Phase II Open-label Randomized Study of Pembrolizumab with or without Bevacizumab in Platinum-resistant Recurrent/Metastatic Nasopharyngeal Carcinoma (R/M NPC)

Background

• Patients with platinum-resistant (Pt-R) R/M NPC have poor prognosis. 

• In these patients, pembrolizumab is not superior to chemotherapy. 

• VEGF is overexpressed in NPC and suppresses anti-tumour immune response; prior single arm studies show impressive tumour response with anti-VEGF and anti-PD1 combination. 

Aim

To compare the efficacy of pembrolizumab with bevacizumab priming vs pembrolizumab in NPC.

Methods

• Patients with Pt-R R/M NPC were randomized 1:1 to 3-weekly pembrolizumab 200mg (Arm A) or with bevacizumab 7.5mg/kg administered 1 week prior to each dose (Arm B), till progression (PD), intolerance, or up to 2 years. 

• Crossover was allowed from Arm A to Arm B at PD. 

• Primary endpoint - Tumor response (ORR) assessed by RECIST 1.1 based on intention to treat. 

• Secondary endpoints - Safety, progression-free survival (PFS) and overall survival (OS). 

• Translational studies were done on serial tumour and blood sampling to determine the immunophenotypic effects of treatments.

Results

• N= 48 patients 

• Median follow-up was 28.3m (IQR: 15.9-55.9).

• Arm B had higher ORR (58.3% vs 12.5% [95% CI for difference: 18.8-72.9, p<0.001]), and longer PFS (median of 13.8m vs 1.6m [HR 0.25, 95% CI 0.13-0.50, p<0.001]) than Arm A. 

• mOS - 18.5m vs 11.7m (HR 0.62, 95% CI 0.29-1.30, p=0.101) 

• Grade 3 adverse events (AEs) - 25% (6/24) vs 8.3% (2/24) in Arms B and A respectively. 

• Incidence of immune related AEs was similar with no grade 4-5 AEs. 

• More patients in Arm B had >80% reduction in baseline plasma EBV DNA during treatment (70.8% vs 21.1%, p=0.001). 

• 13 patients crossed from Arm A to Arm B: 5 (38.5%) had PR, 5 (38.5%) had SD, with median PFS of 5.0m (95% CI 2.8m-NR). 

• Multiplex IHC of tumour showed dramatic increase in density of CD4+ and PAX5+ B cells 8 days after bevacizumab in the good responders with more modest CD8+ T cells. 

• Arm B had increased immune cell infiltrate after 2 cycles of treatment compared with Arm A.

Conclusions

Bevacizumab and pembrolizumab is tolerable and more efficacious than pembrolizumab alone in Pt-R NPC. Mechanistically, bevacizumab enhances immune cell infiltration, specifically humoral immune responses.

Reference

Annals of Oncology (2024) 35 (suppl_2): S613-S655. 10.1016/annonc/annonc1594

Progression-free Survival 2 (PFS2) as a Surrogate for Overall Survival in a Multicentric Real-world Data Cohort of Glioblastoma (GBM)

Background

• GBM is the most common and aggressive primary brain tumor (pBT) with almost unavoidable recurrence. 

• Unfortunately, many late-stage clinical trials fail to replicate preliminary results from early-stage trials, especially important in first-line due to pseudoprogression. 

Aim

To compare the association between OS, PFS and PFS2 calculated from the start of initial treatment to the time of disease progression on subsequent therapy, which appears to have a stronger correlation with OS. Also, to analyze the impact of different treatments after disease progression and the presence of actionable mutations in PFS2.

Methods

• GBM patients (pts) included in an observational cohort from 7 Spanish institutions with next-generation sequencing performed between 2018 and 2022 were analyzed. 

Results

• N= 405 GBM pts 

• Most pts were treated with conventional TMZ and radiation. 

• Second-line chemotherapeutic agent was administered to 378 pts. 

• mOS – 25 mo (High mOS probably related to the temporal selection bias due to NGS)

• mPFS – 12 mo 

• mPFS2 - 16 mo

• Correlation coefficient between OS and PFS was 0.8 (95% CI, 0.75-0-84), while for PFS2, it was 0.85 (95% CI, 0.81-0,88). 

• A significant difference was found between Tier I-II and III-IV in terms of mPFS2 (25 vs 16 mo, HR 2.06, p 0.025). 

• mOS was not reached in tier I-II patients and resulted 25 mo in tier III-IV. 

• mPFS2 between second-line options – 

• Bevacizumab - 13 mo 

• Lomustine - 9.7 mo

• Irinotecan plus Bevacizumab - 12 mo 

• Temozolomide - 18 mo

Conclusion

PFS2 has a stronger correlation with OS than PFS and may be influenced by the chosen second-line therapy, especially when patients with ESCAT I-II molecular alteration only have access to targeted treatment at relapse, thus PFS2 could potentially be used when the choice of first-line therapy may bias the assessment of PFS.

Reference

Annals of Oncology (2024) 35 (suppl_2): S406-S427. 10.1016/annonc/annonc1587

Final Results of Glasdegib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib/II GEINO 1602 Trial.

Background

• Hedgehog pathway has been implicated in resistance against anticancer therapies in glioblastoma (GB). 

• A phase I/II trial was developed with glasdegib (GLG), a SMO inhibitor, in patients with recent diagnosis of GB to improve the efficacy of Stupp scheme. 

• A biomarker study is underway.

Aim

• The primary objective in phase II was 15m overall survival (OS) rate. 

• The study established a futility threshold of 60% for 15m OS to consider the trial positive; accrual required: 70 evaluable pts in Phase II. 

• Biomarkers of Hedgehog pathway, Sonic Hedgehog signaling molecule, GLI1, SMO and the stem cell marker CD133 have been validated in samples of 65 pts.

Methods

• These are the final survival results of the GEINOGLAS phase I/II trial with longer follow-up. 

• Newly diagnosed GB patients (pts) received GLG with standard STSC, radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with GLG monotherapy. 

• The recommended phase II dose (RP2D) was established at 75 mg/QD of GLG. 

Results

• Between 2018 and 2021, 79 GB pts were enrolled, and 74 pts received GLG at 75mg/QD. 

• Median age - 55 years (range: 28-78)

• Male - 54% 

• MGMT methylated - 43.2% 

• At data cutoff (Feb 2024), 58 (78.4%) pts were dead.

• 15m OS rate - 52.1% (95% CI: 41.7-65.2)

• mOS - 15.3 m (95%CI: 14-20)

• 2 years OS rate - 29.2% 

• Risk of death was lower for pts with MGMT methylation (HR: 0.38; 95% CI: 0.21-0.67) and complete resection (HR: 0.16; 95% CI: 0.06-0.41) at multivariable analysis. 

• mPFS - 7.1 mo (95% CI: 6.2-8.6). 

• Performance and neurological status were maintained throughout the study. 

• No new safety alerts

• Biomarkers are needed to identify those subgroups of patients with longer survival and also to understand the role of the hedgehog pathway and cancer stem cells in this disease.

Conclusion

The addition of GLG to standard STSC was administered safely and showed preliminary efficacy for newly diagnosed GBM, with almost 30% pts still alive at data cutoff despite the futility threshold not being surpassed. Translational research will help to define the molecular traits of long-term survivors.

Reference

Annals of Oncology (2024) 35 (suppl_2): S406-S427. 10.1016/annonc/annonc1587

Detection of Circulating Tumor DNA (ctDNA) in Cerebrospinal Fluid (CSF) in Patients with Glioblastoma Treated in Phase I Clinical Trial

Background

• As ctDNA has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. 

• However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. 

• Thus, cerebrospinal fluid (CSF) has emerged as a potential source of ctDNA in the context of brain tumors. 

Aim

To evaluate the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. 

Methods

• CSF samples were done at C2D15 and at progression, after patient’s oral and written consent. 

• CSF was collected by lumbar puncture after local anesthesia and analyzed, after DNA extraction, with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. 

• Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel.

Results

• Between January and April 2024, 5 patients, one woman and four men, aged from 46 to 55 years, were included. 

• All underwent surgical resection at diagnosis, and received ≥1 previous systemic treatment associated with radiotherapy. 

• ≥1 somatic mutation was identified in each of the 5 patients, including EGFR amplification in 2/5 patients (40%). 

• CSF was not available at baseline. 

• 1 patient provided CSF only at progression. 

• 4 patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. 

• At data cut-off, one patient was still on treatment. 

• detectable level of CSF-ctDNA was identified in only 1 patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. 

• The blood analysis of this patient showed only clonal hematopoiesis variants.

Conclusion

It was shown in this small cohort of patients that detection of CSF-ctDNA is technically feasible in clinical practice. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.

Reference

Annals of Oncology (2024) 35 (suppl_2): S406-S427. 10.1016/annonc/annonc1587

Final Results: Randomized Assessment of Cisplatin Dosing Interval for Ototoxicity (RADIO) Trial Comparing Chemoradiation (CRT) with Cisplatin q3weekly to Weekly for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LASCCHN).

Background

• Most patients (pts) with HPV-related oropharyngeal cancer will be cured and live with long-term adverse effects of their treatment.

Aim

To test the hypothesis of less permanent hearing loss with cisplatin given weekly versus q3weekly with RT for LASCCHN in a randomized clinical trial. 

Methods

• Eligible adult LASCCHN pts were planned for curative intent CRT, considered suitable for q3weekly cisplatin and had adequate baseline hearing. 

• RT included 70 Gy/35 fractions to areas of gross disease. 

• Pts were randomized to concurrent cisplatin either 100 mg/m2 days 1, 22 and 43 or 40 mg/m2 weekly x 7 weeks. 

• Co-primary endpoints were the incidence of ≥grade 2 audiometrically measured hearing impairment and hearing-related QoL, both measured at 1 year. 

• All pts provided informed consent for this REB approved trial.

Results

• 99 eligible pts (85 males/14 females) median age 61 years (range, 40-75 years) were enrolled at 3 academic cancer centers in Canada between Feb 2019 and June 2023. 

• Baseline pt characteristics were well balanced. 

• p16-positive oropharyngeal cancer - 94% 

• 50 pts received cisplatin q3weekly for 3 (74%), 2 (22%) or 1 cycle (4%); and 49 pts received weekly cisplatin for a median of 6 cycles (range, 3-7); with similar mean cisplatin doses. 

• Grade 3/4 acute toxicities - 40% vs 47% 

• 47 pts were alive at 1-year in each arm and 1-year audiograms were available for 87 pts (93%). 

• Hearing impairment >grade 2 at 1 year was present in 32 pts (64.0%) treated with q3weekly cisplatin and 20 pts (40.8%) treated with weekly cisplatin (p=0.027). 

• Incidence of tinnitus (92.0% vs 73.5%, p=0.017) and need for hearing amplification (54.0% vs 36.7%, p=0.11) were higher with q3weekly cisplatin. 

Conclusion

Grade 2/3 hearing impairment at 1 year was reduced by 40% with the use of weekly cisplatin given concurrent with RT compared to a q3weekly schedule. Rates of tinnitus and the need for hearing amplification were also reduced. Hearing-related QoL data were collected and will also be presented. Our results support the use of weekly cisplatin in pts with HPV-related LASCCHN to reduce long-term hearing morbidity.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

A Randomised Phase II Study to Evaluate the Efficacy and Safety of Androgen Deprivation Therapy (ADT) vs Chemotherapy (CT) in Patients with Recurrent and/or Metastatic, Androgen Receptor (AR) Expressing, Salivary Gland Cancers

Background

• Salivary duct (SDC) and adenocarcinomas (ADC) (ICDO-coding 8140/3) are aggressive cancers. 

• AR expression is almost universal in SDC, rarely in ADC. 

• The standard of care for recurrent, metastatic or unresectable (R/M/U) AR-expressing tumors is CT. 

• To assess the value of ADT, an EORTC-led randomised phase II study was launched.

Aim

Primary objectives were to show superiority of progression free survival (PFS) of ADT over CT in cohort A, to describe overall response rate (ORR) in cohort B.

Methods

• Patients (pts) with untreated R/M/U AR expressing SDC and ADC (cohort A) were randomised to receive 

• CT (cisplatin 75 mg/m2 + doxorubicin 60 mg/m2 or carboplatin AUC 5 + paclitaxel 175 mg/m2 q3 weeks for a maximum of 6 cycles) or 

• ADT (bicalutamide 50 mg once daily + triptorelin 3.75 mg q 28 days until progressive disease (PD)). 

• A second single-arm cohort (B) received ADT until PD, and it included pretreated pts. 

• Histology was centrally reviewed. 

• IHC AR staining of >70 % was required. 

• Translational studies included HER2 and AR regulation mechanisms. 

• N= 89 pts: 60 in cohort A (29 in ADT and 31 in CT) and 29 in cohort B. Cohort B included 54 pts (25 switched from cohort A upon PD). 

• The majority were male (93%). 

• Median age was 65 (35-80y).  

Results

• Cohort A: 

• mPFS was 4.0 m (95%CI: 3.6-8.7) in the ADT arm and 6.5 m (95%CI: 5.3-8.6) in the CT arm. 

• Neither superiority nor inferiority of ADT over CT were demonstrated. 

• ORR - 23% (ADT) vs 35% (CT). 

• HR for OS (ADT vs CT) - 1.91 (95% CI: 0.92-3.98) (p=0.9580)

• AEs were 96% vs 67% in the CT and ADT arm respectively; 

• G3-5 AEs were 15% in both arms. 

• HER 2 amplification was detected in 17% of cases evenly distributed in the 2 arms. 

• Cohort B: 

• ORR 19% with 1 complete response. 

• mPFS - 3.5 m (95%CI: 2.0-5.9) 

• mOS - 20.2 m (95%CI: 9.8-29.5)

• G3-5 AE were 4%.

Conclusion

PFS in R/M/U AR expressing SGCs ADT did not prove superior nor inferior. ADT sensitivity is seen independently of treatment sequence, line and HER2 amplification. ADT combined with CT and/or with HER2 inhibitors, depending on HER2 status, might represent a rational approach for future studies.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Molecular Characterization of Adult Non-glioblastoma Central Nervous System (CNS) Tumors to Identify Potential Targetable Alterations.

Background

• NGS panels in oncology offer personalized therapies based on genomic alterations, but data on their clinical use and efficacy for non-glioblastoma CNS tumors is limited.

Aim

• To explore the molecular landscape of non-glioblastoma CNS tumors in patients (pts) who underwent FoundationOne®CDx between 11/2019 and 04/2023 at Veneto Institute of Oncology, Padua (Italy), while also assessing access to targetable treatment (TT). 

Methods

• Analysis was conducted on archival tumor, comprising a cohort of 176 pts. Brain tumors were classified per WHO 2021.  

Results

• Cohort was constituted by: 19 Grade 2 IDH mut astrocytomas (A); 35 G3 IDH mut A; 34 G4 A; 29 oligodendrogliomas; 4 diffuse midline gliomas; 3 gangliogliomas; 3 pleomorphic xanthoA; 30 meningiomas; 4 medulloblastomas; 5 ependymomas; 2 neuroblastomas; 3 schwannomas; 4 pituitary adenomas; 1 hemangiopericytoma. 

• Most frequent targetable molecular alterations (ESCAT ESMO Scale IIB-IIIB) were: PIK3CA/B mut (14.2%), NF1 and NF2 mut (10.2 and 13% respectively), BRCA 1-2 mut (8%), POLE mut (7.4%), high tumor mutational burden (TMB) (>10 mut/megabase) (6.8%), PDGFRA alterations (6.2%), BRAF non-V600E alterations (5.1%), RET and ROS1 mut (3.4 and 2.8% respectively), MDM2 amplification (2.3%), FGFR1-2-3 alterations and H3K28M (1.7%), MET amplification (1.7%), ALK rearrangements (1%). 

• NTRK fusions and BRAF V600E have not been detected. 

• 3/4 medulloblastomas pts exhibited a PTCH1 mutation. 

• 4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. 

• Immune checkpoint inhibitors have shown remarkable activity in a meningioma patient, who is undergoing treatment for 12 months and has achieved a complete response according to RANO criteria, while another has had stable disease with alectinib for 7 months. 

• In other cases TT did not demonstrate activity.

Conclusion

The incidence of targetable molecular alterations in adult CNS tumor pts was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

Reference

Annals of Oncology (2024) 35 (suppl_2): S406-S427. 10.1016/annonc/annonc1587

Primary Results from TACTI-003: A Randomized Phase IIb Trial Comparing Eftilagimod Alpha (Soluble LAG-3) plus Pembrolizumab versus Pembrolizumab Alone in First-line Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with CPS ≥1

Background

• Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen-presenting cell (APC) activation & T-cell (CD4/CD8) recruitment/activation. 

• Previous results from a phase II study (NCT03625323) of E plus pembrolizumab (P) showed a promising objective response rate (ORR) in second line head and neck squamous cell carcinoma (HNSCC). 

• An encouraging ORR of 35.5% was recently reported in first line (1L) recurrent or metastatic (R/M) HNSCC patients (pts) with CPS <1 treated with E+P (Cohort B; NCT04811027). We 

Aim

• To report primary results from the randomized Cohort A of TACTI-003 in 1L R/M HNSCC expressing PD-L1 (CPS ≥1).

Methods

• Pts with measurable disease and CPS ≥1 were randomized to receive either E + P or P alone (E: 30 mg SC q2w for 24 weeks then q3w up to 2 yrs. P: 400 mg IV q6w up to 2 yrs). 

• Primary endpoint (EP) - ORR by RECIST 1.1 in evaluable pts (≥1 post-baseline scan). 

• Secondary EPs - ORR by iRECIST, duration of response, progression free survival, overall survival, safety & biomarkers. 

• Imaging was done q9w & PD-L1 was prospectively assessed (22C3).

Results

• N= 138 pts (between Oct 2021–Oct 2023), 118 evaluable (58 in E+P & 60 in P). 

• Median age - 65 yrs (range: 38–87) 

• Male - 74.6%

• Primary tumor sites were hypopharynx (16.1%), larynx (17.8%), oral cavity (28.8%) & oropharynx (37.3%). 

• ECOG PS - 0 in 43.2% & 1 in 56.8% of pts. 

• 52.5% had CPS 1–19 and 47.5% had CPS ≥20. 

• By data cutoff (Mar 11, 2024), 7 (E+P) vs 8 pts (P) experienced Grade ≥3 treatment emergent adverse reactions (TEARs). 

• 3 pts per arm discontinued study treatment due to TEARs. 

• E+P resulted in numerically higher ORR & DCR compared to P only in CPS ≥1 pts, with the largest differential in CPS ≥20.

Efficacy by RECIST 1.1	CPS ≥1		CPS 1–19		CPS ≥20
	E+P, N=58	P, N=60	E+P, N=29	P, N=33	E+P, N=29	P, N=27
ORR, n (%)	19 (32.8)	16 (26.7)	10 (34.5)	11 (33.3)	9 (31.0)	5 (18.5)
DCR, n (%)	42 (72.4)	38 (63.3)	20 (69.0)	22 (67.7)	22 (75.9)	16 (59.3)

 

Conclusion

E+P is well tolerated with positive efficacy data and should be investigated further in HNSCC.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623