Highlights in Breast Cancer

CONGRESS HIGHLIGHTS 327 SPECIAL EDITION

Highlights in breast cancer

J. Blokken, PharmD, PhD1, T. Feys, MSc, MBA1, K. Punie, MD2 1Ariez International, Ghent, Belgium, 2University Hospitals Leuven, Leuven, Belgium

ABSTRACT The 2019 edition of the annual ESMO meeting proved to be a grand cru when it comes to breast cancer studies. In early triple negative breast cancer (TNBC), the KEYNOTE-522 trial demonstrated a significant improvement of pathological complete response rate with the addition of pembrolizumab to neoadjuvant chemotherapy, irrespective of PD-L1 status. In addition to this, the prognostic value of tumour-infiltrating lymphocytes was confirmed in a pooled analysis of patients with TNBC who did not received adjuvant chemotherapy. In the field of metastatic breast cancer, much attention went to overall survival data that were presented for the CDK4/6-inhibitors ribociclib and abemaciclib in combination with fulvestrant (MONA- LEESA-3, MONARCH 2). Interesting results of the phase III BROCADE3 trial were presented in which the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel was evaluated in patients with advanced HER2-negative breast cancer and a germline BRCA mutation. Regarding checkpoint inhibitors in metastatic TNBC, a read-out of a phase III trial with pembrolizumab compared to standard chemotherapy in second- and third-line was presented, as well as important translational data on different immunohistochemical PD- L1 assays from IMpassion130. Finally, two oral presentations focused on the use of CDK4/6-inhibitors in different combination regimens in metastatic HER2-positive breast cancer (MonarcHER) and in TNBC.

HIGHLIGHTS IN EARLY BREAST CANCER phocytes (sTILs).1-3 In addition to this, neoadjuvant pem- KEYNOTE-522: ADDING PEMBROLIZUMAB TO brolizumab plus chemotherapy showed manageable safety NEOADJUVANT CHEMOTHERAPY LEADS TO A and antitumour activity in early TNBC.4.5 In KEYNOTE-522, SIGNIFICANT IMPROVEMENT IN PATHOLOGICAL a total of 1,174 adult patients with newly diagnosed TNBC COMPLETE RESPONSE (PCR) RATE IN EARLY (T1c N1-2 or T2-4 N0-2) and an ECOG performance status TNBC (PS) of 0 or 1 were randomly assigned (2:1) to receive neo- Based on recent phase II data, pembrolizumab monotherapy adjuvant chemotherapy (carboplatin AUC5 q3w or AUC1.5 showed activity with durable responses in selected patients weekly plus paclitaxel in cycles 1-4, doxorubicin/epirubicin in the treatment of metastatic triple negative breast cancer plus cyclophosphamide in cycles 5-8) in combination with (TNBC), with more responses seen in the first-line setting pembrolizumab or placebo followed by surgery and mainte- and in patients with high stromal tumour-infiltrating lym- nance therapy with either pembrolizumab (200 mg q3w for

Please send all correspondence to: T. Feys, MSc, MBA, Ariez international, Oude Houtlei 118, 9000 Ghent, Belgium, Tel: 0479/567890, E-mail: [email protected]. Conflict of interest: K. Punie’s institution has received honararia from Astra Zeneca (consultancy), Eli Lilly (advisory board), Mundi Pharma (speaker fee’s), Novartis (consultancy, advisory board, speaker fee’s), Pfizer (consultancy, speaker fee’s), Roche (consultancy, advisory board, speaker fee’s), Sanofi (research funding), Vifor Pharma (advisory board). The other authors have nothing to disclose and indicate no potential conflict of interest. The selection of the abstracts discussed in this overview are the sole responsibility of the authors and was not influenced by third parties. Keywords: abemaciclib, atezolizumab, breast cancer, BROCADE3, chemotherapy, fulvestrant, IMpassion130, KATE2, KEYNOTE-119, KEYNOTE-522, MONALEESA3, MONARCH2, monarcHER, pembrolizumab, ribociclib, TNBC, trastuzumab, trastuzumab emtansine, trilaciclib, tumour-infiltrating lymphocytes, veliparib.

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9 cycles), or placebo. The analyses presented at ESMO 2019 benefit of the addition of pembrolizumab to neo-adjuvant were the first interim analyses for the co-primary endpoints platinum-containing chemotherapy in early TNBC is not re- pCR and event-free survival (EFS) after a median follow-up stricted to PD-L1 positive patients. A relevant future question of 15.5 months. The pathological complete response (pCR, in early TNBC, besides much biomarker work that needs to defined as ypT0/Tis ypN0), assessed in the first 602 patients, be done for checkpoint-inhibitors, seems to become if plat- significantly increased from 51.2% in the placebo group to inum-containing chemotherapy potentiates or jeopardises 64.8% in the pembrolizumab group (p=0.00055), represent- the optimal potential of checkpoint-blockade in early TNBC. ing a clinically meaningful 13.6% increase. Also when other definitions of pCR were used, the pembrolizumab containing PROGNOSTIC VALUE OF STROMAL TUMOUR- regimen outperformed placebo (ypT0 ypN0: 59.9% vs. 45.3%; INFILTRATING LYMPHOCYTES (STILS) ypT0/Tis: 68.6% vs. 53.6%). Interestingly, the pCR benefit sTILs have been highlighted as a robust prognostic biomark- was seen irrespective of PD-L1 expression levels (PD-L1 pos- er in early-stage triple-negative breast cancer (TNBC), mostly itive: 68.9% vs. 54.9%; PD-L1 negative: 45.3% vs. 30.3%). The in the context of adjuvant chemotherapy.7,8 Until now there vast majority of patients (82%) had a positive PD-L1 status, were limited data on their prognostic value in TNBC patients in this trial defined as a combined positive score (CPS) ≥1 on in the absence of adjuvant chemotherapy. At the 2019 ES- tumour cells, lymphocytes and macrophages with the Da- MO conference, Park et al. presented the results of a pooled ko 22C3 pharmDx assay, and this showed to be an import- analysis of 4 cohorts of TNBC patients that were not treat- ant prognostic factor in early TNBC given the +/- 25% higher ed with chemotherapy. The median age of patients in this pCR rates in the PD-L1 positive compared to the PD-L1 nega- analysis was 65 years, 82.7% had pN0 disease and 69.3% of tive patients. Subgroup analyses suggests the benefit is high- patients did not receive adjuvant radiotherapy. The median er in patients with node-positive disease and with the weekly percentage of stromal TILs was 10% (ranging from 0-90%). carboplatin-regimen which could be plausible taking into The analysis revealed that a higher percentage of sTILs was account the mechanism of action, but of course these latter significantly associated with higher histological grade (p < findings have to be confirmed. 0.001). In this analysis, each 10% increment in stromal TILs Given the fact that recurrences in TNBC often occur ear- (sTILs) corresponded to a hazard ratio of 0.93 (95%CI: 0.87- ly on, the investigators also conducted an early first interim 1.00) for invasive disease-free survival, of 0.89 (95%CI: 0.81- analysis of the event-free survival (EFS). Also with respect to 0.98) for distant disease-free survival and of 0.91 (95%CI: this co-primary endpoint, results were promising, with a fa- 0.82-1.00) for OS. Patients with sTILs ≥30% showed more vourable trend for the pembrolizumab-treated patients with favourable outcomes, which suggests a significant role of im- a hazard ratio of 0.63 (95%CI: 0.43–0.93, prespecified p-val- mune engagement in facilitating a better survival. In fact, the ue boundary not reached). At 18 months, the predicted EFS 5-years OS rate for patients with ≥30% sTILs was reported at rate with chemotherapy plus pembrolizumab was 91.3% as 88.2%, as compared to 80.4% for patients with <30% sTILs. compared to 85.3% with chemotherapy alone.6 The better outcome of patients with ≥30% sTILs was partic- The safety profile of the pembrolizumab-containing regi- ularly pronounced in stage I TNBC. In these patients, the men was consistent with the known toxicity profile of each 5-year OS rate was very high at 98% (95%CI: 95-100) (vs. agent. Grade 3 or higher treatment-related adverse events 89.5% for patients with <30% sTILs). Based on these results, (TRAEs) in the pembrolizumab and placebo groups occurred the authors suggested that in this patient population, the ab- in 76.8% and 72.2% in the neoadjuvant phase and in 5.7 and solute survival benefit of adjuvant chemotherapy could be 1.9% in the adjuvant phase, respectively. Side effects with a minimal (especially taking into account the associated risks potential link to immune therapy occurred in 42% of study and comorbidities). Therefore, a routine evaluation of sTILs participants in the pembrolizumab arm (mostly infusion re- should be considered for adequate prognostication and tai- actions and thyroid dysfunction) as compared to 21% on pla- loring of adjuvant chemotherapy, especially in patients with cebo.6 Fourteen percent of patients in the pembrolizumab low-stage early TNBC.9 arm experienced immune-related grade 3-5 adverse events, These retrospective data are very interesting, but one has to with skin reactions, infusion reactions and adrenal insuffi- be aware of selection bias with half of patients presenting ciency reported most frequently. with grade 1-2 differentiation, indicating enrichment of TN- The data from these first interim analyses are very promis- BC with better prognosis. sTILs are expected to find their way ing. The phase II signal for pCR is now confirmed in all-com- in the near future in prospective de-escalation trials in early ers in phase III and the early difference in EFS is expected TNBC. In strongly selected cases with difficult decisions on to increase with further follow-up. It’s encouraging that the adjuvant chemotherapy indication, e.g. in older adults with

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100

Landmark Analysis 80 RIB + FUL KM RIB + PBO + Estimate FUL FUL 60 PBO + FUL 36 months 67.0% 58.2% RIB + FUL PBO + FUL 42 months 57.8% 45.9% Events/N 167/484 108/242 40 OS, median NR (42.5 - NR) 40.0 (37.0-NR)

Overall Survival, % (95% CI), mo 20 HR (95% CI) 0.724 (0.568-0.924) P value 0.00455

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Time, months No. of patients still at risk Ribociclib 484 470 454 444 436 428 414 402 397 389 374 365 348 334 326 309 300 287 237 159 92 41 14 2 0 Placebo 242 233 227 223 218 213 207 199 194 187 184 174 169 159 155 147 141 134 107 64 37 14 3 0 0

The P value of 0.00455 crossed the prespecified boundary to claim superior efficacy (P <0.01129)

FIGURE 1. Overall survival benefit of adding ribociclib vs. placebo to fulvestrant in the MONALEESA-3 trial.10

pT1cN0 tumours, information on sTILs (if available) could 32.5 months; HR[95%CI]: 0.730 [0.530-1.004]). An update of already be considered as an additional element in the deci- the progression-free survival (PFS) confirmed the previously sion process. reported data of this trial with a median PFS of 20.6 months for ribociclib + fulvestrant vs. 12.8 months for placebo + ful- HIGHLIGHTS IN METASTATIC BREAST vestrant (HR[95%CI]: 0.587[0.488-0.705]). In patients receiv- CANCER ing first-line/endocrine-sensitive treatment, the median PFS HER2-NEGATIVE BREAST CANCER (descriptive analysis) with ribociclib plus fulvestrant versus MONALEESA 3: SIGNIFICANT OS placebo plus fulvestrant was 33.6 vs. 19.2 months (HR[95%- IMPROVEMENT WITH THE ADDITION OF CI]: 0.546 [0.415-0.718]) (14.6 vs. 9.1 months in early relapse RIBOCICLIB TO FULVESTRANT + second line group HR[95%CI]: 0.571[0.443-0.737]). Of note, In the phase III MONALEESA 3 trial the benefit of adding ri- the OS benefit with ribociclib was seen despite the fact that bociclib to fulvestrant as a first- or second-line treatment op- 25% of patients in the control arm received a CDK4/6 inhib- tion for postmenopausal patients with HR+/HER2− advanced itor as any line of subsequent therapy (vs. 11% in the experi- breast cancer (ABC) was assessed. In total, 726 patients were mental arm). Also with respect to the time to the start of first randomised (2:1) to receive ribociclib (600 mg/day, 3 weeks chemotherapy, the addition of ribociclib to fulvestrant had on, 1 week off) plus fulvestrant (500 mg q4w with loading a significant benefit (median not reached vs. 29.5 months; dose after 2w in the first cycle) or placebo plus fulvestrant. HR[95%CI]: 0.696[0.551-0.897]). Finally, also the time to At the data cut-off, the median follow-up of patients was 39.4 progression on the next-line therapy or death (PFS2) was months and 25% of patients in the ribociclib arm were still significantly longer with ribociclib plus fulvestrant, result- on treatment, compared to 13.2% in the placebo arm. The ing in a 10 month longer median PFS2 compared to place- addition of ribociclib to fulvestrant resulted in a statistically bo plus fulvestrant (39.8 vs. 29.4 months; HR[95%CI]: 0.670 significant OS prolongation compared to placebo plus fulves- [0.542-0.830]). The safety profile was consistent with previ- trant (median not reached vs. 40.0 months; HR[95%CI]: 0.724 ously published analyses without any new safety signals.10 [0.568-0.924], p = 0.00455). In a landmark analysis, this survival benefit translates into an absolute OS benefit of 8.8% at MONARCH 2: SIGNIFICANT OS IMPROVEMENT 36 months (67% vs. 58.2%), increasing to 11.9% at 42 months WITH THE ADDITION OF ABEMACICLIB TO (57.8% vs. 45.9%) (Figure 1). The OS benefit seen with riboci- FULVESTRANT clib plus fulvestrant was consistent across all subgroups, and Previous results of MONARCH 2 showed that the addition was seen both in the first-line setting (median OS not reached of abemaciclib to fulvestrant in HR positive, HER2-negative vs. 45.1 months; HR[95%CI]: 0.700 [0.479-1.021]) as in the advanced breast cancer patients resulted in a significant PFS early-relapse plus second-line subgroup (median OS 40.2 vs. improvement (median 16.4 vs. 9.3 months; HR [95% CI]:

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100 Median OS No. of events 90 abemaciclib + fulvestrant: 46.7 months 211 80 placebo + fulvestrant: 37.3 months 127

40 Overall Survival, % 30 9.4 month OS benefit 20 HR (95% CI) = 0.757 (0.606 to 0.945) 10 P=0.0137 0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Time (months) No. at risk abemaciclib + fulvestrant 446 422 410 397 384 364 339 321 302 284 265 246 234 214 202 157 101 58 23 0 placebo + fulvestrant 223 214 201 195 191 178 170 158 148 135 122 115 99 92 82 62 42 15 3 0

FIGURE 2. Overall survival benefit of abemaciclib plus fulvestrant versus placebo plus fulvestrant in the MONARCH 2 trial.12

0.553 [0.449-0.681]; p<0.001) and a significant increase in respectively). In addition, in an exploratory analysis, patients the proportion of patients with a treatment response (objec- in the control arm had a median time to the first use of che- tive response rate [ORR]: 48.1% vs. 21.3%).11 Also for this motherapy of 22.1 months, while this was prolonged to 50.2 trial, ESMO 2019 featured the presentation of OS results. months in patients treated with the abemaciclib-fulvestrant In MONARCH 2, 669 patients were randomised (2:1) to re- combination (HR [95%CI]: 0.625 [0.501-0.779], p<0.0001). ceive abemaciclib 150 mg BID (continuous schedule) in com- The most common grade 3/4 adverse events in the abemaci- bination with fulvestrant 500 mg (N=446) or placebo plus clib group were neutropenia (29.7%), diarrhoea (14.5%) and fulvestrant (N=223). The study enrolled pre-, peri- and post- leukopenia (11.1%). No new safety signals were reported in menopausal patients who were endocrine-resistant (defined this follow-up analysis.12 as progression on first-line ET for ABC, or progression on or The clinically relevant overall survival benefit with the addi- within one year of adjuvant ET), not previously treated with tion of a CDK4/6-inhibitor to fulvestrant is now confirmed chemotherapy and who did not receive more than one line with these phase III results for ribociclib and abemaciclib. of ET in the advanced setting. The median follow-up for the The median PFS of 33.6 months with ribociclib-fulvestrant presented analysis was 47.7 months. in the first-line endocrine-sensitive subgroup of MONALEE- The median OS improved from 37.3 months in the con- SA-3 seems to raise the question which is the optimal endo- trol arm to 46.7 months in the abemaciclib plus fulvestrant crine partner when CDK4/6-inhibition is given in first-line. arm, representing a statistically significant OS benefit of 9.4 The earlier trend in subgroup analysis towards more pro- months (HR [95%CI]: 0.757 [0.606-0.945], p <0.0137) (Fig- nounced PFS benefit with the addition of abemaciclib, in ure 2). In subgroup analysis, the relative OS survival benefit patients with visceral disease compared to patients without seemed to be higher in the subgroup with visceral metastasis visceral disease (which was a stratification factor in MON- (median OS: 40.3 vs. 32.2 months; HR [95%CI]: 0.675 [0.511- ARCH 2), was confirmed for OS. 0.891]), an observation which was earlier made for PFS. In the updated analysis for PFS, the median PFS in the abe- BROCADE 3: COMBINING THE PARP INHIBITOR maciclib plus fulvestrant arm was 16.9 months as compared VELIPARIB TO PLATINUM-BASED to 9.3 months for patients in the placebo plus fulvestrant arm CHEMOTHERAPY (HR [95%CI]: 0.536 [0.445-0.645], p<0.0001). The PFS-rates The BROCADE3 trial is the first phase III trial to evaluate at 36 months were almost three times higher in the abemaci- a PARP inhibitor in combination with platinum-contain- clib group as compared to the control group (29.9% vs. 10.1% ing chemotherapy in patients with advanced HER2-nega-

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HR 0.705 Veliparib + C/P Placebo + C/P [95% CI 0.566-0.877], p = 0.002 PFS by Inv. PFS Events, n/N 217/337 132/172 Median PFS, 14.5 12.6 100 months [95% CI] [12.5,17.7] [10.6,14.4]

80 PFS24 = 34% (vs. 20%) 60 PFS36 = 26% (vs. 11%)

Progression or Death (%) 0 Patients Free from Disease 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Months from Randomisation

No. at Risk Control 172 160 153 140 123 99 82 64 47 39 35 27 23 18 15 15 12 8 8 8 6 5 5 4 3 0 Veliparib 337 316 301 282 250 207 181 154 137 126 107 92 81 72 60 51 45 38 32 25 20 16 8 4 1 1 0

FIGURE 3. Significant improvement in PFS when adding veliparib to chemotherapy in women with HER2-negative advanced breast cancer with germline BRCA mutations.13

tive breast cancer and a germline BRCA mutation. In total, py. However, the responses to veliparib plus chemotherapy 509 patients were randomised (2:1) to receive veliparib (120 did seem to be more durable with a median duration of re- mg BID on days -2 to 5 of each 21-day cycle) plus carbopla- sponse (DoR) of 14.7 months vs. 11.0 months in the control tin (AUC 6 on day 1)/paclitaxel (80 mg/m2 on days 1,8 and arm. Finally, also the PFS2 was significantly better with the 15) or placebo plus carboplatin/paclitaxel. The median age PARP containing regimen at a median PFS2 of 21.3 months was 46 years and about 85% of patients had measurable dis- vs. 17.4 months for the control arm (HR[95%CI]: 0.760[0.603- ease. The vast majority (92%) of patients did not receive pri- 0.959]; p= 0.020) or platinum-based chemotherapy and about two thirds was The addition of veliparib to carboplatin/paclitaxel was cor- previously treated with (neo)adjuvant chemotherapy. Impor- related with higher grade 3/4 thrombocytopenia (40% vs. tantly, 81% of patients did not receive prior chemotherapy in 28%). Any grade anaemia and diarrhoea were also report- the metastatic setting. ed more frequently.13 After a median follow-up of 36 months, the median PFS was The response rates and median PFS achieved in this trial are 14.5 months in the veliparib arm as compared to 12.6 months impressive, irrespective of the addition of veliparib to carbo- in the control arm (HR[95%CI]: 0.705 [0.566-0.877], p= platin-paclitaxel. However, this was predominantly a first- 0.002). Importantly, the observed benefit was durable, with line platinum-naive setting with 52% of patients with ER+/ 26% of patients in the veliparib arm being alive and free of HER2-negative disease, in which combination chemothera- progression at 3 years (as compared to 11% of the patients py with this carboplatin dose in a metastatic setting is not in the control arm) (Figure 3). The PFS benefit was consis- standard practice. The PFS-curve only starts to separate af- tent among all subgroups, except for patients with a history ter discontinuation of chemotherapy. With this trial design, of CNS metastases. In the interim OS analysis, this bene- the real benefit of this approach is largely underestimated fit in PFS did not translate into a significantly better OS for when focusing on median PFS improvement. The proportion patients treated with veliparib (median OS of 33.5 vs. 28.2 of long-term responders is much higher with the veliparib months, HR[95%CI]: 0.945[0.729-1.225], p= 0.666), but for combination, once more indicating the benefit of PARP-in- correct interpretation it has to be mentioned that cross-over hibition in metastatic HER2-negative breast cancer with ger- to veliparib was allowed for patients in the control arm in mline BRCA mutation. The question even though remains case of progression. The clinical benefit rate (CBR; 90.7% vs. if the same benefit could not have been achieved when the 93.2%) and the ORR (75.8% vs. 74.1%) did not differ between PARP-inhibitor was only initiated after chemotherapy discon- veliparib plus chemotherapy and placebo plus chemothera- tinuation, as in ovarian and pancreatic cancer.

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KEYNOTE-119: PEMBROLIZUMAB Despite this is a negative trial, a proportion of patients had MONOTHERAPY VERSUS CHEMOTHERAPY better and sometimes more durable responses on pembroli- FOR PRE-TREATED METASTATIC TNBC zumab monotherapy as compared to chemotherapy. In KEYNOTE-012 and -086, pembrolizumab demonstrated single-agent antitumour activity and a manageable safe- IMPASSION130: POST-HOC ANALYSIS TO ty profile in patients with metastatic TNBC (mTNBC), with ASSESS THE PERFORMANCE OF PD-L1 durable responses in selected patients.1-3 KEYNOTE-119 is IMMUNOHISTOCHEMISTRY ASSAYS IN a randomised, open-label phase III study of pembrolizum- UNRESECTABLE LOCALLY ADVANCED OR ab monotherapy vs. single-agent chemotherapy in partici- METASTATIC TNBC pants with previously treated mTNBC. In total, 622 patients IMpassion130 is a phase III study evaluating atezolizum- with centrally confirmed mTNBC, who received 1 or 2 pri- ab plus nab-paclitaxel vs. placebo plus nab-paclitaxel as a or systemic treatments for mTNBC, had disease progression first-line treatment for patients with mTNBC. In this tri- on or after their latest therapy and previously received an al, atezolizumab plus nab-paclitaxel significantly improved anthracycline or taxane based treatment were randomised PFS in PD-L1 positive patients (PD-L1 positivity defined as (1:1) to pembrolizumab (200 mg Q3W for up to 35 cycles) or PD-L1–stained immune cells [IC] ≥ 1% of the tumour area physician’s choice of capecitabine, eribulin, gemcitabine, or by VENTANA PD-L1 SP142 assay). In addition, PD-L1 pos- vinorelbine (maximum enrolment cap of 60% of total enrol- itive patients also had clinically meaningful OS benefit with ment for each chemotherapy drug). atezolizumab plus nab-paclitaxel (25 vs. 18 months; HR[95%- Two thirds of patients in this trial had a PD-L1 CPS of ≥1, CI]: 0.71 [0.54-0.93]; median follow-up of 18 months).15 In while approximately 30% and 17% had a PD-L1 CPS of ≥10 an exploratory post-hoc analysis presented at ESMO 2019, and ≥20, respectively. Pembrolizumab failed to significantly the analytical concordance of SP142 with two other PD-L1 improve the OS in patients with a PD-L1 CPS ≥10 (HR[95%- IHC assays, and their ability to predict clinical activity was CI]: 0.78[0.57-1.06]; p= 0.057) or CPS ≥1 (HR[95%CI]: evaluated. Available samples from IMpassion130 were eval- 0.86[0.69-1.06]; p= 0.073) nor in the overall study popula- uated for PD-L1 status using the VENTANA SP142 or SP263 tion (HR[95%CI]: 0.97[0.82-1.15]). Nevertheless, the pem- IHC assay (IC ≥ 1%, SP142+ or SP263+) or Dako PD-L1 IHC brolizumab treatment effect did seem to increase with an 22C3 assay (combined proportion score [CPS] ≥ 1, 22C3+) increasing CPS (HR of 0.78, 0.86, and 0.97 respectively). In by central laboratory in a biomarker-evaluable population, the exploratory subgroup of patients with a CPS ≥20, pem- including 614 patients (68% of the intention to treat group) brolizumab seemed to result in a significant OS benefit with for whom the PD-L1 status was determined using the 3 as- a median OS of 14.9 months as compared to 12.5 months says. PD-L1+ prevalence was 46% for SP142+, 81% for 22C3+, in the control arm (HR[95%CI]: 0.58[0.38-0.88]). No sig- and 75% for SP263+. With an overall percentage agreement nificant benefit in terms of PFS was observed in favour of of 64% (SP142 and 22C3) and 69% (SP142 and SP263), the pembrolizumab, irrespective of the PD-L1 CPS. With respect analytical concordance was subpar (< 90%) and as such, the to ORR, no difference was seen between pembrolizumab assays cannot be considered to be equivalent. 22C3 (CPS ≥ 1) and chemotherapy in the overall study population (9.6% vs. and SP263 (IC ≥ 1%) PD-L1 assays identified a larger patient 10.6%), while the ORR was higher with pembrolizumab in population of which SP142+ (IC ≥ 1%) is a subgroup. More- patients with a CPS ≥10 (17.7% vs. 9.2%) and ≥20 (26.3% vs. over, within the 22C3+ and the SP263+ subgroups, SP142+ 11.5%). In addition, responses to pembrolizumab also proved patients had numerically higher sTILs compared with SP142- to be more durable than those to chemotherapy, reflected by patients. Importantly, the clinical benefit observed with a median DoR of 12.2 and 8.3 months, respectively (medi- atezolizumab + chemotherapy in the 22C3+ and SP263+ sub- an not reached vs. 7.1 in patients with a CPS ≥10 and ≥20). groups was shown to be driven by the SP142+ subgroup. The Pembrolizumab monotherapy was generally well tolerated SP142 assay identified patients with the smallest HR point with a lower incidence of grade 3-5 AEs (34.6% vs. 49%). For estimates and the longest median PFS and OS from atezoli- example, pembrolizumab was associated with lower rates zumab plus nab-paclitaxel.16 of nausea (21.6% vs. 10%), diarrhoea (15.4% vs. 5.5%), de- In conclusion, different PD-L1 assays differ significantly in creased appetite (11.6% vs. 4.5%), alopecia (13.4% vs. 0.6%) rate of positivity and are not interchangeable for patient iden- and neutropenia (20.3% vs. 0.3%). In contrast, immune me- tification. The SP142 assay at IC >1% cut-off is the preferred diated and infusion reactions were more common with pem- diagnostic test to identify the subgroup of patients with mT- brolizumab than with chemotherapy (15.5% vs. 3.1%; grade NBC that will most likely benefit from the addition of atezoli- 3-5: 3.2% vs. 1.0%).14 zumab to nab-paclitaxel in first-line.

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TRILACICLIB PLUS GEMCITABINE/ updated safety data from KATE2 were presented. As of the CARBOPLATIN FAILS TO MEET PRIMARY cut-off date (December 11th, 2018), the median follow-up ENDPOINT OF REDUCTION IN SEVERE was 19.0 months in the atezolizumab plus T-DM1 arm and NEUTROPENIA 18.2 months in the placebo plus T-DM1 arm. With 52 OS Trilaciclib is a highly potent, CDK4/6 inhibitor that can in- events reported, the median OS was not yet reached in either duce transient G1-arrest in hematopoietic stem cells and has arm (stratified HR[95%CI]: 0.74[0.42-1.30]). The one-year demonstrated potential to decrease myelotoxicity in preclini- OS rates were comparable between both arms (89.1% and cal studies. In a phase II trial, including 102 mTNBC patients 89.0% for atezolizumab plus T-DM1 and placebo plus T-DM1, who received 0-2 prior chemotherapy regimens for recur- respectively). In the PD-L1 IC+ subgroup (41% of intention rent or metastatic disease, the ability of trilaciclib to reduce to treat population), the one-year OS rates were numerical- gemcitabine/carboplatin-related neutropenia was assessed. ly higher with the atezolizumab plus T-DM1 combination Patients in the study were randomised to gemcitabine/car- compared to placebo plus T-DM1 (94.3% vs. 87.9% respec- boplatin alone on day 1, 8 (group 1), trilaciclib plus gem- tively. Median OS was not reached in either arm; HR[95%- citabine/carboplatin on day 1, 8 (group 2) or trilaciclib plus CI]: 0.55[0.22-1.38]). Grade ≥ 3 AEs (52.6% vs. 44.8%) and gemcitabine/carboplatin (group 3: trilaciclib on day 1, 2, 8, serious AEs (36.1% vs. 20.9%), primarily pyrexia, were more 9 plus gemcitabine/carboplatin on day 2, 9, every 21 days) frequent in the atezolizumab plus trastuzumab emtansine until disease progression or unacceptable toxicity. The addi- arm than in the trastuzumab emtansine arm. These imma- tion of trilaciclib to gemcitabine/carboplatin in patients with ture survival data in small subgroups of patients do not al- mTNBC did not improve the primary myelosuppression end- low to draw hard conclusions, but also in HER2+-disease points of duration of severe neutropenia in cycle 1 and occur- the PD-L1+ subgroup seems to be more prone to the ben- rence of severe neutropenia (p= 0.70 in both cases). In group efit of adding checkpoint-inhibitors to standard-of-care 2, the use of G-CSF was numerically higher (63.6%) than in treatments.19 group 1 (47.1%) and group 3 (40%). There were no significant differences in ORR (33.3%, 50.0% and 36.7% for groups 1, 2 MONARCHER: ABEMACICLIB WITH and 3 respectively) and PFS (mPFS of 5.7, 9.4 and 7.3 months FULVESTRANT AND TRASTUZUMAB respectively) with addition of trilaciclib to gemcitabine/car- SIGNIFICANTLY IMPROVES PFS AND ORR boplatin. In contrast, with both dosing schedules, there was COMPARED WITH CHEMOTHERAPY AND a significant improvement in OS when trilaciclib was add- TRASTUZUMAB ed to gemcitabine/carboplatin (median OS of 12.6, 20.1 and MonarcHER is a phase II study in which 237 postmenopausal 17.8 months for groups 1, 2 and 3 respectively). Trilaciclib did women with HR+, HER2+ advanced breast cancer were ran- not increase high-grade toxicity when added to gemcitabine/ domly assigned (1:1:1) to arm A (abemaciclib 150 mg orally carboplatin, despite patients having received more cycles of Q12H plus trastuzumab IV infusion Q21D plus fulvestrant therapy (median 7 or 8 cycles) compared with gemcitabine/ 500 mg IM Q28D), arm B (abemaciclib + trastuzumab), or carboplatin alone (median 4 cycles).17,18 Given the differenc- arm C (trastuzumab plus investigator’s choice chemotherapy). es in treatment duration and supportive treatments, the sec- Vinorelbine was most frequently used, followed by capecit- ondary efficacy data of this small phase II trial have to be abine, eribulin and gemcitabine. The gated primary objective interpreted with caution. was to compare investigator assessed PFS of arm A to C and, if positive, then B to C. HER POSITIVE BREAST CANCER After 169 events, the median PFS was longer in arm A vs. KATE2: OVERALL SURVIVAL AND UPDATED C (8.3 vs. 5.7 months; HR[95%CI]: 0.673[0.451-1.003]; SAFETY DATA WITH ATEZOLIZUMAB PLUS p= 0.0253) but there was no difference between arms B TRASTUZUMAB EMTANSINE and C (5.7 vs. 5.7 months; HR[95%CI]: 0.943[0.643-1.383]; Previous results of KATE2 failed to demonstrate a statistically p= 0.385). The ORR in arms A, B and C were reported at significant difference in PFS in patients with HER2-positive 35.4%, 16.5% and 22.8%, respectively. The most common advanced breast cancer treated with atezolizumab (1200 mg) grade 3/4 adverse events in arms A, B, and C were neutro- plus T-DM1 (3.6 mg/kg IV q3w) versus placebo plus T-DM1 in penia (26.9%, 22.1%, and 26.4%), leukopenia (10.3%, 2.6%, the ITT population (median PFS: 8.2 vs. 6.8 months). How- and 9.7%), thrombocytopenia (10.3%, 6.5%, and 2.8%), and ever, the median PFS was numerically longer with combina- diarrhoea (9.0%, 6.5%, and 2.8%).20 This small study shows tion treatment in patients with PD-L1 IC+ disease (median promising potential for the combination of CDK4/6-inhibi- PFS 8.5 vs. 4.1 months). At ESMO 2019, OS data as well as tors, endocrine therapy and trastuzumab, however lack of an

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KEY MESSAGES FOR CLINICAL PRACTICE

1. Checkpoint inhibitors get boots on the ground in early TNBC with first phase III data showing significant improvement of pCR-rates and an early hint of relevant EFS improvement when pembrolizumab was added to platinum-containing chemotherapy, irrespective of PD-L1 status (Dako pharmDx 22C3-assay).

2. Phase III data of ribociclib and abemaciclib confirm the clinically relevant improvement of overall survival when a CDK4/6-inhibitor was added to fulvestrant in metastatic ER+/HER2-negative breast cancer.

3. Similar relative OS benefit with ribociclib in first- and second-line setting in MONALEESA3 suggests that the absolute survival benefit of adding a CDK4/6-inhibitor is higher in first- as compared to second-line setting.

4. In patients with germline BRCA mutations and advanced HER2-negative breast cancer, high dose carboplatin-paclitaxel with and without veliparib is associated with high response rates and long PFS in early line setting. Addition of veliparib results in a significant but small PFS benefit of 1.9 months, but a relevant subset of patients in the combination arm had long-term response. The optimal place of PARP-inhibitors in this patient population remains to be determined.

5. Pembrolizumab monotherapy failed to improve overall survival compared to standard of care chemotherapy in 2nd/3rd line metastatic TNBC, however for some patients with the highest PD-L1 expression there seems to be significant activity in later line.

6. In metastatic HER2-positive disease, there seems to be a synergistic effect between CDK4/6-inhibitors and fulvestrant when added to trastuzumab in a heavily pre-treated setting.

7. Stromal TILs also have a prognostic effect in early TNBC patients not treated with adjuvant chemotherapy.

8. Different PD-L1 assays have different positivity rates, prognostic and predictive implications and are not interchangeable.

arm with fulvestrant-trastuzumab makes it difficult to inter- apy for high-risk breast cancer (BC): Results from I-SPY 2. J Clin Oncol. pret the real value of adding abemaciclib to fulvestrant and 2017;35;(15S); Abstract 506. trastuzumab in this trial. 6. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoad- REFERENCES juvant treatment, followed by pembro vs pbo as adjuvant treatment for early tri- 1. Adams S, Loi S, Toppmeyer D, et al. Pembrolizumab monotherapy for previ- ple-negative breast cancer (TNBC). Presented at ESMO 2019; Abstract LBA8_PR. ously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort 7. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infil- B of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):405-11. trating lymphocytes in a phase III randomized adjuvant breast cancer trial in 2. Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previ- node-positive breast cancer comparing the addition of docetaxel to doxorubicin ously treated metastatic triple-negative breast cancer: cohort A of the phase II with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860- KEYNOTE-086 study. Ann Oncol. 2019;30(3):397-404. 7. 3. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in Patients With Advanced 8. Loi S, Drubay D, Adams S, et al. Tumor-Infiltrating Lymphocytes and Progno- Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. sis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast 2016;34(21):2460-7. Cancers. J Clin Oncol. 2019;37(7):559-69. 4. Schmid P, Park YH, Munoz-Couselo E, et al. Pembrolizumab (pembro) + che- 9. Park J, Jonas S, Dieci M, et al. Prognostic value of tumour infiltrating lympho- motherapy (chemo) as neoadjuvant treatment for triple negative breast cancer cytes (TILs) in patients with early-stage triple negative breast cancers (TNBC) in (TNBC): Preliminary results from KEYNOTE-173. J Clin Oncol. 2017;35(15S); Ab- the absence of chemotherapy. Presented at ESMO 2019; Abstract 175O. stract 556. 10. Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the phase 5. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant ther- III MONALEESA-3 trial of postmenopausal patients (pts) with hormone recep-

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tor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced 16. Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemis- breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Presented at try (IHC) assays in unresectable locally advanced or metastatic triple-negative ESMO 2019; Abstract LBA7_PR. breast cancer (mTNBC): Post-hoc analysis of IMpassion130. Presented at ESMO 11. Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in Combination 2019; Abstract LBA20. With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had 17. O’Shaughnessy J, Wright GS, Thummala A, et al. Trilaciclib improves overall Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017;35(25):2875- survival when given with gemcitabine/carboplatin (GC) in patients with metastat- 84. ic triple negative breast cancer (mTNBC) in a randomized phase II trial. Present- 12. Sledge GW, Toi M, Neven P, et al. MONARCH-2: Overall survival of abemac- ed at ESMO 2019; Abstract LBA22. iclib plus fulvestrant in patients with HR+, HER- advanced breast cancer. Present- 18. Tan AR, Wright GS, Thummala AR, et al. Trilaciclib plus chemotherapy versus ed at ESMO 2019; Abstract LBA6_PR. chemotherapy alone in patients with metastatic triple-negative breast cancer: a 13. Dieras VC, Han HS, Kaufman B, et al. Phase III study of veliparib with carbo- multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019 ; Epub platin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated ahead of print. breast cancer. Presented at ESMO 2019; Abstract LBA9. 19. Emens LA, Esteva FJ, Beresford M, et al. Overall survival (OS) in KATE2, a 14. Cortés J, Lipatov O, Im S, et al. KEYNOTE-119: Phase III study of pembroli- phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab zumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously negative breast cancer (mTNBC). Presented at ESMO 2019; Abstract LBA21. treated HER2+ advanced breast cancer (BC). Presented at ESMO 2019; Abstract 15. Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival 305O. (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study 20. Tolaney SM, Wardley AM, Zambelli S, et al. MonarcHER: A randomized phase of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally ad- II study of abemaciclib plus trastuzumab with or without fulvestrant versus tras- vanced or metastatic triple-negative breast cancer (mTNBC). Presented at ASCO tuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ ad- 2019; Abstract 1003. vanced breast cancer (ABC). Presented at ESMO 2019; Abstract LBA23.

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