Keywords
Advanced stage solid cancers - immune checkpoint inhibitors - lymphomas - pembrolizumab
Introduction
The ability of cancer cells to evade immunity is the eighth hallmark of cancer.[1] The tumor cells survive by nil antigen expression and higher immune checkpoint expression.[1],[2] Pembrolizumab, a monoclonal antibody, plays a vital role in boosting the cancer
immunity cycle.
Discovery
In 1891, William Coley reported long-term regression of inoperable cancers when Coley's
toxin (heat-inactivated Streptococcus) was administered.[1] In 1959, the concept that the immune system has the capability of killing malignant
cells evolved.[1] In 1992, Tasuku Honjo discovered that mutation in programmed cell death 1 (PD-1)
augments T-cell activity and inhibits the hematogenous dissemination of cancer cells.
This anti-PD1 character was named as immune checkpoint inhibition.[1],[2]
Phase I trials of the first anti-PD-1 antibody, nivolumab in advanced solid cancers,
showed durable response rates.[3] Simultaneously, the promising results of pembrolizumab (anti-PD-1) in KEYNOTE-001
study among advanced melanoma cases with previous ipilimumab exposure cemented the
role of immune checkpoint inhibitors (ICIs) in oncology.
Mechanism of Action
PD-1 protein (or CD279) is primarily expressed on the surface of activated T-cells,
myeloid cells, and B-cells. It has two ligands, programmed cell death ligand 1 (PD-L1)
and PD-L2. PD-L1 is broadly expressed on various organs, while PD-L2 is restricted
to dendritic cells, macrophages, B-cells, and T-helper 2 cells.[4] Cancer cells express both PD-L1 and PD-L2. Binding of PD-1 to PD-L1/L2 induces phosphorylation
of PD-1 cytoplasmic immunoreceptor tyrosine-based inhibition motif recruiting SHP2
phosphatase. SHP2 then dephosphorylates the T-cell receptor, leading to a reduction
of target cell killing.[4] Pembrolizumab (MK-3475, lambrolizumab) is a humanized IgG4 kappa monoclonal antibody
against PD-1. By blocking PD-1, the signals mentioned above are suppressed, and apoptosis
is induced in tumor cells.[4]
Pembrolizumab distribution and metabolism in the body are not well characterized,
and neither is its drug interactions. Its terminal half-life is 26 days.[5] There are no dose modifications with renal or hepatic dysfunction. It has no carcinogenic
or infertility effects. The drug crosses the placenta, and animal studies have demonstrated
fetal harm. Hence, it is contraindicated in pregnancy, and contraception is advised.
Similarly, breastfeeding is to be avoided.[6],[7] Contraindicated in autoimmune disease since it can induce a disease flare, and the
autoimmune therapy might reduce its efficacy.[8]
Uses
Approval by the US Food and Drug Administration (based on landmark trials)
The indications for pembrolizumab are incorporated in [Table 1].[9],[10],[11],[12],[13],[14]
Table 1
Food and Drug Administration-approved indications for pembrolizumab
|
Type of malignancy
|
Clinical trial evidence
|
|
↑Improved, *Accelerated approval by FDA based on tumor response rate and durability
of response. OS – Overall survival; PFS – Progressionfree survival; ORR – Overall
response rate; DOR – Duration of response; NMIBC – Nonmuscle invasive bladder cancer;
CIS – Carcinoma in situ; TPS – Tumor proportion score; SCT -stem cell transplant;
HBV – Hepatitis B virus; HCV – Hepatitis C virus; FDA – Food and Drug Administration;
BCG – Bacillus Calmette-Guérin; UC – Urothelial carcinoma; EGFR – Estimated glomerular
filtration rate; ALK – Anaplastic lymphoma kinase
|
|
Unresectable or metastatic melanoma
|
KEYNOTE-001 and 006 (↑PFS/OS)
|
|
Melanoma - Adjuvant therapy
|
KEYNOTE-054 (↑RFS in stage III)
|
|
Metastatic NSCLC with no EGFR/ALK rearrangement - First-line therapy
|
KEYNOTE 024 (TPS≥50%)
|
|
KEYNOTE 042 (↑OS without chemo)
|
|
KEYNOTE189 (nonsquamous)
|
|
KEYNOTE 407 (squamous) (↑OS with chemo, TPS ≥1%)
|
|
Metastatic NSCLC - Single agent/second line
|
KEYNOTE 010 (TPS ≥1%), ↑DOR, OS and ORR
|
|
Locally advanced or metastatic UC progressed on platinum-based chemotherapy
|
KEYNOTE 045 (↑OS)
|
|
UC progressed <12 months of neoadjuvant/adjuvant chemotherapy. Platinum ineligible
with locally advanced or metastatic UC
|
*KEYNOTE 052 (↑ORR, DOR)
|
|
High-risk NMIBC BCG unresponsive CIS (cystectomy ineligible/unwilling)
|
*KEYNOTE 057 (single-arm trial) ↑ORR/CR and DOR
|
|
First line in advanced renal cell carcinoma with axitinib
|
KEYNOTE 426 (in first-line versus sunitinib) ↑PFS/OS
|
|
First line in recurrent/metastatic head and neck squamous cell carcinoma
|
KEYNOTE 058 (with chemo ↑OS)
|
|
Recurrent/metastatic head and neck squamous cell carcinoma as second line
|
KEYNOTE 048 (↑OS)
|
|
Recurrent locally advanced or unresectable IIIB or metastatic Merkel cell carcinoma
without any prior therapy
|
*KEYNOTE017 (Phase II) (↑PFS, ORR, and DOR
|
|
Hepatocellular carcinoma progressed on or after treatment with sorafenib or
|
*KEYNOTE 224 (↑ORR and DOR) single-arm
|
|
intolerant to it
|
open-label study
|
|
It is indicated in HBV and HCV seropositive patients with Child-Pugh Class A liver
impairment
|
|
Second line in recurrent or metastatic cervical carcinoma patients
|
*KEYNOTE 158 (↑ORR, DOR)
|
|
Recurrent or metastatic gastric and gastroesophageal adenocarcinomas progressed on
|
*KEYNOTE 059 (cohort 1 as a single agent)
|
|
or after ≥2 lines of therapy
|
(↑ORR, DOR)
|
|
Mismatch repair deficient (dMMR) solid tumors when unresectable or metastatic,
|
*KEYNOTE 16 and 164 (colorectal cancers)
|
|
progressed after prior treatment, make pembrolizumab a biomarker defined tumor
|
(↑ORR and DOR)
|
|
site -agnostic approval from FDA
|
*KEYNOTE 158 (noncolorectal) basket study
|
|
Hodgkin’s lymphoma - Refractory or relapsed after ≥3 lines of therapy
|
*KEYNOTE O87 Nonrandomized open-label trial
|
|
(including auto-SCT)
|
(↑ORR and DOR)
|
|
Primary mediastinal large B cell lymphoma - Refractory or relapsed after ≥2 lines
of therapy
|
*KEYNOTE 170 (↑ORR and DOR)
|
|
Progression on ≥2 lines of therapy in small cell lung carcinoma
|
*KEYNOTE 158 cohort G (basket study) KEYNOTE 028 cohort C1 (↑ORR and DOR)
|
KEYNOTE 522 suggests that adding pembrolizumab to neoadjuvant chemotherapy is beneficial
in stage II/III triple-negative breast cancer (pCR 64.8% vs. 51%).[15],[16],[17] In the PURE-01 study of muscle-invasive bladder cancer, pT0 rate was 37% and the
pT1 rate was 55%, irrespective of variant histology.[18]
Drug Controller General of India and Central Drugs Standard Control Organization approval
Drug Controller General of India and Central Drugs Standard Control Organization have
approved pembrolizumab in metastatic melanoma and the first/second-line treatment
of nonsmall cell lung carcinoma as a single agent.
Dose and Administration Instructions
Dose and Administration Instructions
The fixed (200 mg every 3 weeks) and weight-based (2 or 10 mg/kg) dosing demonstrates
similar pharmacokinetic and toxicity profiles.[19]
Pembrolizumab, in solution or lyophilized powder, should be reconstituted with sterile
water along the walls of the vial and by gentle swirl. Do not shake the vial. Discard
the solution if discoloration and particulate matter. If so, discard it. Withdraw
the required volume and transfer into an intravenous bag containing 0.9% sodium chloride
injection USP or 5% dextrose injection USP. Mix by gentle inversion. Infuse the solution
over 30 min. Store the reconstituted solution at room temperature for <6 h and under
refrigeration (2°C–8°C) for < 24 h.
Toxicities
ICI has demonstrated a wide range of immune-related adverse effects (irAEs) as listed
in [Table 2]. Toxicities are a reflection of the drug regimen combined with it and varieties
of malignancies treated.[20]
Table 2
Immune checkpoint inhibitor-related adverse events with immune checkpoint inhibitors
depending on the site
|
Site
|
Incidence (%)
|
|
IRAE – Immune checkpoint inhibitor-related adverse events; ICI – Immune checkpoint
inhibitor
|
|
Dermatological
|
40-60
|
|
Gastrointestinal
|
5-10
|
|
Endocrine
|
6
|
|
<1% severe
|
|
Pulmonary
|
4-5
|
|
Neurologic
|
<5
|
|
Fatigue
|
16-24
|
|
Hematologic
|
<1
|
|
Renal
|
2
|
|
Ocular
|
<1
|
|
Cardiac
|
<0.5
|
|
Fatal toxicities such as pneumonitis, infections, myocarditis, colitis, hemorrhagic/thrombotic,
and neurologic toxicities have been reported.[21] Others such as Stevens–Johnson syndrome and toxic epidermal necrolysis and infusion-related
reactions can be fatal. Hyper-acute graft-versus-host disease and hepatic veno-occlusive
disease can occur post allogeneic stem cell transplant.[22],[23]
For Grade 1 toxicity, use oral prednisone 0.51 mg/kg/day.[22],[23] For any Grade 2, withhold ICI and give oral or intravenous prednisone 12 mg/kg/day
based on symptoms. Discontinue ICI if > Grade 1 hypophysitis, pneumonitis, or sarcoidosis
and if any Grade 3 or more toxicities. Depending on the grade of toxicity, wean off-steroids
at 2–4 weeks if moderate or 4–8 weeks if severe and resume therapy when the adverse
reaction remains at Grade 1 or less. Permanently discontinue ICI for grade 4 or any
life-threatening adverse event. Infliximab, mycophenolate mofetil, tocilizumab as
well as plasmapheresis or immunoglobulin may be considered in steroid-refractory cases.
Consider rituximab or cyclophosphamide in case of hematologic toxicity.[22],[23]
Take Home
The broad activity of pembrolizumab against various malignancies implies that immune
escape is indeed a crucial step in cancer survival. The optimal duration of treatment
is still unknown – whether 2 years or until progression. The Food and Drug Administration
has accepted supplemental Biologics License Applications for 400 mg every 6 weeks
dosing schedule for pembrolizumab across several indications. This dose schedule will
be more convenient for patients.[24]
The cost of treatment with pembrolizumab varies from 2 to 10 lakhs (INR) per dose,
depending on the schedule and patient body weight. irAEs will add to the cost of treatment.
These events complicate the decision on the sequence of management.
Conclusion
Many upcoming trials will highlight the role of ICIs in the era of targeted therapies.
Translational research is needed to develop predictive biomarkers, elucidate the mechanisms
of resistance, and formulate rational combined modality treatment. Although immuno-oncology
is promising, there are still unanswered questions from curative point of view as
well as in pediatric cancers.
