Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers
. Biomarkers may facilitate identification of these ...responding tumors
. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer
. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC ...models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC.
This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m
(days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with
/
/
alterations, tumor response, and safety.
Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio HR, 0.74; 95% CI, 0.50 to 1.08; 1-sided
= .06 predefined significance level, 1-sided
= .10). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided
= .04). In patients with
/
/
-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided
= .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13%
1%), infection (4%
1%), neutropenia (3%
3%), rash (4%
0%), and fatigue (4%
0%).
Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with
/
/
-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.
Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. ...Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m
orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.
Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC).
To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and ...circulating tumor DNA (ctDNA) in the ABACUS trial.
ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy.
Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected.
The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements.
The median follow-up time was 25 mo (95% confidence interval CI 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio HR 0.60 95% CI 0.24-1.5, p = 0.26, and 0.72 95% CI 0.31-1.7, p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 95% CI 0.09-0.68, p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 95% CI 1.3-13, p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work.
Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future.
We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
Metastatic papillary renal cancer (PRC) has poor outcomes, and new treatments are required. There is a strong rationale for investigating mesenchymal epithelial transition receptor (MET) and ...programmed cell death ligand-1 (PD-L1) inhibition in this disease. In this study, the combination of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) is investigated.
This single-arm phase II trial explored durvalumab (1,500 mg once every four weeks) and savolitinib (600 mg once daily; ClinicalTrials.gov identifier: NCT02819596). Treatment-naïve or previously treated patients with metastatic PRC were included. A confirmed response rate (cRR) of > 50% was the primary end point. Progression-free survival, tolerability, and overall survival were secondary end points. Biomarkers were explored from archived tissue (MET-driven status).
Forty-one patients treated with advanced PRC were enrolled into this study and received at least one dose of study treatment. The majority of patients had Heng intermediate risk score (n = 26 63%). The cRR was 29% (n = 12; 95% CI, 16 to 46), and the trial therefore missed the primary end point. The cRR increased to 53% (95% CI, 28 to 77) in MET-driven patients (n/N = 9/27) and was 33% (95% CI, 17 to 54) in PD-L1-positive tumors (n/N = 9/27). The median progression-free survival was 4.9 months (95% CI, 2.5 to 10.0) in the treated population and 12.0 months (95% CI, 2.9 to 19.4) in MET-driven patients. The median overall survival was 14.1 months (95% CI, 7.3 to 30.7) in the treated population and 27.4 months (95% CI, 9.3 to not reached NR) in MET-driven patients. Grade 3 and above treatment related adverse events occurred in 17 (41%) patients. There was 1 grade 5 treatment-related adverse event (cerebral infarction).
The combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset.
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Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in ...combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached NR). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3-NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596.
LBA4503
Background: New drug combinations are required in advanced clear cell renal cancer (RCC). These potentially include MET inhibition with savolitinib (S) or CTLA-4 inhibition with tremelimumab ...(T). In this study these agents were given alone or in combination with the PD-L1 inhibitor durvalumab (D). Methods: A multinational open-label randomised phase II study assigning patients to one of D, S, DT or DS was performed. Patients with RCC, who had previously received VEGF targeted therapy but not immune checkpoint inhibitors or MET inhibitors were included. Confirmed response rate (cRR) was the primary endpoint. A response rate of at least 50% was required for further exploration. The S arm was closed early due to a lack of efficacy. DNA alterations were measured using Foundation One and PD-L1 analysis was performed with SP263. This abstract details the pre-planned 12-month interim analyses after the cohort completed randomisation. Results: Between 2017 and 2021, 139 patients were randomised (D N=39, S N=22, DT N=39, DS N=39). The median age was 62 years (range: 28 – 85). cRRs for the 4 arms were D=10%, S=5%, DT=28%, DS=13%, which did not meet the primary objective. cRRs in the MET-driven patients (N=17) were D=0% (0/7), S=0% (0/2), DT=50% (1/2), DS=17% (1/6). cRRs in PD-L1+ves for DT and D were 14% (1/7) and 33% (2/6) respectively. 12-month progression-free survival (PFS) rates were D=26% (80% confidence interval CI: 17% - 36%), S=21% (80% CI: 10% - 35%), DT=33% (80% CI: 24% - 43%), DS=17% (80% CI: 10% - 26%). Median overall survival for D=26.1 (80% CI: 16.2 – 32.0) months, S=23.1 (80% CI: 20.6 – 29.7) months, DT=21.9 (80% CI: 16.3 – 31.5) months, DS=16.1 (80% CI: 10.3 – 18.8) months. There was 1 treatment related death in the DT arm. Of the 136 patients who received treatment, grade 3 or more treatment related adverse events occurred in D=10% (4/39), S=26% (5/19), DT=23% (9/39), DS=23% (9/39). Conclusions: This randomised phase II study did not demonstrate significant efficacy for S alone or in combination with D in RCC. The addition of T to D did not demonstrate clearly superior efficacy to D in this setting. Clinical trial information: NCT02819596.
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Background: There is a strong rationale for investigating MET and PD-L1 inhibition in metastatic papillary renal cancer (PRC). We previously reported response rates (RR) and ...progression free survival (PFS) for savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Here we report overall survival (OS) data available 12 months after the last patient was enrolled. Methods: This single arm phase I/II trial explores durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in PRC, with a 4wk savolitinib run in. Treatment naïve or previously treated patients with metastatic PRC were included. Confirmed RR (RECIST v1.1), PFS, tolerability (CTCAE v4.03) and overall survival (OS) were analysed. MET and PD-L1 biomarkers were explored (NCT02819596). Results: 42 patients were enrolled with 41 receiving at least one dose of study treatment. Safety and efficacy analyses were performed on these 41 patients. The median follow up was 14.3 months. IMDC good, intermediate and poor risk disease occurred in 29%, 63%, and 7% of patients respectively. Overall confirmed RR was 27% while median PFS was 4.9 months (95% CI: 2.5 – 12.0 months). Median OS was 12.3 months (95% CI: 5.8 – 21.3 months). Confirmed RR and median OS in the previously untreated cohort (N=27) were 33% and 12.3 months (95% CI: 4.7 – not reached (NR) months) respectively. Treatment related Grade 3/4 toxicity occurred in 34% of patients. No new safety signals were seen. PD-L1 and MET expression were not associated with higher RR (25% and 40% respectively) or longer OS. Conclusions: The combination of savolitinib and durvalumab has clinical activity in PRC and outcomes were not enhanced in biomarker positive cancers. Clinical trial information: NCT02819596.
Abstract
Background: Whilst Atezolizumab + nab-paclitaxel is the new standard of care in patients with PD-L1+ metastatic triple negative breast cancer (BC), the role of immunotherapy in ER+ BC has ...yet to be defined. ECLIPSE, an open label, phase II trial, aims to evaluate the effect of short-term pre-operative immune-modulatory agent combinations on ER+ tumour immune-phenotypes (NCT03395899). Here, we examined the first results of the dynamic changes of PD-L1 expression (≥1% positive immune cell by VENTANA PD-L1 SP142 IHC) and T-cell expansion and activation after 1 cycle of atezolizumab alone or in combination with AKT, MEK or VEGF inhibitors.
Methods: Patients with histologically confirmed, untreated, operable ER+/HER2- primary BC received 1 cycle of atezolizumab alone or atezolizumab + ipatasertib, atezolizumab + cobimetinib, or atezolizumab + cobimetinib + bevacizumab 3 weeks prior to surgery or neoadjuvant therapy. Biopsies were obtained pre and on completion of study treatment. Dynamic changes in biomarkers were compared in 48 evaluable patients, including 41 paired samples.
Results: PD-L1 IC expression significantly increased after 1 cycle of treatment (p < 0.0001). At a 1% IC cutoff, 21/45 patients (47%) were PD-L1 IC-positive (+) at baseline while 34/44 (77%) were PD-L1 IC + post-treatment. Increased tumour cell expression was also found in post-treatment samples (p < 0.01). All post-treatment PD-L1 negative patients (n = 9) were also negative at baseline. Overall, there was a small but significant increase in CD8 + T-cells post-treatment compared to baseline (p = 0.03). In parallel, the number of T-cells that were positive for both CD8 and granzyme B (GZMB) - a T-cell activation marker - increased substantially (p < 0.01). Single GZMB+ cells and single FOXP3+ cells did not change with treatment. In 2 cases, no tumour was detected post-treatment, suggesting a major pathological response. Baseline biopsies of both patients stood out as having the largest amount of CD8+GZMB+ T-cells. Post-treatment tumour bed profiling of these patients showed major infiltration of CD8+ and CD8+GZMB+ T-cells. Dynamic gene expression analysis showed upregulation of genes related to innate immunity and a cytotoxic T-cell transcriptional signature (tGE8), (p < 0.001). Patients were grouped as immune-responsive or non-responsive based on a dynamic increase of CD8+GZMB+ cells. The immune-response group was characterized by increased IFN response signatures and decreased luminal gene signatures at baseline.
Conclusions: Our data indicate that short-term induction treatment with atezolizumab ± targeted treatments induce dynamic changes toward inflamed immune phenotypes both at the morphological and transcriptional level, in patients with operable ER+/HER2- primary BC. These findings might help identify novel immunotherapy combination strategies in this setting, alongside the most appropriate biomarkers that can aid in identifying patients most likely to benefit from these treatments.
Citation Format: Peter Schmid, Mark Kockx, Sung-Bae Kim, Duncan Wheatley, Melissa Mary Phillips, Oliver Hoffmann, Jens U. Blohmer, Seock-Ah Im, Andreas Schneeweiss, Esther Zamora, Yannick Waumans, Pieter-Jan Van Dam, Dieter Peeters, Akhila Wimalasingham, Patricia Marosics, Aaron Prendergast, Kelly Mousa, Javier Cortes, Sherko Kuemmel. Dynamic changes of PD-L1 and T-cell activation in ECLIPSE: A phase II study investigating preoperative immune combination strategies in untreated, operable ER+ primary breast cancer abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-06.
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