A randomized phase II trial of carboplatin with or without nivolumab in metastatic triple-negative breast cancer

Background: Platinum agents induce DNA crosslinking and cause accumulation of genotoxic stress, which leads to immune activation via IFN-γ signaling, making the combination with nivolumab (PD-1 antibody) an attractive strategy to enhance the benefit of either agent alone in metastatic triple-negative breast cancer (mTNBC). Methods: In this phase II open-label, investigator-initiated, multicenter trial, patients with unresectable locally advanced or mTNBC treated with 0-1 prior lines of chemotherapy in the metastatic setting were randomized 1:1 to carboplatin (AUC 6) with or without nivolumab (360 mg) IV every 3 weeks. Stratification factors included: germline BRCA (gBRCA) status, prior neo/adjuvant platinum, and number of prior lines of metastatic therapy. After approval of PD-L1 inhibition for mTNBC, the study was amended to include first-line mTNBC only and PD-L1 status was added as a stratification factor. Patients randomized to carboplatin alone were allowed to crossover at progression to receive nivolumab (+ nab-paclitaxel post-amendment). The primary objective was to compare progression-free survival (PFS) per RECIST 1.1 criteria of carboplatin with or without nivolumab in first-line mTNBC in the S intent-to-treat (ITT) population. Key secondary objectives were objective response rate (ORR), overall survival (OS), clinical benefit rate, and duration and time to objective response. PD-L1 status was confirmed centrally using the SP142 Ventana assay (positive, ≥1% IC). Paired researchbiopsies at baseline, on-treatment and at progression were performed, if safely accessible. The trial closed to accrual prior to reaching target accrual due to approval of PD-1 inhibition in combination with platinum-based chemotherapy for PD-L1+ mTNBC. Results: Between 1/30/2018 and 12/9/2020, 78 patients enrolled. Three patients did not receive protocol treatment, and the safety analysis was conducted among the 75 that received any treatment;37 received carboplatin + nivolumab (Arm A), 38 received carboplatin alone (Arm B). Median age was 59.1 yrs (range: 25.4-75.8). Four patients (5.3%) had a known gBRCA1/2 mutation. Sixty-two (82.7%) patients received 0 prior lines (ITT population) and 13 (17.3%) 1 prior line of metastatic therapy. Sixty-seven patients (89.3%) experienced any grade ≥2 treatment-related adverse event (AE). The most frequent AE were platelet count decrease (n=40;53.3%), anemia (n=36;48.0%), neutrophil count decrease (n=33;44.0%) and fatigue (n=24;32.0%). Grade 3/4 AE were observed in 46 (61.3%) patients, and there was one grade 5 AE (COVID19 pneumonia). Any grade ≥2 immune-related AE (irAE) were observed in 25 of the 37 (67.6%) patients treated with carboplatin + nivolumab. Grade 3/4 irAE were observed in 11 (29.7%) patients. In the ITT population (32 on Arm A;30 on Arm B), median PFS was 4.2 months with carboplatin + nivolumab, and 5.5 months with carboplatin (stratified HR 0.98, 95% CI [0.51-1.88];p=0.95). ORR was 25% vs. 23.3%, respectively. At a median follow-up of 23.5 months, median OS was 17.5 months vs. 10.7 months (stratified HR 0.63, 95% CI [0.32-1.24];p=0.18). In patients with PD-L1+ mTNBC (13 on Arm A;11 on Arm B), median PFS was 8.3 months and 4.7 months, respectively (stratified HR 0.63, 95% CI [0.21-1.89];p=0.41). ORR was 23.1% vs. 27.3%, respectively. Median OS was 17.5 months vs. 9.6 months (stratified HR 0.59, 95% CI [0.20-1.75];p=0.34). Conclusions: Addition of nivolumab to carboplatin in patients with previously untreated mTNBC, unselected by PD-L1 status, did not significantly improve PFS. A trend toward improved PFS and OS was observed in patients with PD-L1+ mTNBC. Tissue, blood and intestinal microbiome biomarker analyses are planned;bulk tumor and single-cell sequencing, and TCR sequencing in peripheral blood are ongoing.

Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the far-reaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

Validation of a predictive model forpotential response to neoadjuvant endocrine therapy(NET) in postmenopausal women with clinical stage II orIII estrogen receptor positive (ER+) and HER2 negative(HER2-) breast cancer (BC): An ALTERNATE trialanalysis (Alliance A011106)

Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promotebreast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NETutility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effectivetreatments. Dowsett et al. recently demonstrated that baseline levels of ER, progesterone receptor (PR), Ki67(>15% vs ≤15%), and Ki67 (>10% vs ≤10%) 2-4 weeks (wks) after starting NET may improve appropriate patient(pt) selection for NET (PMC7280290). The ER, PR and Ki67-based prediction model divides pts with primaryER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER <6or ER 6 and PgR <6), (Group 2) NET may be appropriate and a biopsy for on-treatment Ki67 analysis may beconsidered after 2-4 wks of NET (2A: ER 7 or 8 and PgR <6 and 2B: ER 6 or 7 and PgR ≥6) given that on-treatment Ki67 >10% has been associated with worse outcome (PMC5455353), or (Group 3) NET is appropriate (ER 8 andPgR ≥6). The ALTERNATE trial ( NCT01953588 ) randomized postmenopausal women with clinical stage II or III,ER+ (Allred score 6-8)/HER2- BC to receive anastrozole (ANA), fulvestrant (FUL), or ANA + FUL for 6 months,unless Ki67 was >10% on wk 4 or 12 biopsy, in which case pts were triaged to receive neoadjuvant chemotherapy(NCT) or surgery. As previously reported, the ET-sensitive disease (mPEPI 0 plus pCR) rates were similar acrossthe treatment arms and overall 22% (286 of 1,299) pts had Ki67 >10% at wk 4 or 12. The ALTERNATE trialtherefore provides a large independent data set to evaluate the NET appropriateness model. Results: Among 1,299 eligible pts randomized to receive 6 months of NET, 214 were excluded due to absent HRAllred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of theremaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-studyKi67 >10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141of 468), and Group 3 17% (104 of 607) ( Table 1 ). Among the 1,075 pts in Groups 2 and 3, 260 (24%) pts had Ki67≤15% at baseline (BL), among whom only 14 (5.4%) had Ki67 >10% at wk 4, compared to 231 of the 815 (28.3%)who had BL Ki67 >15% and subsequent Ki67 >10% at wk 4. 2% of pts who remained on NET due to on-treatmentKi67 <10% had PD. Response and PEPI-0 rates by group will be reported. Conclusion: ALTERNATE trial data support a model whereby levels of ER, PR and Ki67 at diagnosis can be usedfor the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. Whenbaseline ER Allred scores are >6 and Ki67 ≤15%, there is a low likelihood of ET-resistant disease. When BL Ki67 is>15%, ET sensitivity is variable, and on-treatment biopsy for Ki67 may assist in triaging regarding NETappropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67was <10%. (Table Presented).

IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer

Background: Based on findings from IMpassion130, international guidelines now recommend atezolizumab (A) + nab-paclitaxel (nP) for patients (pts) with locally advanced or metastatic TNBC (mTNBC) whose tumours express PD-L1 on tumour-infiltrating immune cells (IC). Here we report prespecified final OS and long-term safety results. Methods: The study design and final PFS analysis have been reported (Schmid NEJM 2018). Pts were randomised 1:1 to A + nP or placebo (P) + nP. Co-primary endpoints were PFS (tested in parallel in ITT and PD-L1+ pts) and OS (tested hierarchically in ITT and, if significant, in PD-L1+ pts). Results: As of 14 April 2020, 666/902 pts (73.8%) had died;median OS follow-up was 18.8 mo (IQR, 8.9-34.7 mo). 6% of pts in the A + nP arm and 2% in the P + nP arm remained on any treatment. OS data are in the Table. 460 A + nP arm pts and 430 P + nP arm pts were safety evaluable, of whom 8% and 3%, respectively, received nP for up to 24 mo. Similarly, 5% in the A + nP arm received nP for ≥ 24 mo (vs 1% in the P + nP arm). Respectively, 51% vs 43% had a G 3-4 AE;≈ 1% per arm had a G 5 AE (no new G 5 AEs since last analysis;no patterns seen);24% vs 19% had a serious AE, and 59% vs 42% had an AE of special interest (G 3-4 in 8% vs 5%). No confirmed or suspected COVID-19 AEs were reported. 19% in the A + nP arm and 8% in the P + nP arm had an AE leading to treatment discontinuation (most commonly due to neuropathy);in 18% and 8%, respectively, AEs led to nP discontinuation, and in 8% and 1%, AEs led to A or P discontinuation. Conclusions: While OS differences for A + nP vs P + nP in the IMpassion130 ITT population were not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed in PD-L1+ pts (7.5-mo median OS improvement). A + nP remained safe and tolerable with longer follow-up. Results from this final and mature OS analysis are consistent with prior interim analyses. [Formula presented] Clinical trial identification: NCT02425891. Editorial acknowledgement: Medical writing assistance for this abstract was provided by Ashley J. Pratt, PhD, of Health Interactions, and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd. Funding: F. Hoffmann-La Roche, Ltd. Disclosure: L.A. Emens: Honoraria (self): AbbVie, Amgen, Celgene, Chugai, Gritstone, MedImmune, Peregrine, Shionogi, Syndax;Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca, Bayer, MacroGenics, Replimune, Vaccinex;Travel/Accommodation/Expenses: Bristol Myers Squibb, Genentech/Roche, Novartis;Research grant/Funding (institution): Aduro Biotech, AstraZeneca, The Breast Cancer Research Foundation, Bristol Myers Squibb, Bolt Therapeutics, Corvus, The US Department of Defense, EMD Serono, Genentech, Maxcyte, Merck, The National Cancer Institute, The NSABP Foundation, Roche, The Transl;Licensing/Royalties: Aduro;Advisory/Consultancy: Roche. S. Adams: Research grant/Funding (institution): Genentech;Research grant/Funding (institution): Merck, Amgen, BMS, Novartis, Celgene, Daiichi Sankyo. C.H. Barrios: Advisory/Consultancy: Boehringer- Ingelheim;Advisory/Consultancy: GSK;Advisory/Consultancy, Research grant/Funding (institution): Novartis;Advisory/Consultancy, Research grant/Funding (institution): Pfizer;Advisory/ Consultancy, Research grant/Funding (institution): Roche/Genentech;Advisory/Consultancy: Eisai;Advisory/Consultancy, Research grant/Funding (institution): Merck;Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca;Non-remunerated activity/ies: Bayer;Research grant/ Funding (institution): AbbVie;Research grant/Funding (institution): Amgen;Research grant/Funding (institution): Astellas;Research grant/Funding (institution): BMS;Research grant/Funding (institution): Celgene;Research grant/Funding (institution): Lilly;Research grant/Funding (institution): Medivation;Research grant/Funding (institution): Sanofi;Research grant/Funding (institution): Taiho Pharmaceutical;Research grant/Funding (institution) Mylan;Research grant/Funding (institution): Merrimack;Research grant/Funding (institution): Biomarin;Research grant/Funding (institution): Daiichi Sankyo;Research grant/Funding (institution): Abraxis BioScience;Research grant/Funding (institution): AB Science;Research grant/Funding (institution): Asana BioSciences;Research grant/Funding (institution): Exelixis, Research grant/Funding (institution): ImClone Systems, Research grant/Funding (institution): LEO Pharma;Research grant/Funding (institution): Millennium;Advisory/Consultancy: Merck Sharp and Dohme;Advisory/Consultancy: AstraZeneca. V.C. Dieras: Honoraria (self), Advisory/Consultancy: Roche/Genentech, Pfizer, Lilly, Novartis, Daiichi Sankyo, AstraZeneca, AbbVie, Seattle Genetics, Odonate, MSD. H. Iwata: Honoraria (self), Advisory/Consultancy: Chugai;Honoraria (self), Advisory/Consultancy: Novartis, AstraZeneca, Pfizer, Lilly, Daiichi-Sankyo, Eisai, Kyowa Kirin;Non-remunerated activity/ies: MSD, Bayer, BI, Nihon, Kayaku, Sanofi. S. Loi: Research grant/Funding (institution), Non-remunerated activity/ies: Novartis, BMS, Roche-Genentech, Merck;Research grant/Funding (institution): Puma, Eli Lilly, Pfizer;Unpaid consultant: Seattle Genetics;Unpaid consultant: Pfizer;Unpaid consultant: Novartis;Unpaid consultant: BMS;Unpaid consultant: AstraZeneca;Unpaid consultant: Roche/Genentech;Advisory/Consultancy (institution): Aduro Biotechnology. H.S. Rugo: Research grant/Funding (institution): Pfizer, Novartis, Lilly, Genentech/Roche, Merck, OBI, Eisai, Plexxikon, Immunomedics;Research grant/Funding (institution), Travel/Accommodation/Expenses: Macrogeneics, Daiichi;Travel/Accommodation/Expenses: Puma, Mylan, Genentech/Roche, Novartis, Pfizer;Honoraria (self): Celltrion. A. Schneeweiss: Research grant/Funding (institution): Celgene, Roche, AbbVie, Molecular Partner;Advisory/Consultancy: Roche AstraZeneca;Travel/Accommodation/Expenses: Celgene, Roche, Pfizer;Honoraria (self): Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly. E.P. Winer: Honoraria (self): Lilly, Genentech, Infinite MD, Carrick Therapeutics, GSK, Jounce, Genomic HEalth, Merck, Seattle Genetics;Honoraria (self), Leadership role: Leap. S. Patel: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. V. Henschel: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. A. Swat: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. M. Kaul: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. L. Molinero: Shareholder/Stockholder/Stock options, Full/Part-time employment: F. Hoffmann-La Roche. S.Y. Chui: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech/Roche. P. Schmid: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Spouse/Financial dependant, spouse – consulting for Genentech: Roche;Honoraria (self): Medscape;Honoraria (self), Advisory/Consultancy: AstraZeneca;Honoraria (self): GI Therapeutics;Honoraria (self): Health Interactions;Advisory/Consultancy: Pfizer;Advisory/Consultancy, Research grant/Funding (institution): Novartis;Advisory/Consultancy: Merck;Advisory/Consultancy: Boehringer Ingelheim;Advisory/Consultancy: Bayer;Advisory/Consultancy: EISAI;Advisory/Consultancy: Celegence;Advisory/Consultancy: Puma;Research grant/Funding (institution), Spouse/Financial dependant, spouse – consulting for Genentech: Genentech;Research grant/Funding (institution): Oncogenex.