ESMO 2018 - Update Axel Grothey West Cancer Center, U Tennessee - - PowerPoint PPT Presentation
ESMO 2018 - Update Axel Grothey West Cancer Center, U Tennessee Disclosures Consulting activities (honoraria went to the Mayo Foundation or West Cancer Center) Amgen Bayer Pfizer Roche/Genentech BMS Imclone/Eli-Lilly
Axel Grothey West Cancer Center, U Tennessee
(honoraria went to the Mayo Foundation or West Cancer Center)
I WILL include discussion of investigational or off-label use of a product in my presentation.
Lenz et al
mCRC Grothey et al
Cremolini et al
Arkenau et al
Pishvaian et al
Heinz-Josef Lenz,1 Eric Van Cutsem,2 Maria Luisa Limon,3 Ka Yeung Mark Wong,4 Alain Hendlisz,5 Massimo Aglietta,6 Pilar García-Alfonso,7 Bart Neyns,8 Gabriele Luppi,9 Dana B. Cardin,10 Tomislav Dragovich,11 Usman Shah,12 Ajlan Atasoy,13 Roelien Postema,13 Zachary Boyd,13 Jean- Marie Ledeine,13 Michael James Overman,14 Sara Lonardi15
1USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 2University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; 3Hospital Universitario Virgen del Rocio, Sevilla, Spain; 4Westmead Hospital, Sydney, Australia; 5Institut Jules Bordet, Brussels, Belgium; 6Candiolo
Cancer Institute and University of Torino Medical School, Candiolo, Italy; 7Hospital Gral Universitario Gregorio Marañon, Madrid, Spain; 8University Hospital Brussels, Brussels, Belgium; 9University Hospital of Modena, Modena, Italy; 10Vanderbilt – Ingram Cancer Center, Nashville, TN, USA;
11Banner MD Anderson Cancer Center, Gilbert, AZ, USA; 12Lehigh Valley Hospital, Allentown, PA, USA; 13Bristol-Myers Squibb, Princeton, NJ, USA; 14The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 15Istituto Oncologico Vento IOV-IRCSS, Padova, Italy
Presentation number: LBA18_PR
HIGHLY CONFIDENTIAL
efficacy and safety of nivolumab-based therapies in patients with mCRC (NCT02060188)
5 CheckMate-142
aUntil disease progression or discontinuation in patients receiving study therapy beyond progression, discontinuation due to toxicity, withdrawal of consent, or the study end; bPatients with a CR, PR, or SD for ≥12
weeks divided by the number of treated patients; cTime from first dose to data cutoff BICR = blinded independent central review; CR = complete response; CRC = colorectal cancer; DCR = disease control rate; DOR = duration of response; PFS = progression-free survival; PR = partial response; Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q6W = once every 6 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease
confirmed metastatic or recurrent CRC
local laboratory
1L
Nivolumab 3 mg/kg Q2Wa
Previously treated Previously treated
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W (4 doses and then nivolumab 3 mg/kg Q2W)a Nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6Wa
Primary endpoint:
assessment (RECIST v1.1) Other key endpoints:
DOR, PFS, OS, and safety
N=45
Investigator-assessed Nivolumab + ipilimumab N = 45 ORRa, n (%) [95% CI] 27 (60) [44.3–74.3] Best overall response, n (%) CR PR SD PD Not determined 3 (7) 24 (53) 11 (24) 6 (13) 1 (2) DCRb, n (%) [95% CI] 38 (84) [70.5–93.5]
6 CheckMate-142
aPatients with CR or PR divided by the number of treated patients; bPatients with a CR, PR, or SD for ≥12 weeks divided by the number of treated patients
CI = confidence interval
diagnosis of Lynch syndrome
– The ORR and DCR in patients with a BRAF mutation (n = 17) were 71% and 88%, respectively Investigator-assessed Nivolumab + ipilimumab N = 45 ORRa, n (%) [95% CI] 27 (60) [44.3–74.3] Best overall response, n (%) CR PR SD PD Not determined 3 (7) 24 (53) 11 (24) 6 (13) 1 (2) DCRb, n (%) [95% CI] 38 (84) [70.5–93.5]
7 CheckMate-142
*Confirmed response per investigator assessment
aEvaluable patients per investigator assessment
Best reduction from baseline in target lesion (%) Patientsa 75 100 50
* * * * * * * * * * * * * * * * * * * * * * * * * * *
25 –25 –50 –75 –100 –30%
8 CheckMate-142
aResponse per investigator assessment
months (range, 1.2–13.8 months)
– Median DOR was not reached – 82% of responders had ongoing responses at data cutoff – 74% of responders have already had responses lasting ≥6 months – Most responders (96%) were alive at data cutoff
†
†
12 24 36 54 48 72 6 18 30 42 60 66 78 84 On treatment Off treatment First response Censored with
Censored Death Responders (n = 27) a Weeks
9 CheckMate-142
aPer investigator assessment.
mo = month; NE = not estimable; NR = not reached
Nivolumab + ipilimumab
90 80 70 60 50 40 30 20 10 3 6 9 12 15 18 Progression-free survival (%) Months
45 37 34 24 15 7 7 3 6 9 12 15 18 21 Overall survival (%) Months 45 42 40 38 24 13 1 100 90 80 70 60 50 40 30 20 10
PFSa Nivolumab + ipilimumab N = 45 Median PFS, months (95% CI) NR (14.1–NE) 9-mo rate (95% CI), % 77 (62.0–87.2) 12-mo rate (95% CI), % 77 (62.0–87.2) OSa Nivolumab + ipilimumab N = 45 Median OS, months (95% CI) NR (NE) 9-mo rate (95% CI), % 89 (74.9–95.1) 12-mo rate (95% CI), % 83 (67.6–91.7) PFSa Nivolumab + ipilimumab N = 45 Median PFS, months (95% CI) NR (14.1–NE) 9-mo rate (95% CI), % 77 (62.0–87.2) 12-mo rate (95% CI), % 77 (62.0–87.2) OSa Nivolumab + ipilimumab N = 45 Median OS, months (95% CI) NR (NE) 9-mo rate (95% CI), % 89 (74.9–95.1) 12-mo rate (95% CI), % 83 (67.6–91.7)
clinical benefit as a 1L treatment for MSI-H/dMMR mCRC
– High ORR (60%, with 7% CR) – Durable responses (median DOR not reached) – High rate of disease control for ≥12 weeks (84%) – Most patients had a reduction in tumor burden from baseline (84%) – Median PFS and OS not reached with a median follow-up of 14 months – 12-month PFS and OS rates were 77% and 83%, respectively
low rate of discontinuation due to TRAEs (7%)
with MSI-H/dMMR mCRC
10 CheckMate-142
esmo.org
Fluoropyrimidine (FP) and bevacizumab atezolizumab as first-line treatment for BRAFwt metastatic colorectal cancer: findings from the MODUL trial of biomarker-driven maintenance
Grothey A,1 Tabernero J,2 Arnold D,3 de Gramont A,4 Ducreux M,5 O’Dwyer PJ,6 Van Cutsem E,7 Bosanac I,8 Srock S,8 Mancao C,8 Gilberg F,8 Winter J,8 Schmoll H-J9
1West Cancer Center, Germantown, TN, USA; 2Vall d’Hebron University Hospital, Vall d’Hebron
Institute of Oncology (VHIO), Barcelona, Spain; 3Asklepios Clinic Altona, Hamburg, Germany;
4Franco-British Institute, Levallois-Perret, France; 5Gustave Roussy, Villejuif, Université Paris
Saclay, France; 6Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA;
7University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium; 8F. Hoffmann-La
Roche Ltd, Basel, Switzerland; 9Martin-Luther-University, Halle, Germany
12
immunosuppression to promote T-cell infiltration into the tumour
DC, dendritic cell; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell
Atezolizumab
Promotes T-cell activation by allowing B7.1 co-stimulation1
Bevacizumab
Promotes DC maturation2,11,12
Bevacizumab
Normalizes the tumour vasculature, increasing T-cell infiltration2-6
Bevacizumab
Decreases the activity of immunosuppressive cells (MDSCs and Tregs)2,3,7-10
Atezolizumab
Restores anticancer immunity1 with activity further enhanced through VEGF- mediated immunomodulatory effects
Activated T cells Dendritic cells Tumour antigens Tumour cells
13
Cohort 1
BRAFmut
Cohort 2
BRAFwt
R R
5-FU/LV + cetuximab + vemurafenib FP + bevacizumab + atezolizumab FP + bevacizumab FP + bevacizumab Induction treatmenta,b Biomarker-driven maintenance treatment Cohort 3
HER2+
FP + bevacizumab
Capecitabine + trastuzumab + pertuzumab
R
Cobimetinib + atezolizumab FP + bevacizumab Cohort 4
HER2– BRAFwt
R
T R E A T M E N T U N T I L P D Follow-up
aKey eligibility criteria: histologically confirmed mCRC; measurable, unresectable disease (RECIST 1.1); no prior chemotherapy for mCRC; age ³18 years; ECOG PS £2 bPatients with disease progression following Induction treatment can receive further treatment at the discretion of their physician
Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR); duration of response (DoR); change in ECOG performance status; safety FOLFOX + bevacizumab 8 cycles (16w)
FOLFOX + bevacizumab 6 cycles (12w) then 5-FU/LV + bevacizumab 2 cycles (4w) CR PR SD
14
Cohort 1
BRAFmut
Cohort 2
BRAFwt
R R
5-FU/LV + cetuximab + vemurafenib FP + bevacizumab + atezolizumab FP + bevacizumab FP + bevacizumab Induction treatmenta,b Biomarker-driven maintenance treatment Cohort 3
HER2+
FP + bevacizumab
Capecitabine + trastuzumab + pertuzumab
R
Cobimetinib + atezolizumab FP + bevacizumab Cohort 4
HER2– BRAFwt
R
T R E A T M E N T U N T I L P D Follow-up
aKey eligibility criteria: histologically confirmed mCRC; measurable, unresectable disease (RECIST 1.1); no prior chemotherapy for mCRC; age ³18 years; ECOG PS £2 bPatients with disease progression following Induction treatment can receive further treatment at the discretion of their physician
Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR); duration of response (DoR); change in ECOG performance status; safety FOLFOX + bevacizumab 8 cycles (16w)
FOLFOX + bevacizumab 6 cycles (12w) then 5-FU/LV + bevacizumab 2 cycles (4w) CR PR SD
15
FP + bevacizumab + atezolizumab (n=297) FP + bevacizumab (n=148) Patients enrolled (n=696) BRAFwt/BRAF status unknown patients enrolled into Induction Treatment Population in Cohort 2 (n=634) BRAFmut patients enrolled into Induction Treatment Population in Cohort 1 (n=62; 9%)a Randomized into Maintenance Treatment in Cohort 2 (n=445)
First randomization: Aug 2015; last patient randomization: 9 Nov 2016 Clinical cut-off date: 31 May 2017 (primary analysis); 31 May 2018 (updated analysis)
aBRAF mutations were V600; bMain reasons for not being randomized into Maintenance Treatment Population: disease progression, surgery, violation of criteria
Patients screened (n=824) Not randomized into Maintenance Treatment Population (n=189; 30%)b 2:1 ratio
16
OS PFS
FP + bev + atezo FP + bev Median PFS, months 7.20 7.39 Stratified HR (95% CI) 0.96 (0.77–1.20) p=0.727 FP + bev + atezo FP + bev Median OS, months 22.05 21.91 Stratified HR (95% CI) 0.86 (0.66–1.13) p=0.283
FP+bev+atezo FP+bev Time (months) 3 6 9 12 15 18 21 1.00 0.75 0.50 0.25 0.00 297 224 147 103 70 49 29 15 148 109 74 55 29 21 17 6 24 27 30 6 1 3 1 FP + bev + atezo FP + bev Survival probability 297 293 275 244 214 189 164 104 148 142 130 120 108 94 79 49 70 28 8 30 14 5 Time (months) 3 6 9 12 15 18 21 1.00 0.75 0.50 0.25 0.00 24 27 30 33 FP + bev + atezo FP + bev
FP+bev+atezo FP+bev Survival probability
Median duration of induction treatment phase: 4.1 months; for OS, 51% of patients had an event One MSI patient in the FP + bev + atezo arm had a complete response during the maintenance treatment phase
17
FP + bev + atezo (N=293) FP + bev (N=143) Patients with any TEAEs 276 (94.2) 124 (86.7) Diarrhoea 66 (22.5) 19 (13.3) Nausea 57 (19.5) 24 (16.8) Fatigue 46 (15.7) 22 (15.4) Palmar-plantar erythrodysaesthesia syndrome 42 (14.3) 25 (17.5) Hypertension 44 (15.0) 14 (9.8) Arthralgia 39 (13.3) 4 (2.8) Pyrexia 32 (10.9) 13 (9.1) Asthenia 31 (10.6) 11 (7.7) Peripheral sensory neuropathy 30 (10.2) 15 (10.5)
18
and the largest chemo-immunotherapy study in first-line mCRC reported to date
PFS or OS with the addition of atezolizumab to FP/bevacizumab in the BRAFwt first-line maintenance mCRC population
with no new safety signals identified
strategies to circumvent the complex underlying immune escape mechanisms in patients with MSS CRC
TRIBE2: a phase III, randomized strategy study by GONO in the 1st- and 2nd-line treatment of unresectable metastatic colorectal cancer (mCRC) patients (pts)
C.Cremolini, C.Antoniotti, S. Lonardi, D. Rossini, F. Pietrantonio, S.S. Cordio, S. Murgioni, F. Marmorino, E. Maiello, A. Passardi, G. Masi, E. Tamburini, D. Santini, R. Grande, A. Zaniboni, C. Granetto, F. Loupakis, L. Delliponti, L. Boni, A. Falcone
2018 ESMO Congress
Munich, 19 – 23 October 2018
Study design R 1:1
FOLFOX + bev* FOLFOXIRI + bev*
PD1
5FU/bev 5FU/bev
Progression Free Survival 2
FOLFIRI + bev*
PD2
5FU/bev
PD1
FOLFOXIRI + bev*
5FU/bev
PD2
Arm A Arm B
* Up to 8 cycles
Median follow up = 22.8 mos Arm A N = 340 Arm B N = 339 Events, N (%) 235 (69%) 188 (55%) Median PFS2, mos
16.2 18.9 HR = 0.69 [95% CI: 0.57-0.83] p<0.001
Primary endpoint: Progression Free Survival 2
1st line - Safety Profile
G3/4 adverse events, % patients
FOLFOX + bev N = 336 FOLFOXIRI + bev N = 336 p Nausea
3 6 0.140
Vomiting
2 3 0.419
Diarrhea
5 17 <0.001
Stomatitis
3 5 0.299
Neutropenia
21 50 <0.001
Febrile neutropenia
3 7 0.050
Neurotoxicity
1 2 0.505
Asthenia
6 7 0.633
Hypertension
10 7 0.223
Venous thromboembolism
6 4 0.204
1st line – RECIST Response Rate
Best Response, %
FOLFOX + bev N = 340 FOLFOXIRI + bev N = 339 OR [95%CI], p Complete Response 4% 3% Partial Response 46% 58%
Response Rate 50% 61%
1.55 [1.14-2.10], p=0.005
Stable Disease 40% 31% Progressive Disease 7% 4% Not Assessed 3% 4%
1st Progression Free Survival
Median follow up = 22.8 mos FOLFOX + bev N = 340 FOLFOXIRI + bev N = 339 Events, N (%) 288 (85%) 261 (77%) Median PFS, mos
9.9 12.0 HR = 0.73 [95% CI: 0.62-0.87] p<0.001
2nd Progression Free Survival (Patients alive at the time of PD1)
Median follow up = 22.8 mos Arm A N = 276 Arm B N = 242 Events, N (%) 223 (81%) 169 (70%) Median PFS, mos
5.5 6.0 HR = 0.86 [95%CI: 0.70-1.05] p=0.120
Conclusions
ü The
upfront exposure to the three cytotoxics provides a significant advantage when compared with the pre-planned exposure to the same agents in two subsequent lines of therapy
ü Safety, activity and efficacy results reported with FOLFOXIRI/bev are highly
consistent with those from the previous phase III TRIBE study
ü The choice of the first-line therapy plays a crucial role in the treatment of
mCRC patients as it has a major impact on patients’ outcome
esmo.org
Hendrik-Tobias Arkenau,1 Josep Tabernero,2 Kohei Shitara,3 Mikhail Dvorkin,4 Wasat Mansoor,5 Aliaksandr Prokharau,6 Maria Alsina,2 Michele Ghidini,7 Catia Faustino,8 Vera Gorbunova,9 Edvard Zhavrid,10 Kazuhiro Nishikawa,11 Ayumu Hosokawa,12 Doina Ganea,13 Şuayib Yalçın,14 Giordano D Beretta,15 Robert Winkler,16 Lukas Makris,17 Toshihiko Doi,3 David H Ilson18
1Sarah Cannon Research Institute, Cancer Institute, University College London, London, UK; 2Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology,
Barcelona, Spain; 3National Cancer Center Hospital East, Chiba, Japan; 4Omsk Regional Clinical Centre of Oncology, Omsk, Russian Federation; 5The Christie NHS Foundation Trust, Manchester, UK; 6Minsk City Clinical Oncology Dispensary, Minsk, Belarus; 7Azienda Ospedaliera di Cremona, Cremona, Italy; 8Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal; 9N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; 10N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus; 11Osaka National Hospital, Osaka, Japan; 12University of Toyama, Toyama, Japan; 13Spitalul Judetean de Urgenta Sfantul Ioan cel Nou Suceava, Suceava, Romania; 14Hacettepe University, Ankara, Turkey; 15Humanitas Gavazzeni, Bergamo, Italy; 16Taiho Oncology, Inc., Princeton, NJ, USA; 17Stathmi, Inc, New Hope, PA, USA; 18Memorial Sloan Kettering Cancer Center, New York, NY, USA
TAGS: TAS-102 Gastric Studya
– Stratification: ECOG PS (0 vs 1), region (Japan vs ROW), prior ramucirumab (yes vs no) – Sites: 17 countries, 110 sites; enrolment: February 2016 – January 2018 – Data cutoff date: March 31, 2018 – 384 events were targeted to allowed detection of a HR for death of 0.70 with 90% power at 1-sided type 1 error of 0.025
28
BID, twice daily; BSC, best supportive care; ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; ORR, objective response rate; PFS, progression-free survival; QOL, quality of life; R, randomised; ROW, rest of world
aNCT02500043
Endpoints
– OS
– PFS, safety
– ORR – DCR – QOL – Time to ECOG PS ≥2 R 2:1
Patients with mGC
(including GEJ cancer)
– Fluoropyrimidine – Platinum – Taxane and/or irinotecan – HER2 inhibitor, if available, for HER2+ disease – Refractory to/intolerant
Target sample size: 500
FTD/TPI (TAS-102) + BSC (n=337)
35 mg/m2 BID orally on days 1–5 and 8–12 of each 28-day cycle
Placebo + BSC (n=170)
BID orally on days 1–5 and 8–12 of each 28-day cycle
Primary Endpoint – OS
aITT population; bStratified log-rank test
30
FTD/TPI (n=337)a Placebo (n=170)a Events, no. (%) 244 (72) 140 (82) Median, months 5.7 3.6 HR (95% CI) 0.69 (0.56–0.85) One-sided Pb 0.0003 Two-sided Pb 0.0006 20 40 60 80 100
FTD/TPI Placebo 337 124 31 7 1 240 66 11 4 4 3 7 4 9 7 102 80 51 40 22 16 201 161 328 282 170 47 10 101 29 5 2 2 40 34 17 12 9 7 71 60 158 131
FTD/TPI Placebo OS (%) Time (months)
6 12 18 24 25 3 9 15 21 22 23 19 20 16 17 7 8 10 11 13 14 4 5 1 2 12-month OS: 21% 12-month OS: 13%
OS Subgroup Analysis
31
aTwo patients had primary lesions at both sites; this subgroup was not analysed for OS due to insufficient size; bHER2 status was not available for 99 patients;
results for these patients are not shown
(2 vs ≥3), metastatic sites (1 or 2 vs ≥3), and HER2 status (negative vs positive or not done)
228 ≥65 280 ≥3 80 Asian 286 No Ethnicity 357 White Previous gastrectomy 221 Yes 316 1 338 No ECOG PS 191 Prior ramucirumab 169 Yes Gastric 360 226 No Primary sitea 145 GEJ 281 Yes Prior irinotecan HER2 statusb 94 Positive 459 Yes Prior taxane 408 Europe 194 3 73 Japan 123 ≥4 138 Female 367 No 279 <65
227 1–2 Age (years) Sex 369 Male Peritoneal metastases 140 Yes 0.5 1.0 1.5 2.0 2.5 313 Negative 48 No Favours FTD/TPI Favours placebo 0.5 1.0 1.5 2.0 2.5 Patients Variable Subgroup Patients Variable Subgroup HR (95% CI) HR (95% CI) Favours FTD/TPI Favours placebo 70 Other Region 26 USA 190 2
Secondary Endpoint – PFS
32
aITT population; bStratified log-rank test
FTD/TPI Placebo
337 37 4 122 18 32 20 12 9 2 72 60 314 154 170 8 1 21 2 5 2 1 1 1 12 11 145 41 FTD/TPI (n=337)a Placebo (n=170)a Events, no. (%) 287 (85) 156 (92) Median, months 2.0 1.8 HR (95% CI) 0.57 (0.47–0.70) Two-sided Pb <0.0001
PFS (%) Time (months)
20 40 60 80 100 6 12 14 3 9 7 8 10 11 13 4 5 1 2 6-month PFS: 15% 6-month PFS: 6%
FTD/TPI Placebo
Conclusions
and PFS compared with placebo in heavily pretreated patients with advanced gastric or gastroesophageal junction cancer
– 31% reduction in risk of death (HR: 0.69; 95% CI: 0.56–0.85; one-sided P=0.0003; two-sided P=0.0006) – 2.1-month improvement in median OS (5.7 vs 3.6 months)
and lower risk of ECOG PS deterioration to ≥2 (HR: 0.69; 95% CI: 0.56–0.85; two-sided P=0.0005)
with that seen previously in patients with mCRC
– Dosing delays were used more frequently than dose reduction to manage AEs – No new safety signals were observed in patients with mGC
for heavily pretreated patients with advanced gastric or gastroesophageal junction cancer
35
esmo.org
Michael J. Pishvaian,1 Michael S. Lee,2 Baek-Yeol Ryoo,3 Stacey Stein,4 Kyung-Hun Lee,5 Wendy Verret,6 Jessica Spahn,6 Hui Shao,6 Bo Liu,6 Koho Iizuka,6 Chih-Hung Hsu7
1 Georgetown University Medical Center, Washington, DC, USA; 2 UNC Lineberger Comprehensive Cancer Center,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3 Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 4 Yale School of Medicine, New Haven, CT, USA; 5 Seoul National University Hospital, Seoul, South Korea;
6 Genentech, Inc., South San Francisco, CA, USA; 7 National Taiwan University Hospital, Taiwan
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow 37
CTLA-4, cytotoxic T-lymphocyte–associated protein; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; INV, investigator; IRF, independent review facility; mRECIST, modified Response Evaluation Criteria in Solid Tumours; OS, overall survival; PFS, progression-free survival; PS, performance status; q3w, every 3 weeks; TTRP, time to radiographic progression.
a Endpoints per protocol version 5.
At clinical data cutoff (26 July 2018), 103 patients with HCC treated with atezolizumab + bevacizumab were evaluable for safety and 73 patients were evaluable for efficacy with a minimum follow-up of 16 weeks
Until disease progression, unacceptable toxicity or loss
benefit Eligibility Criteria:
anti–PD-1 or anti–PD-L1 therapeutic antibodies Arm A: unresectable or advanced HCC
Atezolizumab 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w n ≈ 100 Arm B: Gastric cancer Arm C: Pancreatic cancer Arm E: Oesophageal cancer Arm F: Randomised first-line HCC (atezolizumab + bevacizumab vs atezolizumab)
Primary endpointsa (Arm A) § Safety and tolerability, INV-assessed ORR per RECIST v1.1 Key secondary endpoints (Arm A) § INV-assessed DOR, PFS and TTRP per RECIST v1.1 § IRF-assessed ORR, DOR, PFS and TTRP (all per RECIST v1.1 and HCC mRECIST) § OS IRF = independent review facility
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow
38 AFP, α-fetoprotein; EHS, extrahepatic spread; HBV, hepatitis B virus; HCV, hepatitis C virus; MVI, macrovascular invasion; TACE, transarterial chemoembolisation.
a Missing data are not included.
Characteristic Safety-evaluable population (N = 103)
Median age (range), years 62 (23-82) Sex, n (%) Male 83 (81) Female 20 (19) Region, n (%)a Asia (excluding Japan) 59 (57) Japan/USA 42 (41) ECOG PS, n (%) 51 (50) 1 52 (50) Child-Pugh class, n (%) A5 76 (74) A6 21 (20) B7 6 (6)
Characteristic Safety-evaluable population (N = 103)
Cause of HCC, n (%) HBV 51 (50) HCV 30 (29) Non-viral 22 (21) EHS, n (%) 73 (71) MVI, n (%) 55 (53) EHS and/or MVI, n (%) 90 (87) AFP, n (%)a < 400 ng/mL 59 (57) ≥ 400 ng/mL 37 (36) Prior TACE treatment, n (%) 56 (54) Prior radiotherapy, n (%) 37 (36)
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow 39
AE, adverse event; AESI, adverse event of special interest; AST, aspartate aminotransferase, TRAE, treatment-related adverse event.
a One Child-Pugh B7 patient developed Grade 4 drug-induced liver injury on Day 8, was treated with prednisone, and recovered. Sepsis
A second patient developed pneumonitis on Day 20, was treated for pneumonitis and pneumonia and died on Day 22 after refusal of further intensive care. b Any grade or cause. Data cutoff: 26 July 2018.
§ No new safety signals were identified beyond the established safety profile for each individual agent
AEs, n (%) N = 103
Any-grade AEs 95 (92) Treatment related 84 (82) Grade 3/4 AEs 41 (40) Treatment related 28 (27) Grade 5 AEs 5 (5) Treatment relateda 2 (2) Serious AEs 36 (35) Treatment related 19 (18) Atezolizumab any-grade AESIs 56 (54) Bevacizumab any-grade AESIs 48 (47) AE leading to withdrawal from Atezolizumab 8 (8) Bevacizumab 10 (10) Both treatments 6 (6)
Most common AEs (≥ 20% of pts), n (%)b N = 103
Decreased appetite 29 (28) Fatigue 21 (20) Rash 21 (20) Pyrexia 21 (20)
Grade 3/4 TRAEs (≥ 5% of pts), n (%) N = 103
Hypertension
10 (10) Grade ≥ 3 atezolizumab AESIs requiring systemic corticosteroids, n (%)
Pneumonitis 2 (2) Encephalitis autoimmune 1 (1) Drug-induced liver injury 1 (1) Colitis 1 (1) AST increased 1 (1) Gamma-Glutamyltransferase increased 1 (1) Diabetes mellitus 1 (1) Pancreatitis 1 (1)
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow 40
+, censored value; DCR, disease control rate; NR, not reached; SLD, sum of longest diameter. Data cutoff: 26 July 2018.
DCR (CR+PR+SD), n/n (%) 56/73 (77) ≥ 16 wks 48/73 (66) ≥ 24 wks 34/73 (47) Median DOR (range), mo NR (1.6+ to 22.0+) ≥ 6 mo, n/n (%) 12/23 (52) ≥ 12 mo, n/n (%) 6/23 (26) Ongoing response, n/n (%) 19/23 (83) Median follow-up, mo 7.2
Change in SLD from Baseline (%) Time (months)
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow 41
+, censored. Data cutoff: 26 July 2018.
n = 73
Median PFS (range), mo 14.9 (0.5 to 23.9+) PFS events, n (%) 29 (40) 6-month PFS, % 65 Median follow-up, mo 7.2
§ The median OS has not been reached (range, 0.8 to 24.0+ mo)
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow 42
+, censored value.
a Four patients (6%) not evaluable or missing. b EHS/MVI baseline data missing from 1 patient.
Data cutoff: 26 July 2018.
ORR
Overall, n/n (%)a 20/73 (27) CR 4/73 (5) PR 16/73 (22) SD 35/73 (48) DCR (CR+PR+SD) 55/73 (75) PD 14/73 (19) By aetiology, n/n (%) HBV 9/36 (25) HCV 9/23 (39) Non-viral 2/14 (14) By EHS/MVI, n/n (%)b EHS and/or MVI 16/64 (25) MVI negative 11/32 (34) EHS negative 8/22 (36) Neither EHS nor MVI 4/8 (50) Median DOR (range), mo NR (1.6+ to 22.0+) ≥ 6 mo, n/n (%) 9/20 (45) ≥ 12 mo, n/n (%) 5/20 (25)
20 40 60 80 100
Maximum SLD Reduction From Baseline (%) CR PR SD PD NE
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow 43
+, censored value.
a Four patients (6%) not evaluable or missing. b EHS/MVI baseline data missing from 1 patient.
Data cutoff: 26 July 2018.
20 40 60 80 100
CR PR SD PD NE
HCC mRECIST takes into account tumour necrosis and includes contrast enhancement in arterial phase imaging
ORR
Overall, n/n (%)a 25/73 (34) CR 8/73 (11) PR 17/73 (23) SD 30/73 (41) DCR (CR+PR+SD) 55/73 (75) PD 14/73 (19) By aetiology, n/n (%) HBV 13/36 (36) HCV 9/23 (39) Non-viral 3/14 (21) By EHS/MVI, n/n (%)b EHS and/or MVI 18/64 (28) MVI negative 15/32 (47) EHS negative 11/22 (50) Neither EHS nor MVI 7/8 (88) Median DOR (range), mo NR (1.6+ to 22.0+) ≥ 6 mo, n/n (%) 10/25 (40) ≥ 12 mo, n/n (%) 5/25 (20)
Maximum SLD Reduction From Baseline (%)
Pishvaian et al: Atezolizumab + bevacizumab in HCC http://bit.ly/2y9y1ow
§ The combination of atezolizumab + bevacizumab was generally tolerable with a manageable safety profile
§ No new safety signals were identified beyond the established safety profile for each single agent
§ The combination of atezolizumab + bevacizumab showed promising activity
§ The confirmed ORR was 32% per INV-assessed RECIST, 27% per IRF-assessed RECIST and 34% per IRF-assessed HCC mRECIST § Responses were observed in all assessed patient subgroups, including aetiology, region, baseline AFP and tumour burden (EHS and MVI) § Responses were durable, with 52% lasting for ≥ 6 months and 26% lasting for ≥ 12 months per INV-assessed RECIST § The confirmed CR was 1% per INV-assessed RECIST, 5% by IRF-assessed RECIST and 11% per IRF-assessed HCC mRECIST
§ Atezolizumab + bevacizumab may become a promising treatment option for patients with unresectable or advanced HCC
§ The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation for atezolizumab in combination with bevacizumab as first-line treatment for patients with unresectable or advanced HCC
44
RECIST, Response Evaluation Criteria in Solid Tumours v1.1.