Low dose Cancer Immunotherapy (Nivolumab) : Making immunotherapy affordable worldwide.

1st Meaningful Cancer Update 2023 8th April Kathmandu Nepal 1
- Subhas Pandit, MD
(AIIMS),ECMO
Low dose immunotherapy.

1st Meaningful Cancer Update 2023 8th April Kathmandu Nepal
Low dose immunotherapy .
2

“ Our discovery has been described as the cancer
equivalent of penicillin.” – Allison and Honjo

The Beginning: Early days of immunotherapy
4

Basic Tumor Immuno Biology
6

Body ( T cells)
recognize most of
cancers , but don't
mount strong
immune attract
against them.
It is because of
check-points, 2nd
molecule which
checks(stops) the
immune response.
PD1-PDL1 down- regulate T-cell function
7

● Some tumor cells express PDL1
and escape this immune-
surveillance.
● PDL1 is a protein expressed by most of
normal cells, acts as cellular ID card
(recognize self vs non-self )
● It binds to PD1 receptor in T-cell and
deactivate T-cell reaction.

● Checkpoint inhibitor block this negative regulation of T cell, they don’t
stimulate immune system.
● Either PD1 ( T cell ) or PD-L1 (in tumor cells) .
● Works in around 20% , but deep and sustained response.
9

Checkpoints in T cells
10

Precise : Immunotherapy has the potential to kill cancer cells without harming healthy
tissue – a game changer.
Systemic : The immune system can zero in on cancer and attack tumors anywhere in the
body.
Adaptable :As tumors evolve, the immune system adapts in kind, beating cancer at its
own game.
Universal : Immune system-based treatments have the potential to be effective for
virtually all forms of cancer – hacking cancer for good.
Durable : Nature’s own database – immune cells “remember” cancer cells to keep them
from coming back.
11
Hallmarks of immunotherapy

FDA approved immunotherapy drugs.
Checkpoint inhibitors
that block PD1
● Nivolumab 2014
● Pembrolizumab 2014
● Cemiplimab
Checkpoint inhibitors
that block PD-L1
● Atezolizumab -2016
● Avelumab -2017
● Durvalumab -2018
12

Price : 40mg -40,000 and 100mg : 1,00,000 Total: 2.4 lakh every 2 weekly !
Available strength & Dosing
Previously: 3mg/kg q2wkly
13

● Price: 1,98,000 per 100mg
Pembrolizumab dosing
2mg/kg every 3 weekly,
15

Average Nepali patient
16

Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels,
Belgium
17

Method
● January 2016 to December 2018.
● Single-center retrospective analysis
● Cohort of patients with advanced cancers and no standard therapeutic
options
● Flat low dose of 10 mg of nivolumab IV every two weeks. (Standard
dose= 240mg every 2wkly)
18

Results
● N = 18
● Response according to *RECIST criteria
○ CR : 2 patients - Synovial sarcoma: 44 months & colon cancer 8 months
○ PR : 2 patients – Gastric adeno and esophageal sq cell ca
○ SD : 5 patients ( >6mth in 3 of them)
■ Leiomyosarcoma, Ewings sarcoma ,cutaneous SCC, esophagus
adeno
● Overall disease control in 9/18 patients.
19

Swimmer’s plot of response in individual patient
20

Why this is a BOLD study ?
● Authors did a daring task of giving 10mg Nivolumab
● It is just 4% ( 10 / 240 mg) of recommended dose : - proof of concept
● Equivalent to 0.1 mg for 100kg patient.
● 300 Euro in authors country, 70 euro in ours.
● *around Rs 20 thousand every month. → comparable/ cheaper than
chemotherapy or other targeted therapy
21

Why such low dose worked ?
● Phase I trials serves as initial safety studies, with the main objective of
identifying the maximum tolerated dose (MTD).
● Nivolumab dose from 0.1 to 10mg/kg > flat dose response curve and no MTD
was reached
● Japanese phase one trial : 0.1 to 20mg/kg > similar results
● Instead of maximum-tolerable- dose , should we opt for minimum effective
dose ?
22

In the 69 evaluated patients with melanoma, peripheral PD-1 RO was saturated at ≥ 0.3 mg/kg
doses after 8 weeks
23

● Seoul National University Hospital, Seoul, South Korea
● October 2015 and 30 September 2017. at
● Confirmed NSCLC, initial stage IIIB or IV or recurrence
● In the low-dose group, 15 patients received 100 mg fixed dose,
and 3 patients received the 20 mg fixed dose.
26

TAIWAN
29

● Nivolumab demonstrated activity and maximal receptor occupancy at dosages
as low as 0.1 mg/kg every 2 weeks.
● In the 14 patients treated at this low dose (0.1mg/kg) there were four
responses, with a 40% progression-free survival rate at 6 months.
● A follow-up publication reported that 17 patients were treated at 0.1 mg/kg,
six of whom responded, with a median duration of response not reached —>
Sustained response
30

..continued
● Similar results were seen with 0.3 mg/kg. [ 20mg in 60kg]
● In non responders → dose was escalated but no response was seen.
● So if patient fail to response in low dose, they don’t respond in high dose.
● “We propose the execution of randomized trials to test the efficacy of
lower doses of nivolumab compared with standard doses, “ - but who will
pay?
31

Implication of this study
How can it impact our practice ?
► Low-dose nivolumab is scientific and effective in various cancers
and is worth considering as an alternative option to reducing financial
toxicity.
► Patients or country that cannot afford high cost of ICIs might
consider low-dose nivolumab rather than standard-dose nivolumab.
33

Implication of this study,
How can it impact our practice ?
► The efficacy of low-dose nivolumab requires further well-designed
prospective studies, such as a non-inferiority phase III trial with sufficient
sample size.
► Similar principle applies to other immunotherapy drugs too.
34

> Unanswered questions
1. Are patients being overdosed by current
dosing?
1. Should treatment be continued
indefinitely?
35

“ We sincerely hope this treatment will reach far and wide so that
everybody on our planet can benefit from this evolutionary gift for
healthy life. “ - ALLISON & HONJO
Thank You.

Low dose Cancer Immunotherapy (Nivolumab) : Making immunotherapy affordable worldwide.

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