New directions of immune combination: exploration of PD-L1 inhibitors combined with PARP inhibitors in solid tumors

preface

Immune checkpoint inhibitors (ICIs) are effective in the treatment of a variety of solid tumors
as monotherapy or in combination with other drugs.
Preclinical data and early clinical trials have shown a synergistic effect
when PARP inhibitors are used in combination with ICI.
The JAVELIN PARP Medley trial, which evaluated the safety and efficacy of the PD-L1 inhibitor avelumab in combination with the PARP inhibitor talazoparib in solid tumors, including tumors sensitive to PARP inhibitors or tumors sensitive to ICI, were published today in JAMA Oncology
.

JAVELIN PARP Medley is an open-label, multicenter, phase 1b and 2 basket trial conducted in patients with prospectively selected, molecularly defined, locally advanced or metastatic solid tumors, including non-small cell lung cancer (NSCLC), positive DNA damage response (DDR) NSCLC, triple-negative breast cancer (TNBC), hormone receptor positive, human epidermal growth factor receptor 2 (ERBB2) negative, DDR-positive breast cancer, Recurrent platinum-sensitive ovarian cancer (OC), recurrent platinum-sensitive, BRCA1/2 mutant OC, urothelial carcinoma (UC), metastatic castration-resistant prostate cancer (mCRPC), DDR-positive mCRPC and BRCA/ATM-altered solid tumors
.
The primary endpoint of Phase 1b was dose-limiting toxicity (DLT) and the primary endpoint of Phase 2 was objective response rate (ORR).

Between 31 October 2017 and 7 November 2019, there were 223 patients (mean [SD] age 63.
2 [11.
0] years; 117 [52.
5%] males) were enrolled and treated, including 12 patients in stage 1b and 211 patients
in stage 2.
Due to slow enrollment, the solid tumor cohort with DDR-positive NSCLC and BRCA1/2 or ATM alterations was stopped
early.
The data is as of September 21
, 2020.

Study enrollment flowchart

Dose exploration phase

Of the 12 patients in the Phase 1b study, nine (75.
0%) had mCRPC, two (16.
7%) had TNBC, and one (8.
3%) had OC.

In total, 3 patients (25.
0%) developed DLT, of which 2 (16.
7%) developed grade 3 thrombocytopenia and 1 (8.
3%) developed grade 3 neutropenia
.
This led to the discontinuation of two study drugs and led to the permanent discontinuation of DLT
in 1 patient with neutropenia.
RP2D was identified as intravenous avelumab 800 mg every 2 weeks and oral talazoparib 1 mg
once daily.
One patient with advanced OC achieved a complete response (CR) with a duration of response (DOR) of 31.
9 months at data cut-off and one patient with mCRPC achieved a partial response (PR).

Dose expansion phase

Of the 211 patients in the Phase 2 study, 20 (9.
5%) were still receiving treatment at the time of data cut-off; The most common cause of treatment interruption with avelumab and talazoparib was disease progression (131 patients [62.
1%]).

A total of 108 patients (51.
2%) were male; The median (IQR) age was 65.
0 (56.
0 to 70.
0) years
.
Across all cohorts, the median (range) duration of treatment was 4.
6 (0.
46-24.
4) months for avelumab and 4.
4 (0.
02-24.
9) months
for Tarazoparib.

In the NSCLC cohort, the ORR was 16.
7% (95% CI, 7.
0%-31.
4%)
.
The median DOR was 17.
5 (5.
4-17.
5) months
.
The response was observed in only 1 patient with DDR-positive tumors and 6 patients with DDR wild-type tumors and was not associated with
PD-L1 expression.
In the DDR-positive NSCLC cohort, 2 patients had DDR-negative tumors (enrolled according to original eligibility criteria) and 3 patients had DDR-positive tumors
.
Of the 5 patients in this cohort, a confirmed response was achieved (patients with PD-L1-positive, DDR-negative tumors received PR and response was still ongoing at the time of data cut-off).

In the TNBC cohort, the ORR was 18.
2% (95% CI, 5.
2%-40.
3%) and the median DOR was 11.
1 (3.
4-20.
4) months
.
PR was observed in patients with tumors with BRCA mutations; Patients who obtain CR have PD-L1-positive and DDR-negative tumors
.
In the HR-positive, ERBB2-negative, and DDR-positive BC cohort, the ORR was 34.
8% (95% CI, 16.
4%-57.
3%), and responses were observed in 8 patients with DDR-positive tumors (8/19), including 6 patients with tumors with BRCA1/2
mutations.
The median DOR was 15.
7 (3.
9 to ≥20.
6) months, and the response to 3 BRCA-mutated tumors was still ongoing at the time of data cut-off
.

In the platinum-sensitive BRCA wild-type OC cohort, the ORR was 20.
0% (95% CI, 5.
7%-43.
7%) and the median DOR was 3.
9 (2.
3-5.
5) months
.
Of the 4 patients who responded, 2 also had a CA-125 response
.
In the platinum-sensitive, BRCA-mutant OC cohort, the ORR was 63.
6% (95% CI, 30.
8%-89.
1%)
.
In patients with centrally confirmed BRCA-mutated tumors, the ORR was 70.
0% (95% CI, 34.
8%-93.
3%)
.
After a median follow-up of 16.
1 (95% CI, 12.
7 to 21.
9) months, median DOR was not achieved, ranging from 5.
6 to at least 18.
4 months, with four patients having sustained remission
at the time of data cut-off.
Of the 7 patients who responded, 6 also had a CA-125 response
.

In the UC cohort, the ORR was 15.
0% (95% CI, 5.
7%-29.
8%)
.
The ORR of patients who received previous platinum-based therapy was similar to that of patients who did not (4 patients [14.
3%] vs.
2 patients [16.
7%]).

The median DOR was not reached, ranging from 3.
9 to ≥14.
7 months
.
Patients who obtained CR had a BRCA-mutant PD-L1-negative tumor and were still in CR
at the time of data cut-off.

In the mCRPC cohort, no confirmed response rates were reported; However, PSA responses were observed in 2 of 21 patients (95% CI, 1.
2%-30.
4%), all of whom had unmeasurable lesions
.
In the DDR-positive mCRPC cohort, the ORR of patients with measurable lesions was 11.
1% (95% CI, 0.
0%-16.
1%)
.
In the BRCA1/2 or ATM-altered solid tumor cohort, the ORR was 11.
1% (1 patient received PR); The DOR was 9.
13 months and the median progression-free survival (PFS) was 1.
8 months
.

Efficacy data for the dose exploration phase and the dose amplification phase

security

The most common (≥30%) treatment-related adverse events (TRAEs) of any grade were anaemia (135 patients [60.
5%]), thrombocytopenia (110 patients [49.
3%]), neutropenia (77 patients [34.
5%]), and fatigue (69 patients [30.
9%]
).
Grade 3 or 4 TRAE was observed in more than 5% of patients as anemia (75 patients [33.
6%]), thrombocytopenia (48 patients [21.
5%]), and neutropenia (31 patients [13.
9%]).

。 Seventy-nine patients (34.
5%) had a dose reduction in talazoparib due to adverse events (AEs) (regardless of causation), with the most common cause being hematotoxicity, including anemia (38 patients [17.
0%]), thrombocytopenia (34 patients [15.
2%]), and neutropenia (12 patients [5.
4%]).

Seventeen patients (7.
6%) developed TRAE
that led to discontinuation of any study drug.
In the DDR-positive mCRPC cohort, one patient died of acute respiratory syndrome, which the investigators believe is relevant to
the study treatment.
A total of 29 patients (13.
0%) developed any grade of immune-related AEs; Eight patients (3.
6%) had grade 3 or 4 immune-related AEs
.
A total of 48 patients (21.
5%) have experienced any level of infusion-related reactions; One patient (<1%) experienced a grade 3 or 4 infusion-related reaction
.

brief summary

This non-randomized controlled trial is the largest and most histologically diverse basket trial to evaluate the safety and clinical efficacy
of PARP inhibitors in combination with PD-1/PD-L1 inhibitors in prospective subgroup patients with known biomarkers (BRCA1/2 and DDR status).

The results of the study showed that the combination regimen was well tolerated
.
In DDR-positive NSCLC and unselected NSCLC or UC patients, the addition of talazoparib did not improve the clinical activity
of avelumab.
In PARP inhibitor-sensitive tumor types, most responses occur in patients with BRCA mutations, while activity is limited
in patients with BRCA wild-type, DDR-positive tumors.
One potential reason may be that prior chemotherapy, including platinum-based therapy, cross-resistance may affect the BRCA response
.
In addition, due to the small sample size, it was not possible to assess the association
of mitigation with a single BRCA wild-type DDR gene.
Selecting patients by DDR status may guide future treatment strategies
.

Taken together, this study demonstrates the importance of prospective patient selection in future combined studies of
ICI and PARP inhibitors or other DDR inhibitors.
The potential clinical benefit of avelumab plus talazoparib has been observed in patients with TNBC, HR-positive, ERBB2-negative and DDR-positive BC, and OC with BRCA-altered, and further screening of patients and validation
in randomized controlled trials is needed in the future.

References:

Yap TA, Bardia A, Dvorkin M, et al.
Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial.
 JAMA Oncol.
Published online November 17, 2022.
doi:10.
1001/jamaoncol.
2022.
5228.

Edited by Faline

Typesetting: Faline

Execution: Babel

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