The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
The Committee endorsed the recommendations of the EML Cancer Medicine
Working Group with regard to the proposed threshold of four to six months of
overall survival benefit as a guiding principle for prioritizing cancer medicines
for inclusion on the EML, and applied this principle to the consideration of the
immune checkpoint inhibitors.
The Committee noted that there were no treatment options for metastatic
melanoma currently included on the Model List. The Committee recommended
the addition of nivolumab and pembrolizumab to the complementary list of the
EML, for use as first-line monotherapy for treatment of patients with unresectable
and metastatic melanoma on the basis of evidence of significantly increased
overall survival for patients that met the recommended threshold for benefit,
and in the absence of other EML-listed treatment options. Listing should be for
nivolumab with a square box indicating pembrolizumab as a therapeutically
equivalent alternative. The Committee noted that nivolumab was scored as 4/5
on the ESMO-MCBS v1.1 for this indication.
The Committee considered that more mature data would be necessary
before listing of these medicines could be considered for use in adjuvant
indications of radically resected melanoma.
The Committee did not recommend listing of atezolizumab, nivolumab
or pembrolizumab for treatment of patients with metastatic NSCLC at this
time, as the Committee considered that their precise place in the treatment/
immunotherapy of this condition is still evolving. The Committee noted the
evidence of efficacy in the treatment of patients with metastatic NSCLC with
these agents. The Committee observed that the duration of follow up of the single
studies for first-line and second-line immunotherapy in trials for lung cancer was
generally shorter than three years, and considered that data from longer follow
up would better capture the actual magnitude of benefit. By the time of the next
Committee meeting in 2021, more mature data will be available for metastatic
NSCLC and also for use of these agents in locally advanced non-resectable
disease, and as adjuvant therapy.
Furthermore, the Committee noted that the landscape of clinical
development of cancer immunotherapy still has some areas of uncertainty with
regard to the optimal time for introduction of treatment (first- or second-line),
appropriate patient selection, and whether or not use of ICIs in combination with
other medicines is superior.
The Committee expressed concern about the potential budget impact
of oncology medicines, which could be an impediment to access, and countries
may not be able to list these medicines on their national EMLs. Therefore, the
Committee recommended that WHO engage stakeholders to find ways to
facilitate better access and affordability as a high priority through avenues such as
the Medicines Patent Pool, WHO prequalification and collaborative registration
procedures. The Committee also recommended ongoing activities of the EML
Cancer Medicines Working Group to include identification of obstacles to access
and affordability of cancer medicines, and pricing data collection.
The application requested the addition of atezolizumab, nivolumab and
pembrolizumab to the complementary list of the EML:
Atezolizumab: As second-line therapy in locally advanced
or metastatic non-small cell lung carcinoma (NSCLC) after chemotherapy.
Nivolumab: Early and advanced stage melanoma; As second-line therapy after chemotherapy
failure in locally advanced or metastaticNSCLC, regardless of PD-L1 status
Pembrolizumab: Early and advanced stage melanoma; As first-line therapy in NSCLC expressing
PD-L1≥50%, in second-line after chemotherapy failure for NSCLC PD-L1≥1%
Atezolizumab, nivolumab and pembrolizumab belong to the class of PD-1/ PDL1
immune-checkpoint inhibitors (ICI) and had not previously been considered
for inclusion on the EML.
The EML currently includes cytotoxic chemotherapies for NSCLC, but
there are no alternative medicines currently on the EML for the treatment of
Public health relevance
Lung cancer is the most diagnosed and the leading cause of death for cancer
worldwide, with an estimated 2 million new cases and 1.7 million deaths in 2018
(1). Lung cancer is a highly lethal malignancy, with an economic impact estimated
around US$ 8 billion productivity lost in the BRICS countries (2). Moreover, in
the absence of a wide coverage of an effective screening programme in place on
global scale, lung cancer diagnoses occur in advanced stage in more than 60%
of cases, with highly regional variability (3–5). Over 80% of lung cancers are
classified as non-small cell lung cancer (NSCLC). Although targeted therapies
have redefined the therapeutic landscape for some patients, these therapies are
ineffective in patients whose tumours lack the particular genetic mutations/
alterations, constituting the majority of NSCLC patients. For this reason, ICI
therapy is becoming part of the treatment of such patients, in an attempt to
improve survival and quality of life. The ICIs targets are the immune-competent
cells, such as T-lymphocytes and antigen-presenting cells, releasing a tumourinduced
immunosuppressant milieu (e.g. PD-1, PD-L1) or strengthening the
immune-activating signals of the immune response (e.g. GITR, pro- inflammatory
interleukins, interferon-gamma) (6). The availability of ICIs in NSCLC addresses
an unmet need for patients considered to have a poor prognosis in advanced
stages, in the absence of an indication of targeted therapy.
Melanoma is the most lethal form of skin cancer. In 2018, nearly 300 000
new cases were diagnosed worldwide, with over 60 000 deaths (1). As a cancer
related to the exposure to sunlight, melanoma demonstrates greater variation
in incidence rates across different ethnic groups and is more commonly found
among fair-skinned Caucasian populations. Incidence of melanoma peaks at the
7th decade of life; however, though half of the diagnoses are in patients aged
between 55 and 74 years, melanoma is the most common cancer diagnosed in
adolescents and young adults 20–29 years and the most commonly diagnosed
cancers in young adults worldwide (7). Early detection and resection of melanoma
is the most effective treatment strategy, with a traditionally poor prognosis for
metastatic disease (8).
The Phase III KEYNOTE-024 study evaluated pembrolizumab as first-line
treatment in patients with advanced NSCLC showing PD-L1 expression ≥50%, in
the absence of epidermal growth factor receptor (EGFR) mutation or anaplastic
lymphoma kinase (ALK) translocations (non-oncogene-driven NSCLC) (9).
Approximately 30% of screened patients had tumour PD-L1 expression ≥50%.
305 patients were randomized to receive 200 mg pembrolizumab every three
weeks (up to two years) or 4-6 cycles of standard platinum-doublet chemotherapy.
Patients in the chemotherapy group were permitted to cross over to the
pembrolizumab group if they experienced disease progression. In the intentionto-
treat population, progression-free survival (PFS) and overall survival (OS)
were significantly longer in the pembrolizumab group than the chemotherapy
group (PFS: hazard ratio (HR) 0.50, 95%CI 0.37 to 0.68; p<0.001; OS: HR 0.60,
95%CI 0.41 to 0.89; p=0.005). Health-related quality of life measures also
favoured pembrolizumab (10).
An updated survival report with a 25.2 months median follow up,
confirmed the superiority of pembrolizumab over chemotherapy: the HR for
OS was 0.63 (95%CI 0.47 to 0.86), with a median OS of 30.0 months (95%CI
18.3–not reached) in the pembrolizumab arm and 14.2 months (95%CI 9.8 to
19.0) in the chemotherapy arm; the Kaplan-Meier estimate of OS at 12 months
was 70.3% (95%CI 62.3% to 76.9%) for the pembrolizumab group and 54.8%
(95%CI 46.4% to 62.4%) for the chemotherapy group (11). Eighty-two patients,
allocated to the chemotherapy arm, crossed over to receive pembrolizumab upon
meeting eligibility criteria. In term of magnitude of benefit, pembrolizumab
provided a gain of median OS of +15.8 months and +15.5% at one year.
Based on the KEYNOTE-024 trial results, the clinical benefit of
pembrolizumab in the first-line setting measured with the European Society
for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1
received a score of 4 (12).
The first-line use of pembrolizumab was investigated in NSCLC
other than PD-L1>50%, to assess if the benefit was conserved in unselected
populations of patients. The Phase III KEYNOTE-042 trial randomized patients
with NSCLC EGFR/ALK wild type showing PD-L1≥1%, both adenocarcinoma
and squamous NSCLC, to receive either pembrolizumab 200 mg every three
weeks or standard chemotherapy (paclitaxel plus carboplatin or pemetrexed
plus carboplatin), stratifying per PD-L1 expression at three thresholds of
PD-L1: ≥50%, ≥20% and ≥1% (13). 1274 patients were randomized: 637 to
each arm. 599 patients (47.0%) had PD-L1 ≥50%, 818 (64.2%) had ≥20%.
Pembrolizumab improved OS in NSCLC patients with PD-L1≥50% (HR 0.69,
95%CI 0.56 to 0.85), consistent with the results of Keynote-024 for the PD-L1
enriched population. The median OS (up to approximately 38 months) with the
PD-L1 inhibitor was 20.0 months vs 12.2 months with chemotherapy. The HR
for OS was 0.77 (95%CI 0.64 to 0.92) and 0.81 (95%CI 0.71 to 0.93) for PD‑L1
≥20% and ≥1%, respectively. In patients with limited expression of PD-L1
(1–49%) the stratified analysis of survival showed that OS reached 17.7 vs 13.0
months in PD-L1 ≥20% and 16.7 and 12.1 in PD-L1 ≥1%, respectively in these
sub-populations. However, an exploratory analysis of KEYNOTE-042 showed
that the survival advantage associated with pembrolizumab vs chemotherapy in
patients with a tumour proportion score between 1% to 49% was not relevant
(median OS: 13.4 vs 12.1 months; HR 0.92, 95%CI 0.77 to 1.11). The overall
benefit might be driven by the enriched population with high expression of
PD‑L1 as the preponderance of the OS benefit was seen in patients with ≥50%,
the only sub-group gaining more than six months overall survival.
The KEYNOTE-010 trial randomized 1034 patients with previously-treated
squamous (22% of the population) and non-squamous (70%) NSCLC with PDL1
expression of at least 1% of tumour cells to receive pembrolizumab (2 mg/kg
or 10 mg/kg, every three weeks) or docetaxel 75 mg/m2 every three weeks (14).
Approximately two thirds of NSCLC patients screened met the PD-L1 threshold
of 1%, and 28% showed high expression (≥50%), consistent with previous
findings in Keynote-024. Patients were stratified in PD-L1 1–49% and PD-L1
≥50%. OS was longer for pembrolizumab versus docetaxel (2 mg/kg, HR 0.71,
95%CI 0.58 to 0.88; 10 mg/kg, HR 0.61, 95%CI 0.49 to 0.75). Median overall
survival was 10.4 months (95%CI 9.4 to 11.9) for the pembrolizumab 2 mg/kg
group, 12.7 months (10.0 to 17.3) for the pembrolizumab 10 mg/kg group, and
8.5 months (95%CI 7.5 to 9.8) for the docetaxel group. One-year overall survival
was 43.2% vs 52.3% vs 34.6%.
Based on the KEYNOTE-010 trial results, the clinical benefit of
pembrolizumab in the second-line setting measured with the ESMO-MCBS v1.1
was scored at 5/5 (12).
In patients with a PD-L1 tumour proportion score of ≥50%, the greatest
benefit was observed for OS for pembrolizumab 2 mg/kg vs docetaxel with
HR 0.54 (95%CI 0.38 to 0.77; p=0.0002), and for pembrolizumab 10 mg/kg vs
docetaxel HR 0.50 (95%CI 0.36 to 0.70; p<0.0001). Median OS was 14.9 months
and 17.3 months for the 2 mg/kg and 10 mg/kg arms respectively, longer than
the chemotherapy arm (8.2 months). After the primary analysis, crossover from
docetaxel to pembrolizumab was allowed. 36 months overall survival rate was
23% for the pembrolizumab groups (pooling the two dose arms) vs 11% for
The role of nivolumab as second-line treatment of NSCLC has been
investigated two Phase III clinical trials: CheckMate-017 and CheckMate-057.
In CheckMate-017, 272 patients with squamous NSCLC were randomized to
receive nivolumab 3 mg/kg every two weeks, or docetaxel, at a dose of 75 mg/m2
every three weeks (16). The median OS was 9.2 months (95%CI 7.3 to 13.3) in
the nivolumab group vs 6.0 months (95%CI 5.1 to 7.3) in the docetaxel group.
The OS rate at one year was 42% (95%CI 34 to 50) in the nivolumab group vs 24%
(95%CI 17 to 31) in the docetaxel group. OS was improved in those who received
nivolumab (HR 0.59, 95%CI 0.44 to 0.79, p<0.001). The rate of confirmed
objective response was higher with nivolumab than with docetaxel (20%, 95%CI
14 to 28 vs 9%, 95%CI 5 to 15), p=0.008). The median PFS was 3.5 months (95%CI
2.1 to 4.9) in the nivolumab group and 2.8 months (95%CI 2.1 to 3.5) in the
docetaxel group, consistent with the mechanism of action of ICIs, where atypical
patterns of response are described (pseudo progression) and long-lasting postprogression
benefit persisting (17). The level of PD-L1 expression was neither
prognostic nor predictive of any of the efficacy endpoints.
Based on the CheckMate-017 trial results, the clinical benefit of
nivolumab in the second-line setting in squamous cell NSCLC measured with
the ESMO-MCBS v1.1 was scored at 5/5 (12).
In CheckMate-057, 582 patients with non-squamous NSCLC (e.g.
adenocarcinoma) were randomized to nivolumab or docetaxel (18). Nivolumab
improved OS compared to docetaxel: at the time of interim analysis, median
OS was 12.2 months (95%CI 9.7 to 15.0) for nivolumab and 9.4 months (95%CI
8.1 to 10.7) for docetaxel, with a HR of 0.73 (95%CI 0.59 to 0.89; p=0.002).
One-year OS rates were 51% (95%CI 45 to 56) and 39% (95%CI 33 to 45)
for nivolumab and docetaxel, respectively. The survival HRs per sub-group
analysis did not favour nivolumab over docetaxel in the EGFR-mutated NSCLC
population (oncogene-driven disease, HR 1.18) (19). Moreover, the EGFR wildtype
populations seemed to derive the greatest benefit, with HR 0.66 (95%CI
0.51 to 0.86).
Based on the CheckMate-057 trial results, the clinical benefit of
nivolumab in the second-line setting in non-squamous cell NSCLC measured
with the ESMO-MCBS v1.1 was scored at 5/5 (12).
In an updated analysis of CheckMate-017 and CheckMate-057, pooled
two-year OS favoured nivolumab in both squamous and non-squamous
NSCLC (squamous: 29%, 95%CI 24% to 34% vs 16%, 95%CI 12% to 20%;
non‑squamous: 23%, 95%CI 16% to 30% vs 8%, 95%CI 4% to 13%) (20). In
the pooled analysis of OS in the intention-to-treat population (n = 854) with
squamous (n = 272 (31.9%)) and non-squamous (n = 582 (68.1%)) NSCLC,
median OS was 11.1 months (95%CI 9.2 to 13.1 months) with nivolumab vs
8.1 months (95%CI 7.2 to 9.2 months) with docetaxel (HR 0.72, 95%CI 0.62
to 0.84). Higher PD-L1 expression levels were associated with greater OS
benefit with nivolumab (HR 0.42, 95%CI 0.28 to 0.63) in patients with ≥50%
PD-L1 expression, but a benefit was still observed in patients with <1% PD-L1
expression (HR 0.78, 95%CI 0.61 to 0.99). Among nivolumab-treated patients,
37% of confirmed responders with squamous NSCLC and 34% with nonsquamous
NSCLC had ongoing responses after two years’ minimum follow up
and no patient in docetaxel group had an ongoing response. Consistent with
the primary analyses, two-year OS benefit with nivolumab versus docetaxel was
observed in patients with squamous NSCLC regardless of PD-L1 expression
level. However, in patients with non-squamous NSCLC, higher levels of PD-L1
were associated with a greater magnitude of OS benefit with nivolumab. NSCLC
with PD-L1<1% still derived greater benefit from ICI than chemotherapy:
in patients with ≥50% PD-L1 expression, the HR for OS on the basis of two
years’ minimum follow-up was 0.38 (95%CI 0.24 to 0.60) for patients with nonsquamous
The Phase III OAK trial randomized 850 immuno-oncology naive patients
with advanced squamous and non-squamous NSCLC previously treated with
one or two lines of chemotherapy to receive atezolizumab 1200 mg fixed dose
every three weeks or standard docetaxel 75 mg/m² every three weeks (21).
Treatment was administered until unacceptable toxicity or disease progression.
Atezolizumab could be continued beyond disease progression if clinical benefit
was demonstrated despite evidence of radiological disease progression on
computerized tomography (CT) scan, to rule out atypical pattern of response (i.e.
pseudo progression). No crossover to atezolizumab was allowed. Patients were
stratified by PD-L1 expression. OS was improved in the ITT study population
with atezolizumab, reaching a median OS of 13.8 months (95%CI 11.8 to 15.7)
vs docetaxel (9.6 months, 95%CI 8.6 to 11.2), with HR 0.73 (95%CI 0.62 to 0.87,
Based on the OAK trial results, the clinical benefit of atezolizumab in the
second-line setting measured with the ESMO-MCBS v1.1 was scored at 5/5 (12).
Sub-group analysis showed a greater magnitude of benefit in patients
with higher PD-L1 expression, both assessed on tumour cells (TC) or immuneinfiltrating
cells (IC): the net benefit gain in TC1/2/3 or IC1/2/3 population was
+5.4 months (HR 0.74, 95%CI 0.58 to 0.93, p=0.0102) and +5.5 months in
TC2/3 or IC2/3 population (HR 0.67, 95%CI 0.49 to 0.90, p=0.0080).
The role of pembrolizumab was investigated in randomized trials and
cohort studies for metastatic or unresectable locally-advanced melanoma as
monotherapy, both in BRAF-mutated and wild-type tumours.
The Phase I Keynote-001 trial evaluated pembrolizumab 2 mg/kg and
10 mg/kg every two weeks in patients with advanced melanoma (22). Around
one third of the population was pre-treated with ipilimumab. The overall response
rate during receipt of therapy, across all doses, based on assessment by the
investigator according to immune-related response criteria was 38%. An updated
analysis showed an estimated five-year OS rate of 34% in all patients enrolled
(pre-treated with chemotherapy, targeted agents or ipilimumab) and 41% in
treatment-naive patients (23). Median OS was 23.8 months (95%CI 20.2 to 30.4)
and 38.6 months (95%CI 27.2–not reached) in pre-treated and treatment-naive
patients, respectively with a five-year PFS rates of 21% and 29%.
The Phase II Keynote-002 trial assessed the efficacy and safety of
pembrolizumab 2 mg/kg or 10 mg/kg every three weeks vs investigator-choice
chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine,
or oral temozolomide) in patients with ipilimumab-refractory melanoma (1:1
randomization, n=540 patients) (24, 25). Median OS was 13.4 months for 2 mg/
kg, 14.7 months for 10 mg/kg, and 11.0 months for chemotherapy. 18-months
OS rates were 40%, 44%, and 36%; 24-months rates were 36%, 38%, and 30%.
HR for OS was 0.86 (95%CI 0.67 to 1.10) for 2 mg/kg and 0.74 (95%CI 0.57
to 0.96) for 10 mg/kg, with no difference between doses (0.87, 95%CI 0.67 to
1.12). The benefit was consistent across the sub-groups, of age (younger or older
than 65 years), plasma lactate dehydrogenase (LDH) normal or elevated, sex
and BRAF status (mutant or wild-type).
Based on the Keynote-002 trial results, the clinical benefit of
pembrolizumab for melanoma in the second-line setting measured with the
ESMO-MCBS v1.1 was scored at 3/5 (12).
The Phase III Keynote 006 trial assessed pembrolizumab (10 mg/kg every
two weeks or every three weeks) as first-line therapy for advanced melanoma,
versus ipilimumab (3 mg/kg), the standard of care at the time of the investigation
(26, 27). Median OS was not reached in either pembrolizumab group and was
16.0 months with ipilimumab (HR 0.68, 95%CI 0.53 to 0.87 for pembrolizumab
every two weeks vs ipilimumab and 0.68, 95%CI 0.53 to 0.86 for pembrolizumab
every 3 weeks vs ipilimumab). 24-month OS rate was 55% in the two- and threeweek
group, and 43% in the ipilimumab group, showing limited differences
between pembrolizumab dosing schedules.
The CheckMate 037 trial assessed the efficacy and safety of nivolumab (3 mg/kg
every two weeks) in ipilimumab-progressing patients, compared with standard
chemotherapy (dacarbazine, paclitaxel combined with carboplatin every three
weeks) (28). Confirmed objective responses were reported in 31.7% (95%CI
23.5 to 40.8) in the nivolumab group versus 10.6% (95%CI 3.5 to 23.1) in the
chemotherapy arm. However overall survival did not differ between arms, being
15.74 (12.88 to 19.88) in the nivolumab group and 14.39 (11.66 to 18.17) in the
investigator’s choice group (HR 0.95, 95%CI 0.73 to 1.24) (29).
CheckMate 066 tested nivolumab first-line versus dacarbazine, showing
a gain in OS of 73% vs 42% at 1 year (30, 31). Response rates also favoured
nivolumab, 40% vs 14%. Three-year OS survival rates were 51.2% (95%CI
44.1% to 57.9%) and 21.6% (95%CI 16.1% to 27.6%), respectively. The median
OS was 37.5 months (95%CI 25.5 months to not reached) in the nivolumab
group and 11.2 months (95%CI 9.6 to 13.0 months) in the dacarbazine group
(HR 0.46, 95%CI 0.36 to 0.59), with a net benefit of OS of +26.3 months.
CheckMate 067 tested the combination treatment of the two ICIs
nivolumab and ipilimumab against nivolumab monotherapy and ipilimumab
alone in a 1:1:1 ratio (32, 33). Median PFS was 11.5 months (95%CI 8.9 to 16.7)
with nivolumab plus ipilimumab, compared with 2.9 months (95%CI 2.8 to 3.4)
with ipilimumab (HR 0.42; 99.5% CI, 0.31 to 0.57) and 6.9 months (95%CI 4.3
to 9.5) with nivolumab (HR for the comparison with ipilimumab, 0.57, 99.5%CI
0.43 to 0.76, p<0.001). A subgroup analysis according to PD-L1 expression was
performed. Patients with tumours positive for PD-L1, achieved a median PFS
of 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab
group, but in patients with PD-L1–negative tumours, PFS was longer with the
combination therapy than with nivolumab alone (11.2 months (95%CI 8.0 to
not reached) vs 5.3 months (95%CI 2.8 to 7.1)). The four-year follow-up updated
results confirmed the earlier findings: median OS was not reached (95%CI 38.2
to not reached) in the nivolumab plus ipilimumab group, 36.9 months (95%CI
28.3 to not reached) in the nivolumab group, and 19.9 months (95%CI 16.9 to
24.6) in the ipilimumab group. The results of sub-group analyses suggested that
the greatest benefit with the combination of nivolumab and ipilimumab versus
nivolumab alone may occur in the context of negative PD-L1 tumour expression.
In the subgroup of patients with PD-L1–positive tumours, both nivolumab
alone and nivolumab plus ipilimumab resulted in a similar prolongation of PFS
compared to ipilimumab alone. This finding suggested the role of immunotherapy
as monotherapy in “inflamed tumours”, showing high expression of PD-L1
and a role of combination therapy for “non-inflamed” tumours, for which the
combination ICI could derive a major benefit, acting synergistically on different
steps of immune activation.
The clinical benefit of nivolumab for first-line treatment of metastatic
melanoma measured with the ESMO-MCBS v1.1 was scored at 4/5 (12).
Early stage (resected) melanoma
The discussion around the role of immunotherapy in the adjuvant setting of
melanoma is ongoing, with data of OS expected to confirm the optimal strategy
of care, particularly between the ipilimumab and the PD-1 blockers, including
the safety profile.
Pembrolizumab was assessed as an adjuvant agent in the Phase III Keynote 054
trial, for patients with stage III resected melanoma. Patients were randomized
to receive pembrolizumab 200 mg every three weeks for 18 doses or placebo
(n=1019) (34). Pembrolizumab showed a superior relapse-free survival rate,
from 61% to 75.4% at 12 months (HR 0.57, 95%CI 0.43 to 0.74); the data were
consisted across the PD-L1 pre-specified sub-groups.
The CheckMate-238 trial compared high-dose ipilimumab versus nivolumab
3 mg/kg every two weeks up to 12 months (35). Patients with resected stage
III and IV, with no evidence of disease (NED) derived major benefit from
nivolumab: relapse-free survival at 12 months was 70.5% and 60.8%, respectively
(HR 0.65, 95%CI 0.51 to 0.83). At 24-months follow-up, nivolumab was shown
to be superior with +13% of relapse-free survival (35, 36). The benefit was
consistent across the sub-groups of PD-L1 expression, in PD-L1 less than 5% or
5% and more.
In Keynote 024, treatment-related adverse events (TRAE) occurred in 73.4% of
the patients in the pembrolizumab group and in 90.0% of the patients in the
chemotherapy group, of which 53.3% vs 26.6% were Grade 3 (moderate-severe)
to Grade 5 (toxic death) in the chemotherapy and pembrolizumab groups,
respectively. The treatment discontinuation rate was slightly higher in the
chemotherapy arm (10.7%) than the ICI arm (7.1%) due to these TRAEs (9).
TRAEs for pembrolizumab were consistent with an immune-mediated process,
meaning an autoimmune event or an immune-activation syndrome, the most
common being hypo- and hyper-thyroidism (9% and 8%, all Grade 1 and 2,
non-severe events not leading to discontinuation of therapy and registered as
laboratory transient and not clinically relevant alterations of plasma thyroid
hormones), diarrhoea (in 14.3% of the patients), fatigue (10.4%), and pyrexia
(10.4%) in the pembrolizumab group; for chemotherapy, the bone marrow
toxicity (anaemia in 44.0%) and traditional systemic TRAEs were observed
(nausea in 43.3% and fatigue in 28.7%); anti-emetic pre-medication was
allowed per protocol, consistent with institutional and international guidelines
for moderately to highly-emetogenic platinum-containing CT regimens in the
standard of care arm.
In Keynote 042, despite a longer duration of treatment exposure,
Grades 3 to 5 TRAEs occurred much less often with pembrolizumab than with
chemotherapy (17.8% vs 41.0%) (13). Grades 3 to 5 immune-related adverse
events and infusion reactions occurred more frequently among patients treated
with pembrolizumab than with chemotherapy (8.0% vs 1.5%). The respective
rates of treatment discontinuation (9.0% vs 9.4%) and treatment-related deaths
(2.0% vs 2.3%) were comparable between treatment arms.
In the Keynote-010 trial the safety profile favoured pembrolizumab with less
Grade 3–5 adverse events, namely 16% vs 35% in the chemotherapy arm,
and decreased appetite (14%) and fatigue (14%) for ICI and neutropenia (14%),
alopecia (33%), anaemia (13%) and oral mucositis (14%) for chemotherapy (14).
There was no difference in the efficacy or safety of pembrolizumab at 2 or
In the CheckMate-017, treatment-related adverse events, including haematologic
and non-haematologic events, occurred less frequently with nivolumab than
with docetaxel. In the nivolumab group, 58% of the patients had events of any
Grade, of which 7% were Grade 3 or 4; in the docetaxel group, this occurred in
86% of the patients of which 55% were Grade 3 or 4 (16). The safety profile was
consistent with the class side-effects, with no new signals of safety, namely the
most frequently reported TRAEs with nivolumab were fatigue and asthenia and
for docetaxel were neutropenia (33%; 10% febrile neutropenia), fatigue (33%),
alopecia (22%), nausea (23%) and peripheral neuropathy (11%). Respectively
3% and 10% of patients discontinued the treatment for an adverse event in the
ICI and CT arm.
In the CheckMate-057, the safety profile and pattern of adverse events in
non-squamous NSCLC patients were consistent with the data from squamous
population: treatment-related adverse events were observed in 69%/10%/5% in
nivolumab arm and 88%/54%/15% in docetaxel arm for any Grade/Grade 3-4/
discontinuation rate, respectively (18).
In the Phase III OAK trial, tolerability was better with atezolizumab, with 15%
of 609 patients treated with atezolizumab experiencing a Grade 3–4 treatmentrelated
toxicity compared with 43% of 578 patients treated with docetaxel (21).
Fatigue (87 patients (14%)), nausea (53 patients (9%)), decreased appetite
(52 patients (9%)), and asthenia (51 patients (8%)) were the most common
atezolizumab-related adverse events of any grade.
Safety analysis showed a higher incidence of Grade 3–4 TRAEs in patients
receiving chemotherapy (26%) vs pembrolizumab (11% in the 2mg/kg group,
14% in the 10 mg/kg group) (24). The most common serious TRAEs observed
in the combined pembrolizumab treatment groups were diarrhoea and
pneumonitis. There were no treatment-related deaths. Treatment interruption
as a result of TRAEs was needed in 15 (8%) of 178 patients treated with
pembrolizumab 2 mg/kg, 15 (8%) of 179 patients treated with pembrolizumab
10 mg/kg, and 30 (18%) of 171 patients treated with chemotherapy. TRAEs
led to permanent treatment discontinuation in five (3%) patients given
pembrolizumab 2 mg/kg, 12 (7%) given pembrolizumab 10 mg/kg, and 10 (6%)
patients given chemotherapy.
In the Keynote 006 trial, around two thirds of the study population
experienced a TRAE; however, Grade 3 to 5 adverse events that were attributed
to a study drug by investigators occurred in 13.3% of patients receiving
pembrolizumab every two weeks, 10.1%, every three weeks and 19.9% of patients
receiving ipilimumab, respectively, with a safety profile favourable of the PD-1
blocker over CTLA-4 inhibitor (26). The rate of permanent discontinuation of a
study drug because of TRAEs was lower in each pembrolizumab group than in
the ipilimumab group (4.0%, 6.9%, and 9.4%, respectively).
In the CheckMate 066 trial, treatment-related Grade 3/4 adverse events
occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of
205) of dacarbazine-treated patients (30, 31).
In the CheckMate 238 trial, nivolumab showed a major tolerability and
better safety profile with 14.4%/9.7% Grade 3 and 4 adverse events/treatmentrelated
discontinuation, compared with 45.6%/42.6% in the ipilimumab arm
Early stage (resected) melanoma
No data were presented in the application regarding the safety of immune
checkpoint inhibitors for melanoma in the early/resected stage setting.
Cost / cost effectiveness
The application presented a cost-effectiveness analysis of first-line pembrolizumab
in advanced non-oncogene driven NSCLC expressing high levels of PD-L1
(37). Data of safety and efficacy were derived from the Keynote 024 trial (13).
The analysis was conducted from the perspective of a United States third-party
public health care payer (updated to US$, year 2016 values). Pembrolizumab
would be expected to result in an incremental cost of US$ 98 281 per quality
adjusted life year (QALY) gained or an incremental cost of US$ 78 873 per life
year (LY) gained. Including cost of PD-L1 testing had a very small impact on the
model results. With a five-year time horizon, the ICER was US$ 99 998/LY and
US$ 122 024/QALY; with a 10-year time horizon, the ICER was US$ 83 065 and
US$ 103 101/QALY. Base-case results indicated that, compared with standard of
care over a 20-year time horizon, pembrolizumab would be expected to result in
an additional 1.31 LYs and an additional 1.05 QALYs gained.
In the second-line setting, a cost-effectiveness analysis was presented
for pembrolizumab versus docetaxel in the enriched population with PDL1>
50%. Base case results for PD-L1 positive (TPS ≥50%) patients treated with
pembrolizumab showed a mean survival of 2.25 years (38). For docetaxel, a mean
survival time of 1.07 years was estimated. Expected QALYs were 1.71 and 0.76
for pembrolizumab and docetaxel, respectively. The incremental cost per QALY
gained with pembrolizumab vs docetaxel is US$ 168 619/QALY, which is costeffective
in the United States using a threshold of three times GDP per capita.
The cost‑effectiveness of nivolumab for the treatment of advanced melanoma
patients has been investigated in the United Kingdom. A Markov state-transition
model was developed to estimate the lifetime costs and benefits of nivolumab
versus ipilimumab and dacarbazine for BRAF mutation-negative patients
and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutationpositive
patients (39). Nivolumab was the most cost-effective treatment option
in BRAF mutation-negative and mutation-positive patients, with incremental
cost-effectiveness ratios of £ 24 483 and £ 17 362 per QALY, respectively. A
similar analysis was performed for pembrolizumab in advanced melanoma in
Portugal (40). A cost-effectiveness model was developed to analyse the costs and
consequences of treatment with pembrolizumab compared to treatment with
ipilimumab in patients with advanced melanoma not previously treated with
ipilimumab. Pembrolizumab increased life expectancy in 1.57 undiscounted
life-years (LYs) and was associated with an increase in costs versus that of
ipilimumab. The estimated incremental cost-effectiveness ratio was € 47 221 per
QALY and € 42 956 per LY. The authors concluded that considering the usually
accepted thresholds in oncology, pembrolizumab is a cost-effective alternative
for treating patients with advanced melanoma in Portugal.
Atezolizumab (trade name Tecentriq, Genetech Inc.) is available as a 60 mg/mL
injection solution for intravenous use as 840 mg/14 mL and 1,200 mg/20 mL
Nivolumab (trade name Opdivo, Bristol-Myers Squibb) is available as a
10 mg/mL injection solution for intravenous use as 40 mg/4 mL, 100 mg/10 mL
and 240 mg/24 mL single-dose vials.
Pembrolizumab (trade name Keytruda, Merck Sharp & Dohme) is
available as 50 mg lyophyilized powder for intravenous injection and as a 25 mg/
mL injection solution for intravenous use as 100 mg/4mL single-dose vial.
As a result of the Keynote-024 trial, pembrolizumab was approved by the United
States Food and Drug Administration (FDA) and European Medicines Agency
(EMA) as first-line therapy for patients with NSCLC with high PD-L1 expression
(PD-L1≥50%) as assessed by immunohistochemistry. In the approval trial, the
PD‑L1 expression was assessed in FFPE tumour samples at a central laboratory
with the use of the commercially available PD-L1 IHC 22C3 pharmDx assay
(Dako) on histology specimens. However, the assessment of PD-L1 IHC of
cytology cell-block was as reliable as the histology assessment, in independent
assessments (20–22). The PD-L1 IHC 22C3 pharmDx assay is the companion
diagnostic of pembrolizumab first-line with the threshold of “high expression”
PD-L1 tumour proportion score of ≥50%. This finding is clinically relevant since
the collection of a histology sample may be challenging in lung cancer diagnosis,
particularly when bronchoscopy with fine-needle aspirations is used. In detail,
cell block cytology is a technique used in cytopathology (in addition to smears)
for evaluation of tissue from fine needle aspirations or fluid aspiration for
which the cells in solution are then concentrated via centrifuge from cytological
specimens into paraffin blocks that can be cut and stained by the same methods
used for histopathology. Based on this evidence, the use of the cell-block is
considered as a reliable specimen to assess the PD-L1 status, reducing the
need of more invasive procedures and increasing the likelihood to have an
informative specimen in term of prediction to treatment response with few
Pembrolizumab as monotherapy is indicated in the first-line treatment
of advanced EGFR and ALK wild type NSCLC showing PD-L1 hyperexpression
i.e. PD-L1≥50% and for the second-line treatment of advanced NSCLC with
a PD-L1 tumour expression ≥1% after platinum-containing chemotherapy
failure, and in association with chemotherapy for the first-line treatment of
NSCLC, regardless of PD-L1 status. Moreover, pembrolizumab is indicated for
the first-line treatment of metastatic melanoma, with no biomarker for patients’
selection. Patients are treated with pembrolizumab until disease progression or
Comments on the application were received from the WHO Department of
Management of NCDs, Disability, Violence and Injury Prevention. The technical
unit advised that it not support inclusion of these medicines on the EML at this
time, though noting with great interest the emerging data on long-term outcomes
in this clinically relevant class of medicines.
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