Keywords
DCGI India - pembrolizumab - survey - weight-based dose
Introduction
Immunotherapy is a major development in the field of cancer care and therapeutics
in the last decade. First immunotherapy drug ipilimumab got approval in 2011 for advanced
melanoma after showing improved survival in phase 3 trial (NCT00324155).[1] Since then, these drugs are used in almost all cancers. It has improved outcome
in few of the advanced cancers like lung, kidney, and liver. At any given time, hundreds
of trials of immunotherapy drugs are ongoing across the world. These drugs are slowly
being introduced into both adjuvant and neoadjuvant settings. This has led to accelerated
approvals for these drugs in various advanced and early stage cancers. But this progress
is limited to high-income countries. In an era of global cancer equality, patients
from low- and middle-income countries (LMICs) are not able to access these drugs due
to cost constraints. Health insurance coverage (both government and private) is limited
in LMIC. In India, in 2014, t h e mean out-of-pocket expenditure for cancer treatment
was Indian rupee (INR) 57,232. The expenditure is catastrophic for 79% of households
(>10% of household consumption expenditure) and for 43% of them it is distress financing,
meaning forced sale of house or land, borrowing money, or getting contributions from
friends or families.[2] The study from Tata Memorial Hospital, Mumbai, revealed that only 1.6% of patients
received immunotherapy.[3] Efforts are needed to reduce the cost of cancer therapy in LMIC. Various ways to
reduce the cost for immunotherapy drugs need to be explored.
Use of weight-based dosing of pembrolizumab is one such way. Pembrolizumab was used
by the manufacturing company in initial trials as 2 mg per kg every 3-weekly dose.[4]
[5]
[6] At that time, both 100 mg and 50 mg vials were available. But after few years, the
company withdrew the 50 mg vial from the market. They also changed the dosing to fixed
dose of 200 mg given 3-weekly. Now, this has led to the use of extra dose of drug
especially for those patients who have average weight of 50–60 kg. It is wastage of
money as same patient will need less doses in weight-based dosing as compared to a
fixed-dose schedule. The pharmacokinetic studies done on pembrolizumab have shown
that t h e d o s e s 2 mg per kg and 200 mg are equivalent in effect.[7]
[8]
[9] The dose of drugs is carefully decided after phase 1 studies. Both pharmacokinetic
and pharmacodynamic properties of drug along with toxicity profile are taken into
consideration while deciding final approved dose of the drug. The final maximum dose
chosen for phase 3 clinical trials and subsequent drug approval is generally the one
with better efficacy and with lesser toxicity. This is an old concept and needs revision
in present time of targeted therapy and immunotherapy.[10]
According to a Canadian Agency for Drugs and Technologies in Health report, the Canadian
authorities have approved the 2 mg/kg every 3-weekly dose of pembrolizumab across
all tumors based on the basis of initial pembrolizumab clinical trials and modeling
based studies.[8] With the establishment of the equal result of 2 mg/kg every 3 weeks and 200 mg every
3 weeks, there is potential of large cost savings on adopting the 2 mg/kg every 3
weeks as compared to the 200 mg flat dose.[9] The regulatory authorities have considered such weight-based strategies in Israel
and Denmark. Many countries might follow the same in future. Indian regulatory guidelines
from the Drug Controller General of India (DCGI) lack such recommendations.[11] To initiate similar efforts in India, we did this survey as to understand the difficulties
faced by Indian medical oncologists (IMOs) in adopting weight-based immunotherapy.
Materials and Methods
We used Google Forms to conduct this survey and framed the questions according to
the medical oncologist's perspective ([Table 1]). The survey was circulated through social media apps from August 1, 2021, to August
30, 2021. Only medical oncologists from across the country were included as survey
participants. Survey participation was voluntary. Social media apps like WhatsApp
and platforms such as Indian Society of Medical and Pediatric Oncology (ISMPO), the
only official organization of medical oncologist in India, were used to circulate
the survey questionnaires. All the responses to survey were collected in an Excel
spreadsheet and analyzed. The questionnaire mainly focused on the primary objective
of assessment of awareness of weight-based dosing of pembrolizumab among IMOs and
understanding lacunae in adopting the same. Secondary objective was the assessment
of knowledge of global efforts to reduce cost of immunotherapy drugs.
Table 1
Questionnaire and results—pembrolizumab weight-based dosing: conviction and lacunae
in adopting a cost-saving approach (n= 99)
|
S. no
|
Question
|
Answers (options)
|
Results: n (%)
|
|
1
|
How many eligible patients of immunotherapy do not receive IO drug due to cost factor?
|
1. >90%
|
69 (69)
|
|
2. 50–90%
|
22 (22)
|
|
3. <50%
|
8 (8)
|
|
2
|
Until 2015, pembrolizumab was studied at 2 mg/kg every 3 weeks in metastatic melanoma
and mNSCLC. There is no rationale for 200 mg flat dose schedule for consequent trials.
Do you agree?
|
1. Yes
|
85 (85)
|
|
2. No
|
5 (5)
|
|
3. Do not know
|
9 (9)
|
|
3
|
What prohibits you from using pembrolizumab as mg/kg?
|
1. Lack of recommendation by regulatory authorities
|
15 (16)[a]
|
|
2. Lack of recommendation from scientific organizations
|
6 (6)
|
|
3. Both options 1 and 2
|
43 (46)
|
|
4. Lack of studies comparing 2 mg/kg versus flat 200 mg dose
|
23 (25)
|
|
5. Others
|
7 (7)
|
|
4
|
Are you aware of the fact that Canada, Israel, and Denmark have approved pembrolizumab
as 2 mg/Kg every 3 weeks?
|
1. Yes
|
39 (39)
|
|
2. No
|
60 (60)
|
|
5
|
If DCGI agrees to change its recommendation, would you change your practice to mg/Kg?
|
1. Yes
|
89 (89)
|
|
2. No
|
3 (3)
|
|
3. Not sure
|
7 (7)
|
|
6
|
If NCCN adds its recommendation on mg/kg, would you change your practice?
|
1. Yes
|
93 (93)
|
|
2. No
|
1 (1)
|
|
3. Not sure
|
5 (5)
|
|
7
|
If ESMO adds its recommendation on mg/kg, would you change your practice?
|
1. Yes
|
94 (94)
|
|
2. No
|
1 (1)
|
|
3. Not sure
|
4 (4)
|
|
8
|
Are you a medical oncologist?
|
1. Yes
|
99 (100)
|
|
2. No
|
0 (0)
|
|
9
|
How many of years of practice in medical oncology?
|
1. 1–5 years
|
44 (44)
|
|
2. 6–10 years
|
24 (24)
|
|
3. >10 years
|
31 (31)
|
|
10
|
Where do you practice?
|
1. Metro city
|
74 (74)
|
|
2. District
|
14 (14)
|
|
3. Towns
|
11 (11)
|
Abbreviations: DCGI, Drugs Controller General of India; ESMO, European Society of
Medical Oncologists; IO, immuno-oncology; mNSCLC, metastatic non-small-cell lung cancer;
NCCN, National Comprehensive Cancer Network.
a For question no 3, responders were: n = 94.
Statistical Analysis: It was done using descriptive statistics.
Results
A total of 103 responses were received from August 8, 2021, to August 15, 2021. Among
these, 99 responses were from medical oncologists and only these were taken into consideration
for the analysis.
The survey results are depicted in [Table 1]. The responding 44, 24, and 31 of the 99 IMOs have had 1 to 5 years, 6 to 10 years,
and >10 years of practice, respectively. Majority of them, that is, 74% are practicing
in metropolitan cities, followed by 14% in districts, and 11% in towns.
Seventy percent of IMOs reported that 90% of their patients do not receive immuno–oncology
drugs due to the cost factor. Sixty four percent (n = 64) of IMOs responded that the lack of recommendation by scientific organizations
and/or recommendation by regulatory authorities prohibited them from using weight-based
dosing of pembrolizumab. Twenty-three (24%) IMOs do not use mg/kg dosing in view of
lack of studies comparing 2 mg/kg every 3 weeks versus 200 mg every 3 weeks. Only
three IMOs are already using weight-based dosage of pembrolizumab as they s t a t
e d t h a t nothing prohibited them. Five IMOs did not answer this question ([Fig. 1]).
Fig 1 Survey among Indian medical oncologist on factors prohibiting use of mg/kg dosing
of pembrolizumab (n = 94).
Eighty five percent (n = 85) of IMOs agreed that there was no rationale for using only 200 mg every 3 weeks
in subsequent trials of pembrolizumab. Sixty percent (n = 60) were not aware of the fact that countries like Canada, Israel, and Denmark
have adopted the weight-based dose of pembrolizumab. Ninety percent IMOs would change
their practice to weight-based dosing if DCGI recommends mg/kg dosing. Similarly,
93% and 94% of IMOs would change their practice if National Comprehensive Cancer Network
(NCCN) and European Society of Medical Oncologists (ESMO) add mg/kg recommendation
of pembrolizumab in their guidelines ([Fig. 2]).
Fig. 2 Survey among Indian medical oncologists (n = 99) on changing the practice to using mg/kg dosing of pembrolizumab. ESMO, European
Society of Medical Oncologists; NCCN, National Comprehensive Cancer Network; DCGI,
Drugs Controller General of India.
Discussion
Most of the LMIC countries have no individual guidelines for cancer management.
Oncologists from LMICs depend heavily on NCCN or ESMO guidelines for treatment decisions
in absence of any country-specific guidelines. As shown in our survey, almost all
of the oncologists were reluctant to change the practice unless NCCN or ESMO guidelines
recommend to do so. NCCN guidelines generally do not take into consideration financial
stress caused by treatment, which is a vital deciding factor for treatment in LMIC
patients. Recently, NCCN added the mg/kg dosing of pembrolizumab and nivolumab for
malignant melanoma patients;[12] however, restricting such recommendations for other cancer indications is not well
understood. This is a very important issue for change of practice at grassroots level.
We also found that if Indian regulatory authorities, that is, DCGI, endorse such a
recommendation, 90% of IMOs would change the practice. Hence, a coordinated effort
is required between scientific organizations and drug approval authorities like Indian
Council of Medical Research (ICMR) and the Central Drugs Standard Control Organization
(CDSCO). The World Health Organization acknowledged the issue of lack of cancer treatment
guidelines and lack of cost negotiations with the companies in LMICs.[13]
When pembrolizumab was launched, both the 100 mg and 50 mg vials were available. This
was useful for administrating weight-based dosing. In 2017, the parent company withdrew
50 mg vial for reasons less understood. In fact, prescribing information for pembrolizumab
provided by the company still has mention of 50 mg vial.[14] The average weight of an Indian lung cancer patient is lower as compared to western
patients.[15]
[16] For a mean weight of 55 kg, almost double dose of pembrolizumab is used if we use
flat dose. Both pembrolizumab and nivolumab have shown comparable outcomes of weight
based with a flat dose.[17]
[18]
[19] As per report published in 2017, pembrolizumab flat dosing leads to wastage of nearly
1 billion US dollar (USD) per year as 100 mg vial costs around INR 235,000 without
access (USD 3,118).[9] The economic impact of weight-based dosing of pembrolizumab and nivolumab has been
studied extensively and cost benefits are enormous including in the USA and European
countries.[20]
[21]
[22] Negotiations must be done with the company for availability of 50 mg vial by the
concerned regulatory authorities.
In our survey, IMOs that represented India's situation in medical oncology belonged
to a diverse group of professionals from various social strata. They have faced the
obstacle of limited access to the use of immunotherapy drugs. The results of such
surveys as this can be useful for scientific organizations and also policy makers.
Limitations
Our survey is limited by the number of responders. India has almost 250–300 new medical
oncologists coming into clinical practice every year and this survey was exclusive
to them.
Conclusions
Weight-based dosing of pembrolizumab would be accepted if policy makers, regulative
authorities, and IMOs come together and formulate the required guidelines. Such guidelines
will improve accessibility of immunotherapy drugs and lead to huge cost savings. A
coordinated effort is needed among scientific organizations like ISMPO, ICMR, and
CDSCO (DCGI) to formulate India-centric guidelines on the use of pembrolizumab with
weight-based (mg/kg) dose.
