Post-ASCO 2017 Cancer du sein Triple Négatif

Post-ASCO 217 Cancer du sein Triple Négatif A.Ladjeroud, K.Bouzid Centre Pierre et Marie Curie- Alger Oran, 3 Septembre 217

Phase III Investigation of Neoadjuvant Carboplatin ± Veliparib in Combination With Chemotherapy in Early-Stage TNBC

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Phase III Study Design Stratified by BRCA status (mut vs no mut vs unknown), node stage (N vs N1-2), AC schedule (Q2W vs Q3W) 12 weeks Previously untreated women with resectable stage II-IIIA TNBC with documented gbrca testing (N = 634) Veliparib + Carboplatin + Paclitaxel (n = 316) Placebo + Carboplatin + Paclitaxel (n = 16) Placebo + Placebo + Paclitaxel (n = 158) Veliparib 5 mg PO BID; carboplatin AUC 6 mg/ml Q3W; paclitaxel 8 mg/m 2 Q1W. Primary objectives: pcr in breast and ipsilateral axillary nodes (ypt/tis, pn) Doxorubicin + Cyclophosphamide (4 cycles) Surgery Secondary objectives: conversion to BCS eligibility, EFS, OS, safety Tertiary objectives: clinical response rate at Wk 12, pcr + MRD, QoL Geyer CE, et al. ASCO 217. Abstract 52.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Pt Characteristics Characteristic Veliparib + Carboplatin + T à AC (n = 316) Median age (range), yrs > 5 yrs, % 51. (26-79) 52.2 Carboplatin + T à AC (n = 16) 49. (23-76) 45.6 T à AC (n = 158) 5. (22-75) 48.7 Deleterious gbrca mutation, % 14.2 15.6 14.6 Tumor stage, % T1 T2 T3-T4a 11.7 72.5 15.8 Lymph node stage N/N1-N2, % 57./43. 57.5/42.5 59.5/4.5 Planned AC schedule Q2W/Q3W, % 54.7/44.3 55./43.8 56.3/43.7 Longest tumor diameter > 3 mm, % 54.1 55.6 5. 12.5 66.9 2.6 9.5 74.1 16.5 Geyer CE, et al. ASCO 217. Abstract 52.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Pts (%) Pts (%) 1 75 5 25 1 75 5 25 V + Cb + T AC (n = 316) P =.357 pcr P <.1 53.2 57.5 31. V + Cb + T AC (n = 316) Cb + T AC (n = 16) Cb + T AC (n = 16) Early TNBC: Efficacy T AC (n = 158) Rate of Clinical Response P <.1 P =.961 83.4 83.3 55.7 T AC (n = 158) Pts (%) Pts (%) 1 1 75 5 25 75 5 25 V + Cb + T AC (n = 73) Rate of Intent for BCS P =.139 P =.132 61.6 44.1 44.1 V + Cb + T AC (n = 268) P =.739 Cb + T AC (n = 34) Rate of MRD P <.1 Cb + T AC (n = 14) T AC (n = 34) 68.3 7. 47.2 T AC (n = 125) Geyer CE, et al. ASCO 217. Abstract 52.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: pcr by Subgroup Favors Cb + T AC Favors V + Cb + T AC Favors T AC Favors V + Cb + T AC All Pts BRCA1 and/or BRCA2 mutation No mutation in BRCA1 or BRCA2 N Lymph node stage N1-2 Q2W AC dose Q3W Risk Difference (95% CI) -4.34 (-13.8 to 5.1) All Pts 6.52 (-18.1 to 31.1) BRCA1 and/or BRCA2 mutation -6.23 (-16.4 to 4.) No mutation in BRCA1 or BRCA2-1.15 (-13.7 to 11.4) N Lymph node stage -8.39 (-22.5 to 5.7) N1-2 -.5 (-13.2 to 12.2) Q2W AC dose -9.15 (-23.3 to 5.) Q3W Risk Difference (95% CI) 22.15 (13.1 to 31.2) 15.61 (-9.4 to 4.7) 23.18 (13.5 to 32.9) 27.96 (15.8 to 4.2) 15.9 (1.7 to 28.5) 25. (12.9 to 37.1) 18.57 (4.9 to 32.2) -5-4-3-2-1 1 2 3 4 5 Risk Difference (95% CI) -5-4-3-2-1 1 2 3 4 5 Risk Difference (95% CI) Geyer CE, et al. ASCO 217. Abstract 52.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: TEAEs TEAE, % Veliparib + Carboplatin + T à AC (n = 313) Carboplatin + T à AC (n = 158) T à AC (n = 157) Any grade 3/4 85.9 84.8 45.2 Any serious 3.4 26.6 14. AE leading to discontinuation of Veliparib/placebo Carboplatin/placebo Paclitaxel Fatal AE.3 Deaths, including non-tx related 2.9 2.5 2.5 5.8 5.4 11.5 Higher incidence of hematologic and gastrointestinal AEs with carboplatin No increase in sensory neuropathy seen with carboplatin 5.7 6.3 7. 2.5.6 2.5 Geyer CE, et al. ASCO 217. Abstract 52.

Heme GI Other Neoadjuvant Chemotherapy + Carboplatin ± Veliparib TEAE in 1% of pts in any arm during T tx segment, % for Early TNBC: TEAEs Veliparib + Carboplatin + T à AC (n = 313) Carboplatin + T à AC (n = 158) T à AC (n = 157) Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Neutropenia 7. 57.2 61.4 53.2 9.5 2.5 Anemia 61. 24.6 69.6 17.1 1.8 Thrombocytopenia 47.9 1.5 37.3 6.3 Leukopenia 12.8 4.2 15.9 5.1 3.8.6 Nausea 6.4 1.3 62. 28.7 Diarrhea 32.3 1.9 26. 1.3 26.1 Vomiting 2.1 1.3 28.4.6 5.1 Stomatitis 19.5 14.6 1.3 9.5.6 Fatigue 51.8 1.3 52.6 1.3 42.7 Peripheral neuropathy 37.7 1. 4.5 4.1 2.5 Myalgia 18.5 16.5 17.8 Arthralgia 1.2.6 1.1 17.8 Geyer CE, et al. ASCO 217. Abstract 52.

Neoadjuvant Chemotherapy + Carboplatin ± Veliparib for Early TNBC: Conclusions Veliparib + carboplatin + T à AC améliore significativement le taux de pcr comparé au T à AC (53.2% vs 31.%; P <.1) L association de veliparib n améliore pas la pcr / carboplatin + T à AC (53.2% vs 57.5%; P =.36). Confirmant le bénéfice du carboplatine Majoration des toxicités hematologiques, digestives par lassociation du carboplatine au taxol ( plus de réductions de dose de taxol) Geyer CE, et al. ASCO 217. Abstract 52.

OlympiAD: PARP Inhibitor Olaparib Monotherapy in HER2-Negative, BRCA-Mutated MBC

OlympiAD: Study Design Randomized, open-label phase III study Stratified by HR status (ER+ and/or PgR+ vs TNBC), prior CT for metastases (yes vs no), prior platinum tx (yes vs no) Pts with HER2-negative MBC with deleterious or suspected deleterious gbrca mutation; previous anthracycline and taxane, 2 previous lines of CT* for metastatic disease; if HR+, not suitable for ET or progressed on 1 ET (N = 32) Olaparib 3 mg PO BID (n = 25) CT on 28-d cycles (n = 97) Until PD or unacceptable AEs *If platinum-based therapy, pt could not have experienced progression on tx in advanced setting or 12 mos since (neo)adjuvant tx. Physician s choice of: capecitabine 25 mg/m 2 PO Days 1-14; vinorelbine 3 mg/m 2 IV Days 1, 8; or eribulin 1.4 mg/m 2 IV Days 1, 8. Primary endpoint: PFS per RECIST 1.1 (BICR) Secondary endpoints: time to second progression/death, OS, ORR, safety, tolerability, global HRQoL Robson ME, et al. ASCO 217. Abstract LBA4. Robson ME, et al. N Engl J Med. 217;[Epub ahead of print].

OlympiAD: Baseline Characteristics Characteristic, n (%) Olaparib (n = 25) CT (n = 97) Characteristic, n (%) Olaparib (n = 25) CT (n = 97) Median age, yrs (range) 44 (22-76) 45 (24-68) Male 5 (2) 2 (2) White race 134 (65) 63 (65) BRCA mutation status BRCA1 BRCA2 Both HR status ER+ and/or PgR+ TNBC Previous CT for metastasis 117 (57) 84 (41) 4 (2) 13 (5) 12 (5) 51 (53) 46 (47) 49 (51) 48 (49) 146 (71) 69 (71) De novo MBC 26 (13) 12 (12) Measurable disease 2 sites Bone metastases only No. CT lines for MBC 1 2 Physician choice CT Capecitabine Eribulin Vinorelbine 167 (82) 159 (78) 16 (8) 66 (33) 8 (39) 57 (28) N/A 66 (68) 72 (74) 6 (6) 31 (32) 42 (43) 24 (25) 41 (45) 34 (37) 16 (18) Previous platinum tx 6 (29) 26 (27) Robson ME, et al. ASCO 217. Abstract LBA4.

OlympiAD: PFS by BICR (Primary Endpoint) PFS (%) 1 9 8 7 6 5 4 3 2 1 Pts at Risk, n Olaparib CT Progression/deaths, n (%) Median PFS, mos 2 4 6 8 1 12 14 16 18 2 22 24 26 28 Mos 25 177 154 17 94 69 4 23 21 11 4 3 2 1 97 63 44 25 21 11 8 4 4 1 1 1 1 Olaparib 163 (79.5) 7. CT 71 (73.2) 4.2 HR:.58 (95% CI:.43-.8; P =.9) Robson ME, et al. ASCO 217. Abstract LBA4.

OlympiAD: PFS2 by Investigator Assessment PFS2 (%) 1 9 8 7 6 5 4 3 2 1 Pts at Risk, n Olaparib CT Second progression/deaths, n (%) Median PFS2, mos 2 4 6 8 1 12 14 16 18 2 22 24 26 28 Mos 25 199 185 152 123 12 75 44 34 18 8 6 5 2 97 85 69 51 42 31 19 1 7 4 1 1 1 Olaparib 14 (5.7) 13.2 CT 53 (54.6) 9.3 HR:.57 (95% CI:.4-.83; P =.33) Robson ME, et al. ASCO 217. Abstract LBA4.

OlympiAD: OS by Investigator Assessment OS (%) 1 9 8 7 6 5 4 3 2 1 Pts at Risk, n Olaparib CT OS data at 46% maturity. Deaths, n (%) Median OS, mos 2 4 6 8 1 12 14 16 18 2 22 24 26 28 Mos 25 25 199 189 178 159 146 19 78 46 3 18 14 8 4 97 92 85 79 74 69 62 5 34 24 13 9 7 4 2 Olaparib CT 94 (45.9) 46 (47.4) 19.3 19.6 HR:.9 (95% CI:.63-1.29; P =.5665) Robson ME, et al. ASCO 217. Abstract LBA4.

OlympiAD: Secondary Efficacy Endpoints PFS Subgroup HR (95% CI) P Value Overall.58 (.43-.8).9 Prior CT No prior CT ER+ and/or PgR+ TNBC Prior platinum No prior platinum.65 (.47-.91).56 (.34-.98).82 (.55-1.26).43 (.29-.63).67 (.41-1.14).6 (.43-.84) Response Endpoint Olaparib CT ORR (BICR), % CR Median TTR, days 47 45 Median DoR, mos 6.2 7.1 6 9 29 2 Longer time to deterioration ( 1 point decrease from BL) with olaparib vs CT for global HRQoL Median: not reached vs 15.3 mos HR:.44 (95% CI:.25-.77; P =.43) Robson ME, et al. ASCO 217. Abstract LBA4.

OlympiAD: Adverse Events Nausea Anemia Vomiting Fatigue Neutropenia Diarrhea Headache Cough Any-Grade AEs in 15% of Pts 58 4 3 29 27 Decreased white blood cells Decreased appetite Pyrexia Increased ALT Increased AST Hand-foot syndrome 21 2 17 16 16 14 11 9 1 26 15 23 22 15 7 21 12 18 18 17 21 35 5 Olaparib CT Anemia Neutropenia Grade 3 AEs in 2% of Pts Decreased white blood cells Fatigue Leukopenia Decreased platelet count Increased AST Dyspnea Headache Hand-foot syndrome 16 9 3 3 2 2 2 1 1 1 3 1 4 3 2 2 1 26 Olaparib CT 75 5 25 25 5 75 AEs (%) 75 5 25 25 5 75 AEs (%) Robson ME, et al. ASCO 217. Abstract LBA4.

OlympiAD: Conclusions Olaparib en monotherapie est associé à une amélioration de PFS vs CT chez les pts traitées pour CS HER-negative, gbrca-mutaté MBC Médiane PFS: 7. vs 4.2 mos (HR:.58; P =.9) Moins de toxicté de grade 3 AEs Grade 3 AEs: 36.6% vs 5.5% with CT This is the first phase III trial showing benefit of oral PARP inhibitor vs active comparator in MBC Robson ME, et al. ASCO 217. Abstract LBA4.

The ABRAZO Trial: Final results of a phase II study of talazoparib (BMN673) following platinum or multiple cytotoxic regimens in Advanced Breast Cancer patients with germline BRCA 1/ 2 mutations

Talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer or MBC pts with germline BRCA1/2 mutations (ABRAZO): May 214-Fev 216 Nicholas Turner, et al. ASCO 217. Abstract 17.

ABRAZO Trial: Patients characteristics Median age 5 (range, 31 75) years ECOG PS of 58% C1: TNBC / HR+ C2: TNBC / HR+ C1: median number of prior cytotoxic regimens C2: median number of prior cytotoxic regimens 59% / 41% 17% / 83% 2 4 Nicholas Turner, et al. ASCO 217. Abstract 17.

ABRAZO Trial: Final results of a phase II study of talazoparib in LA or MBC with BRCA mutation ORR % ORR by IRF for BRCA1 BRCA2 ORR by IRF for TNBC HR+ 24% 34% 26% 29% Nicholas Turner, et al. ASCO 217. Abstract 17.

ABRAZO Trial: Secondary endpoints C1 (n = 48) C2 (n = 35) DOR by IRF, mo (95% CI) CBR 24 by INV, n (% [95% CI]) PFS by INV, mo (95% CI) OS by INV, mo (95% CI) 5.8 (2.8, not reached) 3.8 (2.8, 1.1) 18 (38% [24, 53]) 23 (66% [48, 81]) 4. (2.8, 5.4) 5.6 (5.5, 7.8) 12.7 (9.6, 15.8) 14.7 (11, 24.4) Nicholas Turner, et al. ASCO 217. Abstract 17.

ABRAZO Trial: Safety Common all grade AEs: Anemia (52%), thrombocytopenia (33%), and neutropenia (27%) Fatigue (45%) Nausea (42%), diarrhea (33%) Grade 3 AEs: Anemia (35%), thrombocytopenia (19%), and neutropenia (15%) Non hematological AEs grade 3 did not occur AEs related to TALA led to drug discontinuation in 3 pts (4%) 4 AEs resulted in death, none related to TALA. Nicholas Turner, et al. ASCO 217. Abstract 17.

ABRAZO Trial: Conclusions TALA (Talazoparib) was well tolerated in MBC pts with a gbrca1/2 mutation, exhibiting promising antitumor activity in C1 and C2. TALA vs physician s choice of treatment in gbrca1/2-mutated MBC is being evaluated in the phase 3 EMBRACA trial (NCT1945775) Nicholas Turner, et al. ASCO 217. Abstract 17.

KEYNOTE-86 (Cohort A): Phase II Evaluation of Pembrolizumab Monotherapy in Heavily Pretreated Metastatic TNBC

KEYNOTE-86 (Cohort A): Study Design International, multicohort phase II study mtnbc pts who progressed on 1 prior systemic therapy; ECOG PS -1; LDH < 2.5 x ULN; tumor biopsy sample available for PD-L1 evaluation (N = 17) Pembrolizumab 2 mg IV Q3W (N = 17) For 2 yrs or until PD, unacceptable toxicity, consent withdrawal, or investigator decision u Endpoints Primary: ORR in overall, PD-L1+ pts; safety Secondary: DoR, DCR, PFS, OS in overall, PD-L1+ pts Assessments Tumor imaging: every 9 wks for 1 yr, then every 12 wks Response: RECIST v1.1 by ICR PD-L1 positive: CPS 1% by IHC at central lab Adams S, et al. ASCO 217. Abstract 18.

KEYNOTE-86 (Cohort A): Baseline Characteristics Characteristic *n = 1 pt with unknown PD-L1 status. All Pts (N = 17*) PD-L1 Positive (n = 15) PD-L1 Negative (n = 64) Median age, yrs (range) 53.5 (28-85) 53. (3-85) 55. (28-8) Female, % 1 1 1 ECOG PS 1, % 47.1 51.4 4.6 LDH > 1 x ULN 51.2 48.6 56.2 Postmenopausal, % 82.4 81. 84.4 Visceral ± nonvisceral disease, % Prior taxane, anthracycline, % 95.9 97.1 93.8 Prior (neo)adjuvant therapy, % 83.5 81.9 85.9 Prior lines of therapy, % 1 2 3 31.2 25.3 43.5 34.3 25.7 4. 26.6 23.4 5. Adams S, et al. ASCO 217. Abstract 18.

KEYNOTE-86 (Cohort A): Best Overall Response Response* All Pts (N = 17 ) PD-L1 Positive (n = 15) PD-L1 Negative (n = 64) ORR, % (95% CI) 4.7 (2.3-9.2) 4.8 (1.8-1.9) 4.7 (1.1-13.4) DCR, % (95% CI) 7.6 (4.4-12.7) 9.5 (5.1-16.8) 4.7 (1.1-13.4) Best overall response, % CR PR SD PD.6 4.1 2.6 6.6 Median TTR, mos (range) 3. (1.9-8.1) -- -- Median DoR, mos (range) 6.3 (1.2+ to 1.3+) -- -- Numerically lower ORR in poor prognosis pt subgroups: LDH > ULN, 3 metastatic organ sites, liver metastases, visceral disease 1. 3.8 21. 62.9 *Median follow-up: 1.9 mos. n = 1 pt with unknown PD-L1 status. DCR = SD 24 wks + CR + PR. 4.7 18.8 57.8 Adams S, et al. ASCO 217. Abstract 18.

KEYNOTE-86 (Cohort A): Survival Outcome All Pts (N = 17*) PD-L1 Positive (n = 15) PD-L1 Negative (n = 64) PFS Median, mos (95% CI) Events, n 3-mo rate, % 6-mo rate, % 2. (1.9-2.) 148 25.5 12.3 2. (1.9-2.1) 9 24.2 13.2 1.9 (1.6-2.) 57 26.6 11.1 OS Median, mos (95% CI) Events, n 6-mo rate, % 9-mo rate, % 8.9 (7.2-11.2) 9 69. 49.8 8.3 (6.9-1.5) 58 71. 47.5 1. (6.2-NR) 32 65.4 52.6 *n = 1 pt with unknown PD-L1 status. Adams S, et al. ASCO 217. Abstract 18.

KEYNOTE-86 (Cohort A):OS By Best Overall Response 1 Response Events/Pt, n/n mpfs, Mos (95% CI) 6-Mo PFS, % 9-Mo PFS, % 8 CR or PR /8 Not reached (NR-NR) 1 1 OS (%) 6 4 SD PD 6/35 66/13 Not reached (12.7-NR) 7.1 (6.3-8.8) 1 64.6 89.6 39. 2 2 4 6 8 9 1 12 14 16 Pts at risk, n Mos CR or PR 8 8 8 8 8 4 2 SD 35 35 35 33 29 16 7 1 PD 13 94 72 63 39 2 4 1 Adams S, et al. ASCO 217. Abstract 18. Reproduced with permission.

KEYNOTE-86 (Cohort A): Safety AEs in 5% of Pts, % Treatment related Fatigue Nausea Decreased appetite Hypothyroidism Diarrhea Asthenia Arthralgia Pruritus Any Grade (N = 17) 6. 2.6 1.6 7.6 7.6 7.1 6.5 5.9 5.9 Grade 3/4 (N = 17) 12.4.6.6 1.8 No deaths due to AEs Treatment-related and immune-related AEs led to discontinuation of pembrolizumab in 4.1% and 1.2% of pts, respectively Immune mediated Hypothyroidism Hyperthyroidism Pneumonitis 18.8 11.2 4.7 3.5 1.2.6 Adams S, et al. ASCO 217. Abstract 18.

LOTUS: Investigation of Ipatasertib, a Novel Akt Inhibitor, in Combination With Paclitaxel as Frontline Therapy for Metastatic TNBC

LOTUS: Study Design International, randomized, placebo-controlled phase II trial Stratified by (neo)adjuvant therapy (yes vs no), chemotherapy-free interval (no prior chemo vs 12 mos vs > 12 mos), PTEN status (H-score of vs 1-15 vs > 15) Pts with locally advanced/metastatic TNBC, ineligible for curative resection, ECOG PS /1, no previous systemic tx for advanced or metastatic disease, tumor tissue available for PTEN assessment by IHC, chemotherapy free for 6 mos (N = 124) Coprimary endpoints PFS in ITT population PFS in PTEN-low subgroup Ipatasertib 4 mg QD Days 1-21 + Paclitaxel Days 1, 8, 15 Q28D (n = 62) Placebo Days 1-21 + Paclitaxel Days 1, 8, 15 Q28D (n = 62) Until PD, unacceptable toxicity, or consent withdrawal Secondary and exploratory endpoints ORR, DoR, OS in ITT and PTEN-low pts PFS, ORR, DoR, OS in pts with PIK3CA/AKT1/PTEN-altered tumors Safety, tolerability, PRO Dent RA, et al. ASCO 217. Abstract 19.

LOTUS: Baseline Characteristics Characteristic ITT PIK3CA/AKT1/PTEN Altered Ipatasertib + Paclitaxel (n = 62) Placebo + Paclitaxel (n = 62) Ipatasertib + Paclitaxel (n = 26) Placebo + Paclitaxel (n = 16) Median age, yrs (IQR) 53.5 (44-63) 53 (45-63) 52 (44-63) 53 (46-6) ECOG PS, n (%) 44 (71) 36* (58) 13 (5) 9 (56) Prior (neo)adjuvant tx, n (%) 41 (66) 4 (65) 18 (69) 1 (63) With taxane 31 (5) 34 (55) 12 (46) 7 (44) Time since chemotherapy, n (%) 12 mos > 12 mos No prior chemotherapy 18 (29) 23 (37) 21 (34) 16 (26) 24 (39) 22 (35) 7 (27) 11 (42) 8 (31) 3 (19) 7 (44) 6 (38) PTEN H-score: /1-15/> 15, % 16/44/4 18/44/39 31/23/46 19/38/44 Metastatic site: lung/liver/ln/ bone, % 44/31/58/26 52/27/61/27 5/27/58/19 56/31/75/5 *n = 4 pts missing data. Pts could have 1 site. Dent RA, et al. ASCO 217. Abstract 19.

LOTUS: PFS in ITT and PTEN-Low Populations Ipat + Pac (n = 62) Pbo + Pac (n = 62) Ipat + Pac (n = 25) Pbo + Pac (n = 23) PFS events, n (%) 39 (63) 45 (73) PFS events, n (%) 16 (64) 18 (78) mpfs, mos (IQR) 6.2 (3.6-12.9) 4.9 (1.9-6.5) mpfs, mos (IQR) 6.2 (3.6-1.9) 3.7 (1.9-9.1) Stratified HR (9% CI).6 (.4-.91) Stratified HR (9% CI).59 (.3-1.16) 1 8 Log-rank P value.37 ITT 1 8 Log-rank P value.18 PTEN Low PFS (%) 6 4 Ipatasertib + Paclitaxel (n = 62) Placebo + Paclitaxel (n = 62) PFS (%) 6 4 Ipatasertib + Paclitaxel (n = 25) Placebo + Paclitaxel (n = 23) 2 2 2 4 6 8 1 12 14 16 Pts at Risk, n Mos Ipat + Pac 62 5 31 22 14 11 6 2 1 Pbo + Pac 62 43 23 13 1 6 3 18 2 4 6 8 1 12 14 16 Mos 25 21 12 9 5 4 23 15 8 6 5 3 2 18 Dent RA, et al. ASCO 217. Abstract 19.

LOTUS: PFS in PIK3CA/AKT1/PTEN-Altered Population (Prespecified Secondary Endpoint) PFS (%) 1 8 6 4 2 Pts at Risk, n Ipat + Pac 26 22 Pbo + Pac 16 11 *As determined by NGS assay. Ipatasertib + Paclitaxel (n = 26) Placebo + Paclitaxel (n = 16) PIK3CA/AKT1/PTEN Altered* Ipat + Pac (n = 26) Pbo + Pac (n = 16) PFS events, n (%) 12 (46) 13 (81) mpfs, mos (IQR) 9. (3.7-NE) 4.9 (1.9-6.3) Unstratified HR (9% CI).44 (.22-.87) 2 4 6 8 1 12 14 16 18 Mos 13 7 1 4 7 3 5 2 3 1 1 1 Dent RA, et al. ASCO 217. Abstract 19.

LOTUS: Other Secondary Efficacy Endpoints Outcome ITT PTEN Low PIK3CA/AKT1/PTEN Altered Ipatasertib + Paclitaxel (n = 62) Placebo + Paclitaxel (n = 62) Ipatasertib + Paclitaxel (n = 25) Placebo + Paclitaxel (n = 23) Ipatasertib + Paclitaxel (n = 26) Placebo + Paclitaxel (n = 16) ORR, n (%) 25 (4) 2 (32) 12 (48) 6 (26) 13 (5) 7 (44) Median DoR, mos (IQR) 7.9 (5.6-NE) 7.4 (3.8-9.2) 6.5 (4.4-NE) 7.5 (7.3-NE) 11.2 (5.6-NE) 6.1 (3.8-7.6) CBR,* n (%) 3 (48) 23 (37) 14 (56) 7 (3) 14 (54) 7 (44) *Defined as best overall response (CR, PR, or SD) + PFS 24 wks. Dent RA, et al. ASCO 217. Abstract 19.

LOTUS: Specific AEs AE, n (%) Ipatasertib + Paclitaxel (n = 61) Placebo + Paclitaxel (n = 62) Any Grade Grade 3 Any Grade Grade 3 Diarrhea 57 (93) 14 (23) 12 (19) Peripheral neuropathy 33 (54) 4 (7) 3 (48) 3 (5) Nausea 3 (49) 1 (2) 21 (34) 1 (2) Asthenia 29 (48) 3 (5) 26 (42) 4 (6) Neutropenia 21 (34) 11 (18) 24 (39) 5 (8) Rash 2 (33) 1 (2) 18 (29) 1 (2) Vomiting 17 (28) 2 (3) 14 (23) Oral mucositis 15 (25) 1 (2) 9 (15) 1 (2) Hyperlipidemia 11 (18) 1 (2) 3 (5) 1 (2) Hepatotoxicity 5 (8) 1 (2) 4 (6) 1 (2) Hyperglycemia 5 (8) 3 (5) Pneumonia 3 (5) 3 (5) 1 (2) Pneumonitis 1 (2) Dent RA, et al. ASCO 217. Abstract 19.

LOTUS: Conclusions First-line ipatasertib + paclitaxel improved mpfs vs placebo + paclitaxel in TNBC Greatest PFS benefit observed in prespecified subgroup analysis of pts with PIK3CA/AKT1/ PTEN-altered tumors mpfs: 9. vs 4.9 mos; HR:.44 (9% CI:.22-.87) Most common AE was diarrhea, which was generally manageable and reversible Ipatasertib discontinued due to diarrhea in only 2 pts (3%) Investigators concluded that LOTUS results support further examination of ipatasertib + paclitaxel in diseases with PI3K/Akt pathway activation Pts with PIK3CA/AKT1/PTEN-altered tumors may benefit most Ipatasertib + paclitaxel being evaluated for MBC in phase III trial and as neoadjuvant for TNBC in randomized phase II FAIRLANE trial (NCT231988) Dent RA, et al. ASCO 217. Abstract 19.