A Phase III Randomized, Open-label Study to Establish the Superiority of Triple Oral Metronomic Therapy (OMCT) used in Addition to Chemotherapy Regimen (Paclitaxel + Carboplatin) Over Chemotherapy Alone for the Treatment of Advanced Unresectable Head and Neck Cancer Squamous Cell Cancer (HNSCC). 

Background

• Advanced HNSCC has poor outcomes and limited treatment options, especially in resource-constrained settings. Immunotherapy is affordable for less than 5% of patients in lower-middle-income countries (LMICs). 
• Triple OMCT, employing low-dose continuous chemotherapy, shows promise, but its safety and efficacy along with chemotherapy remain unproven. 

Aim

To assess whether the addition of OMCT to first-line chemotherapy can improve overall survival (OS) as compared to chemotherapy alone.

Methods

• Phase 3 randomized, prospective, open-label, superiority design study 
• N= 238 patients with advanced HNSCC who were planned for palliative intent platinum-based chemotherapy. 
• The patients were stratified for the site of the tumor and ECOG PS, and were randomly assigned 1:1 to receive-
  1. Arm A - Triple OMCT (Erlotinib 150 mg OD, Celecoxib 200 mg BD and Methotrexate 9mg/m2 once weekly) in addition to 3-weekly paclitaxel carboplatin (PC) chemotherapy or, 
  2. Arm B - PC chemotherapy alone
• Sample size calculation assumed no OS improvement with OMCT+PC (5% type I error, 80% type II error).
• Primary endpoint – OS
• Secondary endpoints - PFS, quality of life (QoL) assessments, and safety. 
• OS and PFS were analyzed via Kaplan-Meier and log-rank test; HR estimated via Cox proportional hazard models.
• QoL was assessed using EORTC QLQ-C30.

Results

• Median age - 47 years
• Males - 97.8%
• ECOG PS 0-1 - 78% patients 
• mOS (Arm A vs B) - 8.3 (95% CI, 6.3-10.4) vs 6.1 months (95% CI, 4.7-7.4) (HR 0.63; 95% CI, 0.47–0.83; p=0.00011). 
• mPFS - 7.6 (95% CI, 6.3-8.8) vs 3.5 months (95% CI, 2.2-4.7) (HR, 2.79; 95% CI, 1.98-3.93; P<0.000). 
• Significant differences in EORTC-C30 were found for the physical functioning domain between baseline and 1-month follow-up visit. 
• PC chemotherapy combined with triple OMCT showed good tolerability
• Common toxicities - Fatigue (40.3%), and hyponatremia (25.4%), similar to the incidence observed with PC chemotherapy alone.

	Arm A	Arm B	Absolute Difference
6 months OS	75.5%	50.4%	25.1%
12 months OS	44.0%	25.5%	18.5%

 

Conclusion

This study demonstrates that the addition of triple OMCT to paclitaxel and carboplatin chemotherapy is an effective and safe treatment option for patients with advanced HNSCC in platinum-sensitive settings. This treatment option is particularly valuable in LMICs, where cetuximab and pembrolizumab are not feasible.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA6053.

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VAMANA: A Phase 2 Study of Low-dose Bevacizumab Plus CCNU in Relapsed/Recurrent Glioblastoma.

Background

• There are limited systemic therapy options for recurrent glioblastomas (rGBM). 
• CCNU and/or Bevacizumab are often used to treat rGBM not amenable to local therapy. 
• The addition of Bevacizumab (10 mg/kg) to CCNU failed to improve overall survival in the EORTC 26101 study. 
• The question is whether the failure was due to the high dose of Bevacizumab used in the study. High doses of Bevacizumab may lead to excessive pruning & destruction of blood vessels, hampering the delivery of CCNU. 
• In vitro & in vivo studies showed that a lower dose of Bevacizumab (1-1.5 mg/kg) has the potential to normalize tumor vasculature leading to improved drug delivery & outcomes. 

Aim 

To evaluate the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM.

Methods

• Phase 2 open-label, single-arm trial 
• N= 46 adults with rGBM with an ECOG PS 0-2 and adequate organ & marrow function. 
• The participants received CCNU 110 mg/m2 PO once a day, on day 1 of a 42-day cycle (max. 8 cycles) with Bevacizumab 1.5 mg/kg intravenously every 3 weeks (max.16 cycles). 
• Appropriate anti-emetic prophylaxis was given. 
• Treatment continued until disease progression, clinical deterioration, or development of intolerable side effects. 
• Response assessment was done with MRI Brain +/- spine at 2 monthly intervals till disease progression. 
• The modified RANO criteria were used for response assessment. 
• Safety assessments were done on day 8 of cycle 1, & days 21 & 42 of each cycle. 
• Primary end-point - Overall survival (OS) 
• Secondary end-points - Progression-free survival (PFS) & safety. 
• A 6-month OS ≥ 40% was the signal to explore this regimen further and if the 6-month OS <20% it would be considered futile. 

Results

• Median age - 42 years (IQR 33-52.75) 
• Males - 78.3% (36/46) 
• ECOG PS 1 - 76.1% (35/46)
• Median follow-up - 15.27 months (95% CI 13.47-17.06)
• Median number of doses of Bevacizumab and CCNU - 4 and 2 respectively
• Three (6.5%) patients completed all planned doses of Bevacizumab and CCNU. 
• Objective response rate (ORR) - 15.2 % (7/46)
• mOS - 6.133 months (95% CI 5.474-6.793)
• 6-month OS - 57.1%
• mPFS - 3.267 months (95% CI 0.850-5.684)
• Most frequent grade 3 or higher toxicities - Neutropenia (7/46, 15.2%), thrombocytopenia (5/46,10.8%), elevated ALT levels (3/46, 6.5%), anemia (2/46, 4.3%) and hyponatremia (2/46, 4.3%).

Conclusion

This study demonstrates the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM (the median OS exceeded the preplanned cut-off of 40%) with an acceptable toxicity profile and no new safety signals. This combination should be explored further in a phase III randomized study.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA2064.

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Adjuvant PD-1 Blockade with Camrelizumab in High-risk Locoregionally Advanced Nasopharyngeal Carcinoma (DIPPER): A Multicenter, Open-label, Phase 3, Randomized Controlled Trial.

Background

Patients with high-risk locoregionally advanced nasopharyngeal carcinoma (NPC) often experience disease relapse even after receiving standard-of-care treatment, e.g. induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). 

Aim

To assess the benefit of PD-1 inhibitor as adjuvant treatment following IC+CCRT in locoregionally advanced NPC. 

Methods

• N= 450 Patients with high-risk locoregionally advanced NPC (T4N1M0 or T1-4N2-3M0) who have received gemcitabine and cisplatin (GP) IC and CCRT were recruited at 11 centers in China.
• They were randomly assigned (1:1) within 2 weeks after the last radiation dose to receive-
  1. Camrelizumab Arm - Intravenous camrelizumab (200 mg once every 3 weeks for 12 cycles or
  2. Standard-therapy Arm – Observation
• Primary endpoint - Event-free survival (EFS).
• It is estimated that approximately 442 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a log-rank test at a two-sided α level of 0.05. 
• Quality of life (QoL) was assessed by EORTC-C30.

Results

• Median follow-up - 37 months (corresponding to 41 months when calculated from the start of standard therapy)
• Estimated 3-year EFS (Camrelizumab Arm vs Standard-therapy Arm) - 86.9% vs 77.4% in the (intention-to-treat population; HR 0.61, 95% CI 0.38–0.96; P = 0.03)
• Grade 3-4 adverse events (AEs) - 11.2% vs 3.2%, including grade 3-4 immune-related AEs in 8 (3.9%) patients in the Camrelizumab Arm. 
• Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab (RECP, 87.8%, 4 (1.8%) patients had grade 3 RECP). 
• Treatment-related deaths - 1 (<1%) (subarachnoid hemorrhage) vs 1 (<1%) patients (nasopharyngeal necrosis)
• During treatment, there was no clinically meaningful deterioration of health-related quality of life associated with the use of adjuvant camrelizumab.

3-yr rate (%)	Camrelizumab  (n = 226)	Standard Therapy  (n = 224)	P Value
Event-free survival	86.9	77.4	0.030
Distant metastasis-free survival	93.3	86.3	0.032
Locoregional recurrence-free survival	93.7	88.0	0.041
Overall survival	96.3	92.8	0.79
Safety population	n = 205	n = 221
Grade 3-4 AEs, n (%)	23 (11.2)	7 (3.2)
Immune-related	8 (3.9)	0
Grade 5 AEs, n (%)	1 (<1%)	1(<1%)
Immune-related	0	0

 

Conclusion

Adjuvant PD-1 blockade with camrelizumab significantly improved EFS in high-risk locoregionally advanced NPC, with mild toxicity and comparable quality of life.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA6000.

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A Randomized, Controlled, Phase 2 Trial of Nivolumab Plus Standard-Dose or Low-Dose Bevacizumab for Recurrent Glioblastoma (NAVAL).

Background

• PD-1/PD-L1 inhibition has demonstrated limited efficacy for recurrent glioblastoma (rGBM) across prior RCTs. 
• VEGF, a proangiogenic factor upregulated in rGBM, contributes to tumor-associated immunosuppression. 
• Preclinical and observational clinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immune response. This RCT evaluated anti-PD-1 plus anti-VEGF therapy for rGBM. 

Aim 

To evaluate anti-PD-1 plus anti-VEGF therapy for rGBM. 

Methods

• Multicenter, open label, phase 2 RCT 
• N= 90 patients (≥18 years) with GBM at first recurrence. 
• Participants received nivolumab (240 mg IV Q2 weeks) and were 1:1 randomized to concurrent 10 mg/kg bevacizumab (standard-dose arm) or 3 mg/kg bevacizumab (low-dose arm) administered IV biweekly. 
• Stratification factors - Age, performance status, extent of resection, and MGMT methylation status. 
• Primary endpoint - Overall survival (OS) at 12 months (OS-12). 
• Other outcomes - Overall objective response rate (ORR), median progression-free survival (mPFS), PFS at 6 months (PFS-6), and safety. 
• Exploratory genomic and immune profiling using CITEseq was performed in 16 patients.

Results

• Median age - 60.6 years (range 27-86)
• MGMT methylated - 35 patients
• MGMT unmethylated - 53 
• MGMT 2 indeterminate 
• Evaluable patients in final analysis – 87
• Median follow-up - 146 days (range 7-1239)
• Complete responses - 3 (3.4%)
• Partial responses - 29 (33.3%)­
• Stable disease - 37 (42.5%)
• Progressive disease - 18 (20.7%)
• OS-12 - 41.1% in standard-dose and 37.7% in low-dose arms 

	N	ORR (%)	Progression Events	Median PFS (95%CI)	PFS-6 (95%CI)	Log-rank P-value
Standard-dose	42	15 (36%)	36 (86%)	141 (119-201)	37.9 (22.8,52.9)	0.83
Low-dose	45	17 (38%)	41 (91%)	139 (92-228)	42.9 (27.9,57.8)

 

 

 

 

•  
• Post-hoc analysis demonstrated survival benefit for patients aged ≥60 years in standard-dose arm. 
• Most frequent toxicities (>20%) - Fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). 
• Grade 3-4 toxicities - Hypertension (7.8%), fatigue (5.6) and non-neurological toxicities. 
• Differential changes across trial arms were seen in myeloid-derived suppressor cells (MDSCs) post-therapy. 
• Network medicine identified VEGF as target to reduce MDSCs. 
• VEGF was found expressed by MDSCs of mainly responder patients. 
• Differential gene expression analysis identified increased pro-inflammatory gene signatures in standard-dose arm.

Conclusion

Overall PFS and OS were similar for nivolumab plus standard- or low-dose bevacizumab for rGBM, with post-hoc survival benefit seen in standard-dose arm in elderly. Standard-dose bevacizumab was associated with increased systemic inflammatory response and reduced immunosuppressive MDSCs.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No 2072.

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Long term Results of Phase 3 Randomized Study Evaluating the Addition of Low Dose Nivolumab to Palliative Chemotherapy in Head and Neck Cancer.

Background

• The addition of low-dose nivolumab to metronomic chemotherapy (MC) improved 1-year overall survival in relapsed and refractory head and neck squamous cell carcinoma (HNSCC). 
• However, sustained benefit over the long term is an important aspect of immunotherapy and it has never been studied in a prospective randomized study for low-dose nivolumab. 

Aim 

To assess sustained benefit over the long term for addition of low-dose nivolumab to metronomic chemotherapy in relapsed and refractory HNSCC. 

Methods

• Open-label randomized phase 3 superiority study
• Adult patients (age= or >18 years), ECOG PS (0-1), relapsed - recurrent or newly diagnosed advanced HNSCC, and normal organ functions were eligible. 
• Patients were randomly assigned 1:1 to –
  1. TMC-I - Oral metronomic chemotherapy consisting of methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, and erlotinib 150 mg daily, with intravenous nivolumab 20 mg flat dose once-every-3-weeks or
  2. TMC - Oral metronomic chemotherapy consisting of methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, and erlotinib 150 mg daily with Systemic therapy was continued till the development of intolerable side effects or progression of disease. 
• Primary endpoint - Overall survival (OS). 
• Landmark analysis was performed to compare OS between 2 arms.  

Results

• Median follow-up - 32.5 months (95% CI 29.6-32.7)
• OS rate in TMC vs TMC-I arm a:
• 1 year OS rate – 20% (95%CI 11.9-29.7) vs 35.5% (95%CI 25-46.2) (HR= 0.6534, 95%CI 0.4473 -0.956: P=0.028)
• 2-year OS rate – 5.3% (95%CI 1.7-12.3) vs 18.4 % (95%CI 10.7-27.8) (HR= 0.6318, 95%CI 0.4476 -0.8919: P=0.009)
• 2.5-year OS rate - 5.3% (95%CI 1.7-12.3) vs 17.1 % (95%CI 9.66.-26.3) (HR= 0.6379, 95%CI 0.4524 -0.8993: P=0.01) 
• The benefit of the addition of nivolumab was independent of other factors like age, gender, ECOG PS, Site of malignancy, time to failure, PDL1 score, and previous exposure to platinum.

Factor	Hazard Ratio	P Value
Arm
TMC	Reference	0.001
TMC-I	0.525 (0.356-0.777)
Age
Non-Elderly	Reference-	0.315
Elderly	1.281(0.790 - 2.079)
Gender
Female	Reference	0.446
Male	0.781(0.413-1.476)
ECOG PS
0	Reference	0.705
1	1.154(0.55- 2.421)
Site
Non-Oral	Reference	0.562
Oral	1.121(0.635 - 2.306)
Previous Platinum
No	Reference	0.240
Yes	1.412(0.794 - 2.511)
Tumor PDL1 score
>50	Reference
1-50	2.143(1.343 - 3.421)	0.014
0	1.652(0.881 - 3.097)	0.117
Unknown	1.125(0.565 - 2.243)	0.737
Time to failure on previous treatment
<6 months	Reference
6-12 months	0.816(0.254-2.624)	0.562
>12 months or upfront	1.200(0.670-2.153)	0.733

 

Conclusion

The addition of low-dose nivolumab to triple metronomic chemotherapy leads to a tripling of OS thus suggesting that even low-dose nivolumab has sustainable benefits. The benefit observed is irrespective of known prognostic factors in HNSCC.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA6054.