JCO: Dosage reduced by 90%, efficacy doubled! PD-1 inhibitors work better with this regimen

For patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC), the EXTREME regimen (cisplatin, fluorouracil, and cetuximab) and KEYNOTE 048 (pembrolizumab with or without cisplatin and fluorouracil) are currently authoritative National Comprehensive Cancer Network (NCCN) guidelines for Class 1 recommendations [1].

However, the cost of treatment with PD-1 inhibitor monotherapy is $60,000 to $80,000
per year.
Even with the EXTREME regimen, the annual cost of treatment is $40,000 (cetuximab is a targeted agent).

For economic reasons, fewer than 5% of patients have access to these regimens, especially in low- and lower-middle-income countries [2-4].

A team of researchers led by Kumar Prabhash from the National Institute of Homi Baba, India, has been working to find a low-cost and effective treatment
option for HNSCC.
They first reported that low-dose methotrexate and celecoxib oral beaten chemotherapy were more effective than cisplatin in relapsed or metastatic HNSCC [5].

They further added erlotinib to this beating chemotherapy regimen and optimized the dose of methotrexate to achieve a response rate of 42.
9 percent in patients with platinum-refractory HNSCC [6].

Recently, Prabhash's team conducted a randomized Phase III efficacy clinical trial (CTRI/2020/11/028953) to explore the efficacy
of low-dose nivolumab combined with beat-to-beat chemotherapy in patients with HNSCC undergoing palliative care.
The results were published in the prestigious journal Journal of Clinical Oncology [7].

The dose of nivolumab used in this study was a fixed dose of 20 mg every 3 weeks, compared with the approved dose of 3 mg/kg/2 weeks, the low dose was equivalent to 1/13.
5 of the normal dose based on the body weight of a 60 kg patient, and such a low dose of nivolumab combined with beat chemotherapy could improve the one-year survival rate of HNSCC patients receiving palliative care from 16.
3% to 43.
4%, showing good efficacy and safety
.

Screenshot of the first page of the paper

A total of 151 patients were selected for this study, 75 patients received beat-to-beat chemotherapy with methotrexate + celecoxib + erlotinib (TMC group), and 76 patients received an additional low-dose nivolumab (fixed dose 20 mg/3 weeks) (TMC-I group).

A cycle
every 21 days.
Withdraw from the trial only if the
disease progresses or becomes intolerable.
The primary endpoint of the study was overall survival
.

In terms of efficacy, the median follow-up was 10.
9 months
.
The 1-year survival rate was 16.
3%, the median overall survival (OS) was 6.
7 months, the median progression-free survival (PFS) was 4.
6 months, the response rate was 45.
3%, and the median duration of response (DoR) was 3.
3 months; the 1-year survival rate was 43.
4%, the median OS was 10.
1 months, the median PFS was 6.
6 months, the response rate was 59.
2%, and the median DoR was 8.
7 months
.

Just increasing the low dose of nivolumab can extend the median overall survival from 6.
7 months to 10.
1 months, and the 1-year survival rate is increased by 25%, the effect is very significant, and the improvement in patient survival is mainly due to the fact that patients in the TMC-I group have longer DoR and PFS
after using immunotherapy.

In patients with platinum-refractory HNSCC, the Checkmate-141 trial showed that nivolumab alone (3 mg/kg/two weeks) increased median OS from 5.
1 to 7.
5 months and one-year survival from 16.
6 to 36.
0 percent compared with standard regimens (methotrexate, docetaxel, or cetuximab) [8].

Although limited by patient characteristics and not directly comparable across studies, the benefits of TMC-I regimens with single-agent treatment of HNSCC with full-dose PD-1 inhibitors
are relatively close.

Overall versus progression-free survival

In terms of safety, the incidence of adverse events above grade 3 in the TMC group was 50%, while that in the TMC-I group was 46.
1%, which was not much
different.

Adverse event status was compared between the two groups

In summary, the combination of beat-to-beat chemotherapy combined with low-dose nivolumab in this study could clearly improve multiple efficacy indicators
compared with beat-to-beat chemotherapy alone without increasing adverse effects.

This study has enormous societal implications because, despite revolutionizing the field of cancer treatment with immune checkpoint inhibitors (ICIs), these drugs are difficult to use in low- and lower-middle-income countries [5,9].

The TMC-I regimen used in this study cost $4370.
1 per year, which is 5% to 9%
of the cost of other full-dose immunotherapies.
Since low-dose ICIs can also significantly improve prognosis, further exploration of low-dose ICIs in other cancers may be a boon
for patients in low-income countries.

So how was the dose of nivolumab used in this study determined? Laboratory data show that 0.
3 mg/kg nivolumab is sufficient to occupy 70% of PD-1 receptors [10], providing a theoretical possibility for the use of this dose; At a low dose of 0.
3 mg/kg, the interval of administration every three weeks can also maintain the required blood concentration [11].

The average weight of patients with HNSCC who received palliative care was generally less than 60 kg, which means that 18 mg of nivolumab is sufficient
.
Retrospective analysis of other cancers also suggested the effectiveness of low-dose nivolumab [12-13], which led the team to choose a dose
of 20 mg.

The study also had some limitations
.
First, this study did not compare the efficacy of low-dose nivolumab with full-dose nivolumab, so the results of the study are only applicable to patients who
cannot receive full-dose nivolumab.
In addition, since the lesions of oral cancer patients in India are mainly confined to the oral cavity, it is unclear how effective this regimen is in
HPV-associated oropharyngeal cancer.

The commentary published in the Journal of Clinical Oncology pointed out that "the current situation of tumor immunotherapy is similar to that of HIV drugs 20 years ago, when highly effective drugs were available only in rich countries, and in Africa, where HIV prevalence is high, drugs are difficult to obtain because of high prices, resulting in many patient deaths
.
" Similarly, immunotherapy is highly effective for some tumors but out of reach
for most patients in poor countries.
As doses and costs are reduced, many patient deaths are avoidable, and ultra-low doses of drugs will provide a much-needed solution
for these patients.
”[14]

References:

[1] Pfister DG, Spencer S, Adelstein D, et al.
Head and Neck Cancers, Version 2.
2020, NCCN Clinical Practice Guidelines in Oncology.
J Natl Compr Canc Netw.
2020; 18(7):873-898.
doi:10.
6004/jnccn.
2020.
0031

[2] Noronha V, Patil VM, Joshi A, et al.
A tertiary care experience with paclitaxel and cetuximab as palliative chemotherapy in platinum sensitive and nonsensitive in head and neck cancers.
South Asian J Cancer.
2017; 6(1):11-14.
doi:10.
4103/2278-330X.
202558

[3] Patil VM, Abraham G, Noronha V, et al.
The Pattern of Care of Use of Nivolumab in Head and Neck Cancers - Audit From a Tertiary Cancer Centre.
Clin Oncol (R Coll Radiol).
2021; 33(5):342.
doi:10.
1016/j.
clon.
2021.
01.
004

[4] Ignacio DN, Griffin JJ, Daniel MG, Serlemitsos-Day MT, Lombardo FA, Alleyne TA.
An evaluation of treatment strategies for head and neck cancer in an African American population.
West Indian Med J.
2013; 62(6):504-509.
doi:10.
7727/wimj.
2013.
046

[5] Patil V, Noronha V, Dhumal SB, et al.
Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial.
Lancet Glob Health.
2020; 8(9):e1213-e1222.
doi:10.
1016/S2214-109X(20)30275-8

[6] Patil VM, Noronha V, Joshi A, et al.
Phase I/II Study of Palliative Triple Metronomic Chemotherapy in Platinum-Refractory/Early-Failure Oral Cancer.
J Clin Oncol.
2019; 37(32):3032-3041.
doi:10.
1200/JCO.
19.
01076

[7] Patil VM, Noronha V, Menon N, et al.
Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study [published online ahead of print, 2022 Oct 20].
J Clin Oncol.
2022; JCO2201015.
doi:10.
1200/JCO.
22.
01015

[8] Ferris RL, Blumenschein G Jr, Fayette J, et al.
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.
N Engl J Med.
2016; 375(19):1856-1867.
doi:10.
1056/NEJMoa1602252

[9] Noronha V, Abraham G, Patil V, et al.
A real-world data of Immune checkpoint inhibitors in solid tumors from India.
Cancer Med.
2021; 10(5):1525-1534.
doi:10.
1002/cam4.
3617

[10] Brahmer JR, Drake CG, Wollner I, et al.
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
J Clin Oncol.
2010; 28(19):3167-3175.
doi:10.
1200/JCO.
2009.
26.
7609

[11] Peer CJ, Heiss BL, Goldstein DA, Goodell JC, Figg WD, Ratain MJ.
Pharmacokinetic Simulation Analysis of Less Frequent Nivolumab and Pembrolizumab Dosing: Pharmacoeconomic Rationale for Dose Deescalation.
J Clin Pharmacol.
2022; 62(4):532-540.
doi:10.
1002/jcph.
1984

[12] Zhao JJ, Kumarakulasinghe NB, Muthu V, et al.
Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience.
Oncology.
2021; 99(3):192-202.
doi:10.
1159/000512000

[13] Yoo SH, Keam B, Kim M, et al.
Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity.
ESMO Open.
2018; 3(5):e000332.
Published 2018 Jul 25.
doi:10.
1136/esmoopen-2018-000332

[14] Mitchell AP, Goldstein DA.
Cost Savings and Increased Access With Ultra-Low-Dose Immunotherapy [published online ahead of print, 2022 Oct 20].
J Clin Oncol.
2022; JCO2201711.
doi:10.
1200/JCO.
22.
01711