2. T cell infiltrate predicts better prognosis in most cancer types
Fridman et al,
Nature Review Cancer, 2012
3. Zhang, et al. N Engl J Med 2003
TIL Absent
40%
CD3+
Stroma
Islet
TIL Present
55%
4. Not all CRC patients have TILs. Why?
Zhang, et al. N Engl J Med 2003
After CR with chemotherapy, only patients
with TILs survive or are in remission long-term
5. Meta-analysis of intraepithelial TIL impact in ovarian cancer:
10 studies; 1,815 patients
Hwang et al, Gynecol Oncol 2011
TIL favors survival
TIL favors death
14. Patients:
• response lasting ≥6 months to first-line platinum therapy
• considered to have PROC per investigator’s assessment (eg, pts not eligible for further platinum)
• ≤ 5 prior treatment lines
• primary platinum-refractory (PRef) disease excluded, not secondary PRef disease
Treatment: niraparib 200 mg orally once daily + pembrolizumab 200 mg IV every 21 days.
Primary and secondary endpoints: ORR = CR+PR and disease control rate (DCR = CR+PR+SD).
Results:
• 60/62 pts evaluable for response assessment (≥1 on-study scan).
• Median age 60 years.
• Median prior lines of chemotherapy 2 (range: 1-5).
• 64% of pts PROC (PFI < 6 months), 19% pts PRef disease (PFI < 30 days), and 17% platinum-sensitive
• 20 pts remain on treatment and 11 have received treatment for ≥6 months.
• 60 evaluable pts, ORR/DCR 25%/68%; 11 tumor BRCA (tBRCA) mut evaluable pts, ORR/DCR were 45%/73%.
• Responses in 11/38 PROC pts, 2/11 PRef pts, and 1/10 PSens pts (platinum status unknown in 1 responder)
Conclusions: With ORR of 25% in all PROC and ORR of 45% in tBRCAmut pts, niraparib + pembrolizumab
appears promising. Additional evaluation of this combination in ROC is warranted. No new safety signals were
identified with the combination
TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib +
pembrolizumab in patients (pts) with advanced triple-negative breast
cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort.
15. An open-label, Phase II basket study of olaparib
and durvalumab (MEDIOLA):
Results in germline BRCA-mutated,
platinum-sensitive relapsed ovarian cancer
Yvette Drew,1 Maja de Jonge,2 Sook-Hee Hong,3 Yeon Hee Park,4 Anita Wolfer,5 Jennifer Brown,6
Michelle Ferguson,7 Martin E Gore,8 Ricardo Alvarez,9 Christopher Gresty,10 Helen Angell,10
Kassondra Meyer,11 Maria Learoyd,10 Mei Tang,12 Mark Lanasa,11 Pia Herbolsheimer11
and Susan M Domchek13
1Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK; 2Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands;
3Seoul St Mary's Hospital, Catholic University of Korea, Seoul, South Korea; 4Samsung Medical Center, Seoul, South Korea; 5Lausanne
University Hospital, University of Lausanne, Lausanne, Switzerland; 6Beatson West of Scotland Cancer Centre, Glasgow, UK; 7NHS
Tayside, Dundee, UK; 8The Royal Marsden Hospital, London, UK; 9Cancer Treatment Centers of America, Augusta University, Augusta,
GA, USA; 10AstraZeneca, Cambridge, UK; 11AstraZeneca, Gaithersburg, MD, USA; 12Medimmune Oncology, Inc., Gaithersburg, MD,
USA; 13Basser Center for BRCA, University of Pennsylvania, Philadelphia, PA, USA
Funded by AstraZeneca; ClinicalTrials.gov number NCT02734004
16. *Patient later achieved a PR after receiving durvalumab + olaparib combination
AE, adverse event; CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease
2
2
2
2
1
1
1
3
3
3
1
1
1
2
3
6
3
4
2
2
1
1
1
1
3
3
3
2
1
1
2
1
On study treatment
CR
PR
SD
PD (RECIST)
NE
Discontinuation due to AE
Discontinuation due to patient decision
Death
Prior lines
of chemo
Time to progression or treatment discontinuation (N=32)
0 28 56 84 112 140 168 196 224 252 280 308 336 364 392 420 448
Study Day
DCR at 12 weeks: 81% (90% CI 66%, 92%)
12 weeks
*
17. multicenter, randomized, phase III JAVELIN Ovarian 200 trial (NCT02580058),
556 patients with platinum-resistant or -refractory ovarian cancer randomized to receive :
• A: avelumab intravenously (IV) at 10 mg/kg every 2 weeks in 4-week cycles
• B: avelumab IV at 10 mg/kg every 2 w in 4-w cycles plus PLD at 40 mg/m2 IV every 4 w in 4-w cycles
• C: PLD at 40 mg/m2 IV every 4 w in 4-w cycles
Patients:
• histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer
• platinum-resistant/-refractory disease
• ≤ 3 lines of systemic therapy
• measurable disease
1° endpoints were superior OS or PFS for one or both avelumab arms versus PLD
2° EP: objective response rate (ORR)
ORR : 13.3% (95% CI, 8.8%-19.0%) for avelumab combined with PLD (Arm B), 3.7% (95% CI, 1.5%-7.5%) for single-agent
avelumab (Arm A), and 4.2% (95% CI, 1.8%-8.1%) for PLD alone
A Study Of Avelumab Alone Or In Combination With Pegylated Liposomal
Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone In Patients
With Platinum Resistant/Refractory Ovarian Cancer (JAVELIN Ovarian
200)
HR for PFS of 0.78, did not meet the prespecified criteria for superiority (repeated confidence interval [RCI], 0.587-
1.244; one-sided P value = .0301).
OS endpoint with the avelumab combination not met (HR, 0.89; RCI, 0.744-1.241; one-sided P value = .2082).
18. International, multicenter, open-label, randomized JAVELIN Ovarian 100 trial (NCT02718417) evaluating
avelumab in combination with and/or following platinum-based chemotherapy in treatment-naïve
patients with locally advanced or metastatic epithelial ovarian cancer (adjuvant)
JAVELIN Ovarian PARP 100 (NCT03642132), an open-label, multicenter, phase III study randomizing
patients with previously untreated advanced ovarian cancer to
1. avelumab plus platinum-based chemotherapy followed by maintenance therapy of avelumab in
combination with talazoparib
2. avelumab plus platinum-based chemotherapy followed by maintenance therapy of Talazoparib
3. chemotherapy plus bevacizumab, followed by bevacizumab maintenance
PAOLA1: first-line treatment, platinum-based chemotherapy plus bevacizumab followed by maintenance
bevacizumab +/- olaparib/placebo
Ongoing studies (not exhaustive)
19. Bevacizumab 15mg/kg q3w
+
atezolizumab 1,200mg q3w
Investigator’s choice
Phase II trial of bevacizumab + aspirin + atezolizumab
in platinum-resistant ovarian cancer: trial design
Optional biopsy Bevacizumab 15mg/kg q3w
+
atezolizumab 1,200mg q3w
+
aspirin 325mg/day
Bevacizumab 15mg/kg q3w
Bevacizumab 15mg/kg q3w
+
atezolizumab 1,200mg q3w
Atezolizumab 1,200mg q3w
Recurrent,
platinum-resistant
ovarian, fallopian
tube or primary
peritoneal cancer
Atezolizumab 1,200mg q3w
+
aspirin 325mg/day
Pre-cycle 3
Continue treatment until PD
1:1:1:1
Upon progression:
continue tumour
assessment q9w until PFS2
Mandatory biopsy
(Anita Wolfer)
Lana Kandalaft
George Coukos
Editor's Notes
Forest plot 1815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71-2.91).
In patients with CD3+ and CD8+ positive TILs, hazard ratios were in the same direction of association, but hazard ratios for the CD3 markers were less significant.41 Therefore intraepithelial CD8+ TILs appear to be the standard for prognostic evaluation of TILs in ovarian cancer.
The PD-1 antagonist nivolumab was tested at 1 or 3 mg/kg every 2 weeks in 18 patients with relapsed platinum-resistant disease regardless of PD-L1 expression; 61% of patients had received >4 prior lines of chemotherapy. There was a 17% overall response rate (ORR) and a 44% disease control rate (DCR=CR+PR+SD), with 2 CR, 1 PR, and 5 patients with SD (Hamanishi et al., 2014).
A phase 1b study tested the PD-1 antagonist pembrolizumab at 10 mg/kg every 2 weeks in 26 patients with heavily treated PD-L1+ ovarian cancer; about 81% of patients had received >4 prior lines of chemotherapy (Varga et al., 2015). The PD-L1 expression rate in pre-screened patients was 51%. There was a durable ORR of 11.5%, and a DCR of 34.6%, with 1 CR, 2 PR, and 6 patients with SD. Seven adverse events of special interest included 5 patients with thyroid dysfunction, 1 with myositis, and 1 with pancreatitis
he PD-L1 antagonist avelumab was given at 10 mg/kg every 2 weeks in a phase 1b study of 75 patients with platinum-resistant or chemotherapy-refractory ovarian cancer regardless of PD-L1 expression; 68% of patients had >3 prior lines of chemotherapy (Disis et al., 2015). Of the 75 patients enrolled, 67 were evaluable for response, with an ORR of 10.7%, and a DCR of 54.7%, with no CR, 8 PR, and 33 patients with SD. The drug was generally well tolerated, with an 8% rate of immune-related adverse events that included 4 cases of hypothyroidism, 1 case of arthritis, and 1 case of myositis. The treatment-related discontinuation rate was 12%. Preliminary analysis suggests that responses may be higher in patients with lower disease burdens, fewer prior lines of chemotherapy, and platinum-sensitive disease. These trends will require confirmation with longer follow-up and future studies. A phase 1 study of another PD-L1 antagonist, BMS-936559, revealed one objective response in 17 ovarian cancer patients (Brahmer et al., 2012).
Nivolumab was tested at 1 or 3 mg/kg every 2 weeks
18 patients with relapsed platinum-resistant disease regardelss of PDL-1 expression
61% of patients had received >4 prior lines of chemotherapy.
17% overall response rate (ORR) and a 44% disease control rate (DCR=CR+PR+SD), with 2 CR, 1 PR, and 5 patients with SD (Hamanishi et al., 2014).
Pembrolizumab:
A phase 1b at 10 mg/kg every 2 weeks in 26 patients with heavily treated PD-L1+ ovarian cancer
81% of patients had received >4 prior lines of chemotherapy (Varga et al., 2015).
The PD-L1 expression rate in pre-screened patients was 51%.
There was a durable ORR of 11.5%, and a DCR of 34.6%, with 1 CR, 2 PR, and 6 patients with SD.
Seven adverse events of special interest included 5 patients with thyroid dysfunction, 1 with myositis, and 1 with pancreatitis.
Avelumab (PD-L1 antagonist)
10 mg/kg every 2 weeks in a phase 1b study of
75 patients with platinum-resistant or chemotherapy-refractory ovarian cancer regardless of PD-L1 expression
68% of patients had >3 prior lines of chemotherapy (
75 patients enrolled, 67 were evaluable for response,
ORR of 10.7%,
DCR of 54.7%, with no CR, 8 PR, and 33 patients with SD.
well tolerated, with an 8% rate of immune-related adverse events that included 4 cases of hypothyroidism, 1 case of arthritis, and 1 case of myositis. The treatment-related discontinuation rate was 12%.
Preliminary analysis suggests that responses may be higher in patients with lower disease burdens, fewer prior lines of chemotherapy, and platinum-sensitive disease.
A phase 1 study of another PD-L1 antagonist, BMS-936559, revealed one objective response in 17 ovarian cancer patients (Brahmer et al., 2012).