 67 months, the study failed to meet its primary endpoint of bone metastasis-free survival (BMFS). However, a suggested benefit was observed on the secondary endpoint time-to-bone metastases as the first recurrence in an exploratory analysis (HR 0.76; 95% CI 0.63-0.92).

Another Phase III study on Dmab, the ABCSG-18 (NCT00556374) presented the impact of adjuvant Dmab on disease-free survival (DFS) in 3425 postmenopausal women with HR-positive EBC on adjuvant AI-therapy.⁷Gnant M et al. J Clin Oncol 2018;36(suppl): Abstr 500 At median 72-month follow-up the 5-year DFS-rate was 89.2% and the 8-year DFS-rate was 80.6% (78.1-83.1) in the Dmab + AI arm, compared to 87.3% and 77.5% for patients who received PBO plus AI, respectively. The authors concluded the DFS was significantly improved in the Dmab+AI arm (HR= 0.82; 95% CI, 0.69-0.98l; Cox P=0.026 – not corrected for multiplicity).

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ASCO 2018 breast cancer TNBC MBC ABC ASCO18 PHEREXA D-CARE ABCSG-18 ASTRRA TEXT-SOFT MONARCH-2 MONALEESA-3-SANDPIPER BOLERO-6 KEYNOTE-162 TONIC-TOPACIO GeparNeuvo

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Figure 1. Data of selected HER2-positive and HR-positive ASCO 2018 breast cancer studies

A=anthracycline; ABC=advanced breast cancer; AI=aromatase inhibitor; AKT-Pw=AKT-pathway (i.e.PIK3CA/AKT1/PTEN); BC=breast cancer; BMFS=bone metastasis free survival; BRCA=breast cancer gene; C=cyclophosphamide; CAP=capecitabine; CBR=clinical benefit rate; CDK4/6=cyclin-dependent kinase 4 and 6; CIS=cisplatin; CTx=chemotherapy; DCR=disease control rate; DFS=disease-free survival; DOR=duration of response; DRFI=distant recurrence-free interval; EBC=early breast cancer; ET=endocrine therapy; EVE=everolimus; EXE=exemestane; HER2=human epidermal growth factor receptor 2; HR=hazard ratio; HRD=homologous recombination deficiency; HR-positive=hormone receptor-positive; INV=investigator-assessed; MBC=metastatic breast cancer; mo=months; mTOR=mammalian target of rapamycin; mu=mutation; NE=not evaluated; NIVO=nivolumab; NR=not reached; NS=not statistically significant; OfS=ovarian function suppression; ORR=objective/overall response rate; OS=overall survival; pCR=pathological complete response; PD-L1=programmed death ligand 1; PFS=progression-free survival; PI3K=Phosphoinositide 3-kinase; PIK3CA=Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; PM=postmenopausal; POC=proof of concept; RCB=residual cancer burden; RTx=radiotherapy; SOC=standard of care; T=taxane; TNBC=triple negative breast cancer; TTBMR=time-to-bone metastasis as a 1st recurrence; VELI=veliparib.

In premenopausal women

The ASTRRA study (NCT00912548) investigated the efficacy of adding ovarian function suppression (OfS) to tamoxifen (TAM) in 1483 premenopausal HR-positive breast cancer patients who had completed (neo)adjuvant CTx and undergone definitive surgery.⁸Noh WC et al. J Clin Oncol 2018;36(suppl): Abstr 502 With a median follow-up of 63 months, the 5-year estimated DFS was 91.1% in the combination group and 87.5% in the TAM-only group (P=0.029).

The TEXT (NCT00066703) and SOFT (NCT00066690) trials studied the efficacy of OfS in 4891 premenopausal HR-positive HER2-negative breast cancer patients.⁹Regan MM et al. J Clin Oncol 2018;36(suppl): Abstr 503 Participants were randomly assigned to receive EXE plus OfS, TAM+OfS or TAM alone. A composite recurrence risk index (CRI) was calculated for each patient, compromising the patient’s age, nodal status, tumour size and grade, and oestrogen receptor (ER), progesterone receptor (PR), and Ki67 level expression. The overall 8-year distance recurrence-free interval (DRFI) was 91% ranging ~100% for the lowest CRI-level of 0.2 to 63% for the highest CRI level of 3.4. In the combined TEXT and SOFT populations, 4690 patients received OfS. At a median follow-up of 9 years, the 8-year DFS-rate was 86.8% in the EXE+OfS group compared to 82.8% in the TAM+OfS group (HR for recurrence, a second invasive cancer, or death=0.77; 95% CI, 0.67-0.90; P<0.001). Premenopausal patients with HR+/HER2-negative breast cancer and high risk of recurrence by CRI have an approximately 10-15% absolute improvement in the 8-year DRFI when treated with EXE+OfS vs TAM+OfS or TAM alone. The risk in 'lower score' CRI groups was furhter reduced.

Using cyclin-dependent kinase (CDK) 4/6 inhibitors

New data focused on the efficacy and safety of cyclin-dependent kinase (CDK) 4/6 inhibitors. The safety and efficacy of CDK4/6 inhibitor abemaciclib (ABE) was investigated in women with HR-positive, HER2-negative advanced breast cancer (ABC) in the Phase III MONARCH 2 study (NCT02107703).¹⁰Neven P et al. J Clin Oncol 2018;36(suppl): Abstr 1002 During the ASCO 2018, a subgroup analysis of the MONARCH 2 study in pre/perimenopausal women (N=114) was presented. Pre- and perimenopausal women in the MONARCH 2 were required to receive OfS with a gonadotropin-releasing hormone (GnRH) agonist (e.g., goserelin, leuprorelin, triptorelin) before study start. Participants were randomised 2:1 to receive ABE + fulvestrant (F) (N=72) or PBO + F (N=42). The median PFS was not reached for ABE+F and was 10.5 months for PBO+F arm (HR=0.45; 95% CI, 0.26-0.75; P=0.002). The objective response rate (ORR) was 60.8% for ABE+F vs 28.6% for PBO+F (P=0.006). Complete responses (CR) were observed in 3.9% of ABE+F-treated patients vs 0% in patients receiving PBO+F. The most common any-grade adverse events (AEs) for ABE+F were diarrhoea (87.3%), neutropenia (59.2%), and leukopenia (43.7%). In the PBO+F arm, these AEs were observed in 23.8%, 7.1%, and 4.8% of patients respectively.

The Phase III MONALEESA-3 study (NCT02422615) investigated the use of ribociclib (RIB) with F in 726 postmenopausal women with HR-positive, HER2-negative ABC.¹¹Slamon DJ et al. J Clin Oncol 2018;36(suppl): Abstr 1000 The primary efficacy endpoint, investigator-assessed median PFS, was met. Median PFS was 20.5 months for RIB+F vs 12.8 months for PBO+F (HR=0.59; 95% CI, 0.48-0.73; P<0.001). The efficacy was consistent in endocrine treatment-naïve patients and patients pretreated with up to 1 line of endocrine therapy for ABC. The ORR was 41% for RIB+F vs 29% for PBO+F (P=0.003). The clinical benefit rate (CBR) measured 69% vs 60% (P=0.015), respectively. Frequent all-grade AEs that occurred in ≥30% of patients were neutropenia (70% vs 2%), nausea (45% vs 28%), and fatigue (31% vs 33%), all for RIB+F vs PBO+F respectively. Notably, Grade 3/4 neutropenia was observed in 54% (RIB+F) vs 0% (PBO+F) of patients, G3/4 increased ALT in 9% (RIB+F) vs <1% (PBO+F), G3/4 increased AST in 6% (RIB+F) vs 1% (PBO+F), and post-baseline QTcF-interval >480 ms occurred in 6% (RIB+F) vs 3% (PBO+F) of patients.

In the MONALEESA-7 (NCT02278120) subgroup analysis of 672 premenopausal HR-positive, HER2-negative ABC patients, the median PFS was increased when adding RIB to ET (TAM or non-steroidal AI [NSAI])+OfS group vs the PBO plus ET+OfS group.¹²Hurvitz SA et al. J Clin Oncol 2018;36(suppl): Abstr 1047 The improvement in PFS was observed in patients who received one-line of prior CTx (N=94) and patients without prior CTx (N=578). In patients pretreated with CTx, the PFS was 16.6 vs 9.0 months (HR=0.55; 95% CI, 0.31-0.95) and the ORR was 32% vs 27% (P=0.262), both for RIB+ET+OfS vs PBO+ET+OfS respectively. In patients without prior CTx, the PFS was 24.7 vs 14.5 months (HR=0.57; 95% CI, 0.44-0.72) and the ORR was 54% vs 38%, again for RIB+ET+OfS vs PBO+ET+OfS respectively. ORR was also significantly increased in the RIB group without prior CTx. Although adding RIB to ET+OfS was beneficial in premenopausal patients with HR+, HER2- ABC regardless of previous CTx, the data suggests patients who received CTx before entering the MONALEESA-7 study had numerical shorter PFS and lowered ORR when compared to patients without prior CTx.

CDK4/6: pooled and translational data

Four other studies looked at the treatment effect of CDK4/6 inhibition in combination with endocrine therapy (ET).^13-16 A joint analysis of 666 postmenopausal HR+ HER2-negative patients untreated for ABC in the PALOMA 2 study (PAL2 [NCT01740427]) and 521 pre- and postmenopausal HR+ HER2-negative patients whose disease has progressed after prior ET in the PALOMA3 trial (PAL3 [NCT01942135]) showed that adding palbociclib (P) to ET, either L (PAL2) or F (PAL3), had a significant increase in PFS regardless of the length of initial treatment-free interval (TFI [PAL2]) or disease-free interval (DFI [PAL3]).¹³Finn RS et al. J Clin Oncol 2018;36(suppl): Abstr 1023 The analysis also revealed that both Luminal A and Luminal B subtypes benefitted from the addition of PAL to ET in both studies.

The United States Food and Drug Administration (US FDA) pooled analysis on the benefits of CDK4/6 inhibitor in less common breast cancer subsets; PR-negative, de novo metastatic, and lobular histology.¹⁴Gao JJ et al. J Clin Oncol 2018;36(suppl): Abstr 1024 The investigators determined that addition of a CDK4/6 inhibitor to ET provided similar reduction of risk of disease progression or death in less common breast cancer subtypes as is reported for the broad population per product indication. Nevertheless, it was noted that questions remain on the selection of patients who may derive more benefit and in what setting to best prescribe CDK4/6 inhibitors.

The MONALEESA-2 (NCT01958021) investigated the addition of RIB to L vs PBO + L in 668 postmenopausal patients with HR+, HER2-negative ABC.¹⁵Hortobagyi GN et al. J Clin Oncol 2018;36(suppl): Abstr 1022Gene expression analysis by NanoString 230-gene nCounter® GX Human Cancer Reference panel assessed correlations between high and low messenger RNA expression level and PFS outcomes. The investigators looked at gene expression involved in the breast cancer CDK pathway (ESR1, RB1, E2F1), gene expression implicated in CDK4/6 inhibitor resistance (CDK2, CCNE1, FGFR1), and gene expression involved in alternative pathways (cell cycle control, PI3K pathway, MAPK pathway, RTKs). The addition of RIB was beneficial for all gene expression levels in all genes. However, there was a trend towards greater benefit of RIB in high ESR1 expression and low RTK expression

In the PAL3 study (NCT01942135), mechanisms of resistance to the CDK4/6 inhibitor used were investigated using circulating tumour DNA (ctDNA) analysis in tissue samples of 125 PAL+F patients and 68 PBO+F patients.¹⁶Turner NC et al. J Clin Oncol 2018;36(suppl): Abstr 1001 Evolution of driver gene mutations was more common in patients progressing late on PAL+F treatment but uncommon in patients experiencing early progression. A paired exome analysis was performed in 16 patients receiving PAL+F and showed frequent clonal evolution, but copy number profiles remained constant before and after treatment. Furthermore, the outcomes showed that breast cancer driver mutations are similar regardless of treatment with PAL+F or F alone, with acquired PIK3CA and ESR1 Y537S mutations which may contribute to F resistance. At end-of-treatment (EOT), RB1 mutations emerged in 4.8% of PAL+F patients. RB1 mutations were not observed at EOT in patients receiving PBO+F.

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Figure 2. Data of selected CDK4/6 and PI3K/mTOR inhibitor ASCO 2018 breast cancer studies

HER2-negative disease

Concluding the ASCO hormone-sensitive breast cancer coverage is the Phase I/II study (NCT02379247) with the novel PI3K inhibitor alpelisib (ALP – BYL719) in combination with nab-paclitaxel (NP) in HER2-negative MBC.¹⁷Sharma P et al. J Clin Oncol 2018;36(suppl): Abstr 1018The study encompassed a Phase I 3+3 dose-finding part to determine the recommended Phase II dose (RP2D), ORR and PFS, and a Phase II part to expand the ORR and PFS investigations. In total 43 patients enrolled in Phase I (N=10) and Phase II (N=33) and 42 patients were evaluable for response. The ORR with ALP+NP was 57% (CR=2, partial response [PR]=22). Stable disease ≥16 weeks was observed in 21% of patients. The median PFS was 9 months. By next-generation sequencing 17/42 (40%) of patients were found to have tissue and ctDNA PIK3CA mutations. The ctDNA/tissue concordance was 70%. Patients with PIK3CA mutation had better median PFS compared to those without PIK3CA mutations, 13 vs 7 months (HR=0.39; P=0.03). Notable, in the study population 74% had received prior CTx (84% taxane) for MBC, 30% of patients had triple-negative breast cancer (TNBC), and 84% was reported to have visceral metastases. Grade 3/4 AEs were hyperglycaemia (29%), neutropenia (31%), anaemia (12%) and diarrhoea (7%).

Another Phase III study (NCT02253459) study in 405 heavily pretreated anthracycline- and taxane-refractory MBC patients included both TNBC as well as HR-positive, HER2-negative breast cancer patients to investigate the epothilone analogue utidelone (UTI)+C vs C alone.¹⁸Xu B et al. J Clin Oncol 2018;36(suppl): Abstr 1003 The intention-to-treat (ITT) population demonstrated a median OS of 14.8 months in the combination group vs 12.2 months in the C alone group (HR=0.63, 95% CI, 0.45─0.88; P=0.005) and the 24-month OS-rate was 39.0% for UTI+C vs 26.6% C alone (P=0.015). The most common Grade 3 AE in the UTI+C arm was peripheral neuropathy (25%) which was manageable and reversible. UTI was associated with only mild myelosuppression which is remarkable for a microtubule inhibitor. No liver toxicities were reported.

A phase II study (NCT02282345) of neoadjuvant poly(ADP-ribose) polymerase-inhibitor (PARPi) talazoparib (TALA) in operable breast cancer with BRCA mutation (BRCA+) recruited 3 HR-positive, HER2-negative patients and 17 TNBC patients.¹⁹Litton JK et al. J Clin Oncol 2018;36(suppl): Abstr 508 The primary endpoint was residual cancer burden (RCB), with RCB 0 and 1 having a positive expected outcome when compared to higher RCB scores. At the time of publication, 19 patients were evaluable. The investigators reported that once daily TALA given preoperatively without CTx produces significant pCR, 53% (10/19) of patients achieved an RCB0 and 63% (12/19) of patients had an RCB score of 0 or 1. One Grade 4 toxicity was reported (thrombocytopenia [5%]). Grade 3 toxicities were anaemia (40%), neutropenia (15%), and urinary tract infection (5%). Common grade 1/2 toxicities included nausea, fatigue, neutropenia, alopecia, dizziness and dyspnoea. Nine patients continued at a lower dose.

Advances in the management of TNBC

The Phase III BrighTNess (NCT02032277) study investigated the addition of PARPi veliparib (VELI) to CTx in 634 stage II-III TNBC patients and assessed the prognostic and predictive role of homologous recombination deficiency (HRD) assay for carboplatin (CPt) and PARPi response.²⁰Telli ML et al. J Clin Oncol 2018;36(suppl): Abstr 519 Patients received treatment with either VELI+CPt+T, PBO+CPt+T, or dual PBO+T, all followed by cyclophosphamide plus doxorubicin (AC). The HRD-status was determined for 438 patients. The results showed higher rates of pCR in HRD-positive (HRD+) patients across all treatment arms; Patients treated with CPt had the highest pCR in both HRD+ and HRD-negative (HRD-) subsets, regardless of the addition of VELI. Irrespective of the treatment received, HRD+ patients had higher pCR rates when compared to HRD- patients in the same treatment arm.

The Phase II, investigator-initiated, double-blind, randomised-controlled PAKT study (NCT02423603) investigated the addition of novel AKT inhibitor AZD5363 to T as first-line therapy in 140 women with metastatic TNBC (mTNBC).²¹Schmid P et al. J Clin Oncol 2018;36(suppl): Abstr 1007 The primary endpoint was PFS and had a predefined significance level of 0.10. The PFS results in the ITT population showed a median PFS of 5.9 months for AZD5363 vs 4.2 months for PBO (P=0.06 [one-sided]). The median OS was 19.1 months for AZD5363 vs 12.6 months for PBO (P=0.04 [two-sided]). Activating mutations of the AKT-pathway were found in 24% of patients. These patients with PIK3CA/AKT1/PTEN-alterations had improved PFS outcome (HR=0.30) and longer OS (HR=0.37). Grade 3 and higher AEs included diarrhoea (12% vs 1%), infection (4% vs 1%), neutropenia (3% vs 3%), rash (4% vs 0%) and fatigue (4% vs 0%), all for AZD5363+T vs PBO+T respectively.

The Phase II, double-blind, randomised-controlled LOTUS study (NCT02162719) reported the updated OS results of adding AKT inhibitor ipatasertib (IPAT) to T as first-line therapy in 124 women with mTNBC. Previously, Kim et al. had reported the PFS outcome; median PFS was 6.2 months for the IPAT combination vs 4.9 for PBO+T (stratified HR=0.60; 95% CI, 0.37–0.98; P=0.037)²²Kim SB et al. Lancet Oncol 2017;18(10):1360–72 Patients whose tumour harboured PIK3CA/AKT1/PTEN-alterations had a better outcome when receiving the AKT-inhibitor: 9.0 months vs 4.9 months with PBO (unstratified HR=0.44; 95% CI, 0.20–0.99). The updated OS results presented at ASCO 2018 did not reach statistical significance but showed a trend towards improved 1-year OS-rate in favour of IPAT vs placebo (85% vs 70%).²³Dent R et al. J Clin Oncol 2018;36(suppl): Abstr 1008 The median OS was 23.1 for IPAT+T vs 18.4 months for PBO+T (stratified HR=0.62; 95% CI, 0.37–1.05).

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Figure 3. Data of selected HER2-negative and TNBC ASCO 2018 breast cancer studies

With immunotherapy

A Phase II single-arm study (NCT02730130) assessed the efficacy and safety of programmed death 1 (PD-1) inhibitor pembrolizumab (PEMBRO) in combination with radiotherapy (RTx) in heavily pretreated women (N=17) with mTNBC and at least two measurable lesions of which one requiring RTx. PD-1 ligand (PD-L1) expression status was not required for study participation.²⁴McArthur HL et al. J Clin Oncol 2018;36(suppl): Abstr 1017The primary endpoint measured an abscopal tumour response (ORR) at Week 13 in the non-irradiated lesion(s). Nine women were evaluable for response. The ORR was 33% (all partial responses: 60%, 54%, and 34% decrease in size) and the disease-control rate (DCR) was 44%. Five patients (56%) had disease progression (PD) at Week 13. Eight women were not evaluable for response, five died due to disease-related complications and 3 progressed before Week 13. The AE-profile was mild, common AEs included fatigue, myalgia and nausea. The authors concluded that the addition of RTx to PD-1 blockade may be a promising strategy for improving response rates in pretreated mTNBC.

The TOPACIO/KEYNOTE-162 (NCT02657889) is a Phase I/II study to evaluate the safety and efficacy of combining PARPi niraparib with PD-1 immune-checkpoint inhibitor PEMBRO in 54 patients with mTNBC.²⁵Vinayak S et al. J Clin Oncol 2018;36(suppl): Abstr 1011 Twelve (22%) of the enrolled TNBC patients had deleterious BRCA mutations (BRCAmut). In 9 (17%) of patients BRCAmut were not tested or showed indeterminate results. The investigators reported 3 (7%) CRs and 10 (22%) PRs matching an ORR of 29%. The DCR was 49% with 9 (20%) patients having stable disease (SD). The remainder 23 (51%) patients had PD. Among the 12 patients with BRCAmut the ORR was 67% (1 CR and 7 PR) and the DCR was 75% (1 SD). Three BRCAmut patients had PD. The median PFS in the BRCAmut group was 8.1 months. PD-L1-positiveness (PD-L1+) was defined as a combined proportion score (CPS) ≥1%. In the PD-L1+ group the ORR was 33% vs 15% in PD-L1-negative patients. Common treatment-related AEs (TRAEs) Grade ≥3 were thrombocytopenia (13%) and anaemia (11%).

Another PD-1 antibody, nivolumab (NIVO), was evaluated as maintenance therapy after five different induction therapy options (RTx or CTx or NIVO single-agent) in 66 metastatic TNBC patients in the adaptive Phase II TONIC trial (NCT02499367).²⁶Kok M et al. J Clin Oncol 2018;36(suppl): Abstr 1012Among all patients (N=66) the ORR was 20% (2 CRs, 11 PRs). Two patients (3%) had SD >24 weeks, matching a CBR of 23%. Induction with single-agent NIVO resulted in an ORR of 17% (2/12). ORRs for NIVO following induction with other therapies was: RTx 8% (1/12), doxorubicin 35% (6/17), cyclophosphamide 8% (1/12) and cisplatin 23% (3/13).

Finally, the Phase II neoadjuvant GeparNeuvo study (NCT02685059) investigated the addition of PD-L1-inhibitor durvalumab (DURVA) to a taxane-anthracycline-cyclophosphamide (TAC) containing regimen in 174 patients with operable TNBC.²⁷Loibl S et al. J Clin Oncol 2018;36(suppl): Abstr 104 A pCR was observed in 84 of 174 pts (48.3%). Serious AEs (SAEs) were reported in 34.5% of patients and immune-related AEs of special interest (irAESI) were reported in 27.6% of patients. The combination of TAC CTx with DURVA showed a feasible option associated with pCR-rate in TNBC.

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Figure 4. Data of selected ASCO 2018 breast cancer immunotherapy studies

REFERENCES

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Earl HE et al. J Clin Oncol 2018;36(suppl): Abstr 506

Sawaki M et al. J Clin Oncol 2018;36(suppl): Abstr 510

Guarneri V et al. J Clin Oncol 2018:36(suppl): Abstr 507

Murthy RK et al. J Clin Oncol 2018;36(suppl): Abstr 1015

Coleman RE et al. J Clin Oncol 2018;36(suppl): Abstr 501

Gnant M et al. J Clin Oncol 2018;36(suppl): Abstr 500

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Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).

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Talazoparib FDA approved for gBRCAm HER2‑negative breast cancer says:

18th October 2018 at 8:53 PM

[…] (gBRCAm) locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Patients should be selected for the PARP inhibitor (PARPi)-treatment using the FDA-approved […]

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Ribociclib FDA label updated to include pre- and perimenopausal women says:

21st July 2018 at 11:42 PM

[…] randomised double-blind, placebo-controlled study, the MONALEESA-3 (NCT02422615), investigated the combination ribociclib plus fulvestrant in 726 postmenopausal […]

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SPOTLIGHT ON BREAST CANCER

ASCO 2018 Breast Cancer Keywords

Management of HER2-positive breast cancer

HER2-positive/HR-positive disease

Controlling brain metastasis

Strategies in managing hormone receptor-positive breast cancer patients

In postmenopausal women

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