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Immune-checkpoint inhibition in the treatment of advanced non-small cell lung cancer: a focus on special populations

June 2023 Cancer trials Tom Feys

In recent years, immune checkpoint inhibition (ICI), either alone or in combination with chemotherapy, emerged as the standard of care for patients with non-oncogene driven metastatic non-small-cell lung cancer (mNSCLC).1 While the efficacy and safety of these ICI-based treatment strategies was convincingly demonstrated in a number of clinical trials and real-world studies,2-14 the clinical management of certain NSCLC populations remains to be more challenging. This includes patients without the expression of programmed death-ligand 1 (PD-L1), patients with brain or liver metastases, elderly patients or patients with a poor performance status and immunocompromised patients. This article will address the available data with ICI in each of these subgroups, with a focus on the data obtained with pembrolizumab.

Patients without PD-L1 expression

PD-L1 expression is a well-known predictive biomarker for a response to ICI-based therapy in patients with mNSCLC.15 While data show that the clinical benefit of ICI-based therapy increases with an increasing level of PD-L1 expression, this does not rule out a clinical benefit in patients with no or very low levels of PD-L1 expression. In fact, results of a recent meta‐analysis, including a total of 1,132 previously untreated patients with PD‐L1‐negative, non-oncogene driven, non-squamous mNSCLC from seven randomized clinical trials (RCTs) showed that immunotherapy combined with chemotherapy improves the objective response rate (ORR; HR[95%CI]: 2.81[1.69-4.65]), progression-free (PFS; HR[95%CI]: 0.63[0.55–0.74], p < 0.001) and overall survival (OS; HR[95%CI]: 0.68[0.56–0.82], p < 0.001) compared to chemotherapy alone.16 These findings confirm the data from an exploratory analysis zooming in on PD-L1 negative mNSCLC patients enrolled in three RCTs comparing pembrolizumab plus chemotherapy to chemotherapy alone.17 This analysis included a total of 444 PD-L1 negative mNSCLC patients (i.e., a TPS <1%) enrolled in KEYNOTE-021 Cohort G* (carboplatin-pemetrexed with/without pembrolizumab, non-squamous histology), KEYNOTE-189 (carboplatin-pemetrexed with/without pembrolizumab, non-squamous histology), or KEYNOTE-407 (carboplatin-taxane with/without pembrolizumab, squamous histology). Of these patients 256 received chemotherapy-pembrolizumab, while the remaining 188 were treated with chemotherapy alone. Among these PD-L1 negative patients, the addition of pembrolizumab to chemotherapy significantly prolonged the median OS with about 8 months (median OS: 19.0 vs. 11.4 months; HR[95%CI]: 0.63[0.50-0.79]). At the 3-year landmark, this translated into an OS rate of 24.9% with pembrolizumab-chemotherapy as compared to 13.8% with chemotherapy alone (Figure 1). In addition, also the PFS (HR[95%CI]: 0.68[0.56-0.83]) and the ORR were significantly improved when pembrolizumab was added (50% vs. 29.8%).17

Figure 1.  OS for Pembrolizumab-chemotherapy vs. chemotherapy alone in PD-L1 negative mNSCLC patients.17

As such, these findings provide a basis to also consider an ICI-chemotherapy combination as the standard of care for patients with PD‐L1‐negative, non-squamous NSCLC without driver mutations. The latter is also reflected by the most recent ESMO guidelines for the treatment of non-oncogene driven mNSCLC stating that combinations of platinum-based chemotherapy and an anti-PD-(L)1 inhibitors are preferred over chemotherapy alone in patients with advanced NSCLC regardless of their tumor PD-L1 status. With respect to the ICI-chemotherapy combination, these guidelines state that results from KEYNOTE-407 place the combination of pembrolizumab plus carboplatin and (nab)-paclitaxel as the standard choice in patients with metastatic squamous NSCLC, whereas the results from KEYNOTE-189 identify pembrolizumab in combination with pemetrexed and platinum chemotherapy as a standard treatment option in non-squamous mNSCLC, regardless of the PD-L1 expression level.1

Patients with brain metastases

About a third of NSCLC patients will develop brain metastases (BMs) over the course of their disease, with considerable morbidity and mortality. Unfortunately, patients with BMs are generally underrepresented in clinical trials and the available prospective data are limited to patients with asymptomatic and stable BMs. Nevertheless, according to recent evidence, ICIs also seem to exert anticancer activity against active or treated central nervous system (CNS) metastases.

Indeed, several pooled analyses of pivotal RCTs have shown that immunotherapy is effective in improving the outcome for NSCLC patients regardless of the presence of BM. For example, a pooled analysis from KEYNOTE-001, -010, -024 and -042* (all evaluating pembrolizumab monotherapy) showed a significantly longer OS with pembrolizumab vs. chemotherapy in mNSCLC patients with a PD-L1 expression ≥50%, regardless of the presence of BM at baseline (HR 0.83 and HR 0.78 in patients with and without BM, respectively).18

Similarly, a retrospective, pooled analysis of KEYNOTE-021*, -189, and -407 investigated the outcomes of 171 NSCLC patients with previously treated or untreated stable BM who were treated with pembrolizumab combined with a platinum-based chemotherapy or chemotherapy alone.19 In total, 20 of these patients had received prior radiotherapy to the brain. In this analysis, both the OS (HR[95%CI]: 0.48[0.32-0.70]; 1-year OS rate: 62.9% vs. 34.9%) as the PFS (HR[95%CI]: 0.44[0.31-0.62]; 1-year PFS rate: 29.9% vs. 6.6%) proved to be significantly longer for BM patients treated with pembrolizumab plus chemotherapy vs. chemotherapy alone (Figure 2). Also in terms of ORR and duration of response, the pembrolizumab-chemotherapy proved to be better than chemotherapy alone, irrespective of the presence of BM.19

Figure 2. OS results from a pooled analysis of pembrolizumab combination trials (KEYNOTE-021G, KEYNOTE-189, KEYNOTE-407) in patients with or without brain metastases.19

In conclusion, in both studies the median OS was longer in the ICI-chemotherapy arm than in the chemotherapy alone arm, irrespective of the presence of BMs. Based on the results discussed above, it seems safe to say that ICI-based therapy should also be the standard of care for treatment-naïve patients with non-oncogene driven mNSCLC and stable brain metastases. Of note, retrospective studies have also suggested efficacy of immunotherapy in patients with active BM.20,21 While these findings are encouraging, Further studies are needed to confirm whether immunotherapy can be a treatment option for mNSCLC patients with active BM.

Patients with liver metastases

The liver is a common (~15-20%) metastatic site in NSCLC and liver metastases are associated with a poor prognosis.22 Owing to the complicated microenvironment of metastatic liver lesions, the efficacy of ICIs in NSCLC patients with liver metastases has been the subject of an ongoing debate. A meta-analysis of 8 RCTs specifically looked into the clinical benefit of adding a PD-1/PD-L1 inhibitor to chemotherapy in mNSCLC patients with and without liver metastases. In this study, the addition of an ICI to chemotherapy decreased the risk of progression by 40% and the risk of death by 29% in patients without liver metastases. Interestingly, fairly similar results were observed in patients with liver metastases, where the addition of an ICI decrease the risk of progression by 31%, with a 21% reduced death risk. As such, these data suggest that both NSCLC patients with and without liver metastases obtain a comparable benefit with ICI-based therapy.23

In line with this, also a recent real-world study indicates that PD-1/PD-L1 inhibitors are effective in NSCLC patients with liver metastases (N=61). However, the efficacy was somewhat inferior to what was observed in patients without liver metastases, indicating that ICI-based therapy does not overcome the dismal prognostic impact of liver metastases.24 Finally, Gadgeel et al. performed an analysis zooming in on patients with liver metastases included in the KEYNOTE-189 study, evaluating carboplatin-pemetrexed with or without pembrolizumab in non-squamous mNSCLC (N=66).25 Among patients with liver metastases, the addition of pembrolizumab to chemotherapy significantly improved the OS (median: 12.6 vs. 6.6 months; HR[95%CI]: 0.62[0.39-0.98]) and PFS (median 6.1 vs. 3.4 months; HR[95%CI]: 0.52[0.34-0.81]) (Figure 3). These findings are fairly similar to what was achieved in the subgroup of patients without liver metastases, with a HR for OS and PFS of 0.58 and 0.48, respectively.25

Figure 3. OS with carboplatin-pemetrexed with or without pembrolizumab in KEYNOTE-189 for patients with and without liver metastases.25

Patients with KRAS of STK11 mutations

KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation in NSCLC, with a prevalence of about 25%.26 Over the years, conflicting data have been reported on the role of KRAS mutations as a prognostic or predictive factor in mNSCLC. However, a recent meta-analysis and literature review on this topic does suggest that the presence of KRAS mutation is indeed a negative prognostic factor for survival and response outcomes in this setting.27 To assess the potential impact of KRAS mutations on the efficacy of pembrolizumab plus chemotherapy, Gadgeel et al. performed an exploratory analysis of the KEYNOTE-189 trial.28 In total, KRAS mutation data were available for 289 patients treated enrolled in this study. Of these patients, 89 (31%) were found to be KRAS mutation positive, with a KRASG12C mutation in 37 patients (13%). Interestingly, the PFS benefit obtained from adding pembrolizumab to chemotherapy proved to be similar for patients without a KRAS mutation (HR[95%CI]: 0.40[0.29-0.57]), for patients with any KRAS mutation (HR[95%CI]: 0.47[0.29-0.77]) and for patients harboring a KRASG12Cmutation (HR[95%CI]: 0.48[0.22-1.06]). Both in patients with and without a KRAS mutation, this PFS benefit translated into a marked improvement in OS (median 21 vs. 14 months; HR[0.79[0.45-1.38] and median 23 vs. 9 months; HR[95%CI]: 0.55[0.37-0.81], respectively).28

In addition to KRAS, also mutations in the tumor suppressor gene STK11 (a.k.a. LKB1) have been associated with poorer clinical outcomes in patients with NSCLC.29 In another exploratory analysis of KEYNOTE-189, researchers looked into the impact of STK11 mutations on the efficacy of pembrolizumab plus chemotherapy.30 Among the 289 patients with available data, 54 (19%) had an STK11 mutation. Among patients treated with pembrolizumab plus chemotherapy those harboring an STK11 mutation had a numerically lower ORR (31% vs. 17%) and a shorter median PFS (6 vs. 10 months) and OS (17 vs. 23 months) than patients with wildtype STK11, confirming the negative prognostic impact of STK11 mutations in this setting. However, pembrolizumab plus chemotherapy was associated with a better outcomes than placebo plus chemotherapy regardless of the STK11 mutation status.30

Based on the results of these two exploratory analyses it is safe to say that pembrolizumab plus pemetrexed and a platinum should be the standard of care for patients with metastatic, non-squamous NSCLC, irrespective of the KRAS or STK11 mutation status.

Figure 4. OS with carboplatin-pemetrexed with or without pembrolizumab in KEYNOTE-189 for patients with and without a KRAS mutation.28

Patients with pre-existing auto-immune disease

The fear for severe immune-related adverse events (irAEs) or exacerbation of underlying autoimmune disease (AID) formed the rationale to exclude patients with pre-existing AID from the pivotal clinical trials evaluating ICI-based therapy in mNSCLC. Nevertheless, pre-existing AID is an important comorbidity among lung cancer patients, with data indicating an incidence of 14-25%.31 To address this issue, several real-world studies have evaluated the safety and efficacy of ICI in patients with advanced cancer and a concomitant (history of) AID.32-45 In brief, these studies indicate that pre-existing AID does increase the risk for the development of irAEs. However, this excess morbidity is largely limited to mild or moderate AID flares, without an increased incidence of grade 3/4 irAEs, or an increased rate of AE-related treatment discontinuations.32-37 In terms of efficacy, the presence of AID does not seem to have an impact. In fact, data show similar response rates and a comparable PFS and OS for ICI-treated advanced NSCLC patients with and without AID.32-37 Importantly, the studies mentioned above mainly included patients with inactive AID. However, small patient series and case reports have illustrated that ICI-based therapy can also be safe and effective in patients with active AID who receive concomitant therapy with a selective immunosuppressant.40-44 In this active AID setting, it is important to underscore that the selectivity of the immunosuppression is relevant. In fact, data indicate that corticosteroid use at the time of ICI initiation is associated with a poorer outcome in patients with advanced NSCLC.38-40

Based on the results of these and other studies, Haanen et al. developed practical recommendations on the use of ICI in advanced cancer patients with AID. These guidelines recommend a personalized, two-step strategy when considering an ICI in patients with active AID. In a first step, prior to the ICI initiation, all non-specific immunosuppression (i.e., steroids) should be discontinued and replaced by the most appropriate, selective immunosuppression. Once the AID is stable, the ICI treatment can be initiated. Importantly, this process needs to be closely monitored by a multidisciplinary team to detect any AID flares at an early stage and allow an early intervention.46 In this paper, specific algorithms have been formulated to optimize ICI-based therapy in patients with rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, polymyalgia rheumatica, giant cell arteritis, spondyloarthritis, antisynthetase syndrome, hypereosinophilic syndrome, systemic sclerosis, Sjogren’s syndrome and sarcoidosis.

While there is still much to learn about the use of ICI-based therapy in NSCLC patients with pre-existing AID, the available data show that the presence of AID should not be a reason to automatically forego on this treatment modality. In fact, the use of ICI seems to be safe and effective in NSCLC patients with non–life-threatening and inactive AID, despite a higher incidence of low-grade irAEs. Nevertheless, close monitoring and vigilance for the development of irAEs or AID flares is highly recommended. For NSCLC patients with active AID, a personalized strategy, including a switch towards selective immunosuppression prior to ICI initiation together with an active monitoring program, can be considered when ICI therapy seems a valid treatment option.

Patients with a poor performance status

All published phase III studies evaluating ICIs in the mNSCLC setting have excluded patients with a performance status (PS) ≥2. As a result, the only available data on this issue come from subgroup analyses of phase II studies, retrospective series and expanded access programs.47-50 In brief, these studies show that the survival with ICI-based therapy among these patients is shorter than what is observed in patients with a PS 0-1, although the toxicity does not seem to increase.47-50 The only clinical trial that specifically looked into PS 2 patients consists of the single-arm PEPS2 trial (N = 62). In this study, pembrolizumab monotherapy proved to be safe, with a durable clinical benefit (i.e., no progressive disease at 18 weeks) in 22%-53% of patients.51

On this topic, the most recent ESMO guidelines acknowledge that there are insufficient data on the use of monotherapy ICI in patients with a PS 2, However, this treatment option can be considered based on the results of the PEPS2 trial. In contrast, chemotherapy–ICI has not been formally evaluated in this setting and cannot be recommended.1

Conclusions

ICI-based therapy has become standard of care in the first-line treatment of patients with non-oncogene driven mNSCLC. However, the increased use of ICI in clinical practice also brings about challenges, including the treatment of patients who would have been ineligible, or were underrepresented in the different registrational clinical trials. Overall, the data discussed in this paper suggest that ICI-based therapy is safe, effective, and feasible in patients without PD-L1 expression, elderly patients, patients with brain or liver metastases, and patients with an AID, or PS 2. However, there remains to be a need for dedicated, prospective trials evaluating ICI-based therapy in these challenging populations.

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Abbreviations: AE = Adverse Event; AID = Autoimmune Disease; ALK = Anaplastic Lymphoma Kinase; BM = Brain Metastases; BRAF = v-raf murine sarcoma viral oncogene homolog B1; Chemo = Chemotherapy; ChT = Chemotherapy; CI = Confidence Interval; CNS = Central Nervous System; EGFR = Epidermal Growth Factor Receptor; ESMO = European Society for Medical Oncology; HER2 = Human Epidermal growth factor Receptor 2; HR = Hazard Ratio; ICI = Immune Checkpoint Inhibition; irAEs = Immune-Related Adverse Events; ITT = Intention-to-Treat; KRAS = Kirsten Rat Sarcoma Virus; LKB1 = Liver kinase B1; MET = MET proto-oncogene; mNSCLC = metastatic non-small-cell lung cancer; Mo. = Months; mOS = Median Overall Survival; MT = Mutation Type; N = Number; NGS = next generation sequencing; No. = Number; NSCLC = non-small-cell lung cancer; NTRK = Neurotrophic Tyrosine Receptor Kinase; ORR = Objective Response Rate; OS = Overall Survival; OS = Overall Survival; p = p-value; PD-1 = Programmed Death-1; PD-L1 = Programmed death-ligand 1; PFS = Progression-Free Survival; PS = Performance Status; RCTs = Randomized Clinical TrialsRET = Ret Proto-Oncogene;ROS1 = ROS proto-oncogene 1; STK11 = Serine/threonine kinase 11; TPS = Tumor Proportion Score; WT = Wild Type.

*According to KEYTRUDA SmPC, KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations

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1. NAME OF THE MEDICINAL PRODUCT KEYTRUDA 25 mg/ml concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial of 4 ml of concentrate contains 100 mg of pembrolizumab. Each ml of concentrate contains 25 mg of pembrolizumab. Pembrolizumab is a humanised monoclonal anti-programmed cell death‑1 (PD‑1) antibody (IgG4/kappa isotype with a stabilising sequence alteration in the Fc region) produced in Chinese hamster ovary cells by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion. Clear to slightly opalescent, colourless to slightly yellow solution, pH 5.2 – 5.8. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Melanoma KEYTRUDA as monotherapy is indicated for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage IIB, IIC or III melanoma and who have undergone complete resection (see section 5.1). Non‑small cell lung carcinoma (NSCLC) KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous non‑small cell lung carcinoma in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous non‑small cell lung carcinoma in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic non‑small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. Classical Hodgkin lymphoma (cHL) KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. Urothelial carcinoma KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy (see section 5.1). KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1). Head and neck squamous cell carcinoma (HNSCC) KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see section 5.1). KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy (see section 5.1). Renal cell carcinoma (RCC) KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma in adults (see section 5.1). KEYTRUDA, in combination with lenvatinib, is indicated for the first line treatment of advanced renal cell carcinoma in adults (see section 5.1). KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (for selection criteria, please see section 5.1). Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers: Colorectal cancer (CRC) KEYTRUDA as monotherapy is indicated for adults with MSI-H or dMMR colorectal cancer in the following settings: first‑line treatment of metastatic colorectal cancer; treatment of unresectable or metastatic colorectal cancer after previous fluoropyrimidine‑based combination therapy. Non-colorectal cancers KEYTRUDA as monotherapy is indicated for the treatment of the following MSI‑H or dMMR tumours in adults with: advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum‑containing therapy in any setting and who are not candidates for curative surgery or radiation;unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy. Oesophageal carcinoma KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma, in adults whose tumours express PD‑L1 with a CPS ≥ 10 (see section 5.1). Triple‑negative breast cancer (TNBC) KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early‑stage triple‑negative breast cancer at high risk of recurrence (see section 5.1). KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple‑negative breast cancer in adults whose tumours express PD‑L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease (see section 5.1). Endometrial carcinoma (EC) KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation. Cervical cancer KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD‑L1 with a CPS ≥ 1. 4.2 Posology and method of administration Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. PD-L1 testing If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, 4.8, and 5.1). MSI/MMR testing If specified in the indication, patient selection for treatment with KEYTRUDA based on MSI‑H/dMMR tumour status should be confirmed by a validated test (see sections 4.1 and 5.1). Posology The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL or patients aged 12 years and older with melanoma is 2 mg/kg bodyweight (bw) (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies. Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). Atypical responses (i.e. an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed. For the adjuvant treatment of melanoma or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. For the neoadjuvant and adjuvant treatment of TNBC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment. Dose delay or discontinuation (see also section 4.4) No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld or discontinued to manage adverse reactions as described in Table 1. Table 1: Recommended treatment modifications for KEYTRUDA Immune-related adverse reactions/Severity (Treatment modification) Pneumonitis: Grade 2 (Withhold until adverse reactions recover to Grades 0-1*), Grades 3 or 4, or recurrent Grade 2 (Permanently discontinue); Colitis: Grades 2 or 3 (Withhold until adverse reactions recover to Grades 0-1*), Grade 4 or recurrent Grade 3 (Permanently discontinue); Nephritis: Grade 2 with creatinine > 1.5 to ≤ 3 times upper limit of normal (ULN) (Withhold until adverse reactions recover to Grades 0-1*), Grade ≥ 3 with creatinine > 3 times ULN (Permanently discontinue); Endocrinopathies: Grade 2 adrenal insufficiency and hypophysitis ( Withhold treatment until controlled by hormone replacement), Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis, Type 1 diabetes associated with Grade ≥ 3 hyperglycaemia (glucose > 250 mg/dL or > 13.9 mmol/L) or associated with ketoacidosis, Hyperthyroidism Grade ≥ 3 (Withhold until adverse reactions recover to Grades 0-1* For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued.), Hypothyroidism (Hypothyroidism may be managed with replacement therapy without treatment interruption.); Hepatitis: NOTE: for RCC patients treated with pembrolizumab in combination with axitinib with liver enzyme elevations, see dosing guidelines following this table. Grade 2 with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times ULN or total bilirubin > 1.5 to 3 times ULN (Withhold until adverse reactions recover to Grades 0-1*), Grade ≥ 3 with AST or ALT > 5 times ULN or total bilirubin > 3 times ULN (Permanently discontinue), In case of liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT increases ≥ 50% and lasts ≥ 1 week (Permanently discontinue); Skin reactions: Grade 3 or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (Withhold until adverse reactions recover to Grades 0-1*), Grade 4 or confirmed SJS or TEN (Permanently discontinue); Other immune-related adverse reactions: Based on severity and type of reaction (Grade 2 or Grade 3) (Withhold until adverse reactions recover to Grades 0-1*), Grades 3 or 4 myocarditis, Grades 3 or 4 encephalitis, Grades 3 or 4 Guillain-Barré syndrome (Permanently discontinue), Grade 4 or recurrent Grade 3 (Permanently discontinue). Infusion-related reactions: Grades 3 or 4 (Permanently discontinue). Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4). * If treatment-related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of KEYTRUDA, or if corticosteroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks, KEYTRUDA should be permanently discontinued. The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-related myocarditis is not known. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-related adverse reactions, unless otherwise specified in Table 1. For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until adverse reactions recover to Grades 0-1. KEYTRUDA in combination with axitinib in RCC For RCC patients treated with KEYTRUDA in combination with axitinib, see the SmPC regarding dosing of axitinib. When used in combination with pembrolizumab, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer (see section 5.1). For liver enzyme elevations, in patients with RCC being treated with KEYTRUDA in combination with axitinib: • If ALT or AST ≥ 3 times ULN but < 10 times ULN without concurrent total bilirubin ≥ 2 times ULN, both KEYTRUDA and axitinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or sequential rechallenge with both medicines after recovery may be considered. If rechallenging with axitinib, dose reduction as per the axitinib SmPC may be considered. • If ALT or AST ≥ 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroid therapy may be considered. KEYTRUDA in combination with lenvatinib When used in combination with lenvatinib, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued in accordance with the instructions in the lenvatinib SmPC for combination with pembrolizumab. No dose reductions are recommended for KEYTRUDA. Patients treated with KEYTRUDA must be given the patient alert card and be informed about the risks of KEYTRUDA (see also package leaflet). Special populations Elderly No dose adjustment is necessary in patients ≥ 65 years (see sections 4.4 and 5.1). Renal impairment No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has not been studied in patients with severe renal impairment (see sections 4.4 and 5.2). Hepatic impairment No dose adjustment is needed for patients with mild or moderate hepatic impairment. KEYTRUDA has not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of KEYTRUDA in children below 18 years of age have not been established except in paediatric patients with melanoma or cHL. Currently available data are described in sections 4.8, 5.1 and 5.2. Method of administrationKEYTRUDA is for intravenous use. It must be administered by infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first.For instructions on dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.8 Undesirable effects Summary of the safety profile Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of pembrolizumab (see “Description of selected adverse reactions” below). The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. Pembrolizumab in monotherapy (see section 4.2)The safety of pembrolizumab as monotherapy has been evaluated in 7,631 patients across tumour types and across four doses (2 mg/kg bw every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bw every 2 or 3 weeks) in clinical studies. In this patient population, the median observation time was 8.5 months (range: 1 day to 39 months) and the most frequent adverse reactions with pembrolizumab were fatigue (31%), diarrhoea (22%), and nausea (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions (see section 4.4). The incidences of immune‑related adverse reactions were 36.1% all Grades and 8.9% for Grades 3‑5 for pembrolizumab monotherapy in the adjuvant setting (n=1,480) and 24.2% all Grades and 6.4% for Grades 3‑5 in the metastatic setting (n=5,375). No new immune‑related adverse reactions were identified in the adjuvant setting. Pembrolizumab in combination with chemotherapy (see section 4.2) When pembrolizumab is administered in combination, refer to the SmPC for the respective combination therapy components prior to initiation of treatment. The safety of pembrolizumab in combination with chemotherapy has been evaluated in 3,123 patients across tumour types receiving 200mg, 2mg/kg bw or 10mg/kg bw pembrolizumab every 3 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were anaemia (55%), nausea (54%), fatigue (38%), neutropenia (36%), constipation (35%), alopecia (35%), diarrhoea (34%), vomiting (28%), and decreased appetite (27%). Incidences of Grades 3‑5 adverse reactions in patients with NSCLC were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone, in patients with HNSCC were 85% for pembrolizumab combination therapy and 84% for chemotherapy plus cetuximab, in patients with oesophageal carcinoma were 86% for pembrolizumab combination therapy and 83% for chemotherapy alone, in patients with TNBC were 80% for pembrolizumab combination therapy and 77% for chemotherapy alone, and in patients with cervical cancer were 82% for pembrolizumab combination and 75% for chemotherapy alone. Pembrolizumab in combination with tyrosine kinase inhibitor (TKI) (see section 4.2) When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. For additional axitinib safety information for elevated liver enzymes see also section 4.4. The safety of pembrolizumab in combination with axitinib or lenvatinib in advanced RCC, and in combination with lenvatinib in advanced EC has been evaluated in a total of 1,456 patients with advanced RCC or advanced EC receiving 200 mg pembrolizumab every 3 weeks with either axitinib 5 mg twice daily or lenvatinib 20 mg once daily in clinical studies, as appropriate. In these patient populations, the most frequent adverse reactions were diarrhoea (58%), hypertension (54%), hypothyroidism (46%), fatigue (41%), decreased appetite (40%), nausea (40%), arthralgia (30%), vomiting (28%), weight decreased (28%), dysphonia (28%), abdominal pain (28%), proteinuria (27%), palmar plantar erythrodysaesthesia syndrome (26%), rash (26%), stomatitis (25%), constipation (25%), musculoskeletal pain (23%), headache (23%) and cough (21%). Grades 3 5 adverse reactions in patients with RCC were 80% for pembrolizumab in combination with either axitinib or lenvatinib and 71% for sunitinib alone. In patients with EC, Grades 3-5 adverse reactions were 89% for pembrolizumab in combination with lenvatinib and 73% for chemotherapy alone. Tabulated summary of adverse reactions Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy or other anti-tumour medicines or reported from post-marketing use of pembrolizumab are listed in Table 2. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Adverse reactions known to occur with pembrolizumab or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy. For additional safety information when pembrolizumab is administered in combination, refer to the SmPC for the respective combination therapy components. Table 2: Adverse reactions in patients treated with pembrolizumab*: Infections and infestationsMonotherapy:Common: pneumonia, In combination with chemotherapy:Common: pneumonia, In combination with axitinib or lenvatinib: Very common: urinary tract infection; common: pneumonia. Blood and lymphatic system disorders Monotherapy: Very Common: anaemia; Common: thrombocytopenia, neutropenia, lymphopenia; Uncommon: leukopenia, immune thrombocytopenia, eosinophilia; Rare: haemolytic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis, In combination with chemotherapy:Very Common:neutropenia, anaemia,thrombocytopenia, leukopenia; Common: febrile neutropenia, lymphopenia; Uncommon: eosinophilia; Rare: haemolytic anaemia, immune thrombocytopenia, in combination with axitinib or lenvatinib: Very common: anaemia, Common: neutropenia, thrombocytopenia, lymphopenia, leukopenia; Uncommon: eosinophilia. Immune system disorders Monotherapy:Common: infusion-related reactiona; Uncommon: sarcoidosis; Not known: solid organ transplant rejection, In combination with chemotherapy:Common: infusion-related reactiona; Rare: sarcoidosis, In combination with axitinib or lenvatinib: Common: infusion-related reactiona. Endocrine disorders Monotherapy: Very Common: hypothyroidismb; Common: hyperthyroidism; Uncommon: adrenal insufficiencyc, hypophysitisf, thyroiditisd; Rare: hypoparathyroidism, In combination with chemotherapy:Very Common: hypothyroidismb, Common:, adrenal insufficiencyc, thyroiditisd, hyperthyroidisme Uncommon: hypophysitisf; Rare: hypoparathyroidism, In combination with axitinib or lenvatinib: Very common: hypothyroidism; Common: adrenal insufficiencyc, hyperthyroidism, thyroiditisd; Uncommon: hypophysitisf; Rare: hypoparathyroidism, Metabolism and nutrition disorders Monotherapy: Very Common: decreased appetite; Common: hyponatraemia, hypokalaemia, hypocalcaemia; Uncommon: type 1 diabetes mellitusg, In combination with chemotherapy:Very common: hypokalaemia, decreased appetite; Common:  hyponatraemia, hypocalcaemia; Uncommon: type 1 diabetes mellitus, In combination with axitinib or lenvatinib Very common: decreased appetite; Common: hyponatraemia, hypokalaemia, hypocalcaemia; Uncommon: type 1 diabetes mellitusg. Psychiatric disorders Monotherapy: Common: insomnia, in combination with chemotherapy:Very Common: insomnia, in combination with axitinib or lenvatinib: Common: insomnia. Nervous system disorders Monotherapy: Very Common: headache; Common: dizziness, neuropathy peripheral, lethargy, dysgeusia; Uncommon: myasthenic syndromeh, epilepsy; Rare: Guillain-Barré syndromej, encephalitisi, myelitisk, meningitis (aseptic)l, in combination with chemotherapy:Very common: neuropathy peripheral, headache, dizziness, dysgeusia; Common: lethargy; Uncommon: encephalitisi, epilepsy; Rare: Guillain-Barré Syndromej, myasthenic syndrome, in combination with axitinib or lenvatinib: Very common: headache, dysgeusia; Common: dizziness, neuropathy peripheral, lethargy; Uncommon: myasthenic syndromeh, encephalitisi. Eye disorders Monotherapy: Common: dry eye; Uncommon: uveitism; Rare: Vogt-Koyanagi-Harada syndrome, In combination with chemotherapy: Common: dry eye;Rare: uveitism, In combination with axitinib or lenvatinib:  Common: dry eye; Uncommon: uveitism; Rare: Vogt-Koyanagi Harada-syndrome. Cardiac disorders Monotherapy: Common:cardiac arrhythmia† (including atrial fibrillation); Uncommon: myocarditis, pericardial effusion, pericarditis, In combination with chemotherapy: Common:cardiac arrhythmia† (including atrial fibrillation); Uncommon: myocarditisn, pericardial effusion, pericarditis, In combination with axitinib or lenvatinib: Common: cardiac arrhythmia† (including atrial fibrillation); Uncommon: myocarditis; pericardial effusion. Vascular disorders Monotherapy: Common: hypertension; Rare: vasculitiso, In combination with chemotherapy: Common: hypertension; Uncommon: vasculitiso, In combination with axitinib or lenvatinib: Very common: hypertension; Uncommon: vasculitiso. Respiratory, thoracic and mediastinal disorders Monotherapy: Very Common: dyspnoea, cough; Common: pneumonitisp, In combination with chemotherapy:Very common: dyspnoea, cough;Common: pneumonitisp, In combination with axitinib or lenvatinib: Very common: dyspnoea, cough; Common: pneumonitisp. Gastrointestinal disorders Monotherapy: Very common: diarrhoea, abdominal painq, nausea, vomiting, constipation; Common: colitisr, dry mouth; Uncommon: pancreatitiss, gastritis, gastrointestinal ulcerationr; Rare: small intestinal perforation, In combination with chemotherapy:  Very common: nausea, diarrhoea, vomiting, abdominal painq, constipation; Common: colitisr, gastritis, dry mouth; Uncommon: pancreatitiss, gastrointestinal ulcerationt; Rare: small intestinal perforation; In combination with axitinib or lenvatinib: Very Common: diarrhoea, abdominal painq, nausea, vomiting, constipation; Common: colitisr, pancreatitiss, gastritis, dry mouth;Uncommon: gastrointestinal ulcerationt; Rare: small intestinal perforation. Hepatobiliary disorders Monotherapy: Common: hepatitisu; Rare: cholangitis sclerosing, In combination with chemotherapy:  Common: hepatitisu, Rare: cholangitis sclerosingv, In combination with axitinib or lenvatinib: Common: hepatitisu. Skin and subcutaneous tissue disorders Monotherapy: Very common: pruritusw, rashx; Common: severe skin reactionsy, erythema, dermatitis, dry skin, vitiligoz, eczema, alopecia, dermatitis acneiform; Uncommon: psoriasis, lichenoid keratosisaa, papule, hair colour changes; Rare: Stevens-Johnson syndrome, erythema nodosum, toxic epidermal necrolysis, In combination with chemotherapy: Very common: alopecia, rashx, pruritusw; Common: severe skin reactionsy, erythema, dermatitis acneiform, dermatitis, dry skin, eczema; Uncommon: psoriasis, lichenoid keratosisaa, vitiligoz, papule; Rare: Stevens‑Johnson syndrome, erythema nodosum, hair colour changes, In combination with axitinib or lenvatinib: Very common: rashx, pruritusw; Common: severe skin reactionsy, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia; Uncommon: eczema, lichenoid keratosisaa, psoriasis, vitiligoz, papule, hair colour changes; Rare: toxic epidermal necrolysis, Stevens Johnson syndrome. Musculoskeletal and connective tissue disorders Monotherapy: Very Common: musculoskeletal painbb, arthralgia; Common: myositiscc, pain in extremity, arthritisdd Uncommon: tenosynovitisee; Rare: Sjogren’s syndrome, In combination with chemotherapy: Very Common: arthralgia, musculoskeletal painbb, myositiscc;Common: pain in extremity, arthritisdd; Uncommon: tenosynovitisee; Rare: Sjogren’s syndrome, In combination with axitinib or lenvatinib: Very common: arthralgia, musculoskeletal painbb, myositiscc, pain in extremity; Common: arthritisdd; Uncommon: tenosynovitisee; Rare: Sjogren’s syndrome. Renal and urinary disorders Monotherapy: Uncommon: nephritisff; Rare: cystitis noninfective, in combination with chemotherapy: Common: acute kidney injury; Uncommon: nephritisff, cystitis noninfective, in combination with axitinib or lenvatinib: Common: nephritisff; Rare: cystitis noninfective. General disorders and administration site conditions Monotherapy: Very common: fatigue, asthenia, oedemagg, pyrexia; Common: influenza like illness, chills, In combination with chemotherapy: Very common: fatigue, asthenia, pyrexia, oedemagg; Common: influenza like illness, chills, In combination with axitinib or lenvatinib: Very common: fatigue, asthenia, oedemagg, pyrexia, Common: influenza like illness, chills. Investigations Monotherapy: Common: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased, blood creatinine increased; Uncommon: amylase increased, In combination with chemotherapy:Very common: alanine aminotransferase increased, aspartate aminotransferase increased; Common: blood creatinine increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased; Uncommon: amylase increased, In combination with axitinib or lenvatinib: Very common: lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased; Common: amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia. * Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination. †Based upon a standard query including bradyarrhythmias and tachyarrhythmias. The following terms represent a group of related events that describe a medical condition rather than a single event: a. infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion related hypersensitivity reaction, cytokine release syndrome, and serum sickness); b. hypothyroidism (myxoedema and immune-mediated hypothyroidism); c.  adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); d. thyroiditis (autoimmune thyroiditis, thyroid disorder, and thyroiditis acute); e. hyperthyroidism (Basedow’s disease); f. hypophysitis (hypopituitarism, lymphocytic hypophysitis); g. type 1 diabetes mellitus (diabetic ketoacidosis); h. myasthenic syndrome (myasthenia gravis, including exacerbation); i. encephalitis (autoimmune encephalitis, noninfective encephalitis); j. Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy); k. myelitis (including transverse myelitis); l. meningitis aseptic (meningitis, meningitis noninfective); m. uveitis (chorioretinitis, iritis and iridocyclitis); n. myocarditis (autoimmune myocarditis); o. vasculitis (central nervous system vasculitis, aortitis, giant cell arteritis); p. pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis, and immune-mediated lung disease); q. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); r. colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis, and immune-mediated enterocolitis); s. pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis); t. gastrointestinal ulceration (gastric ulcer and duodenal ulcer); u. hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis); v. cholangitis sclerosing (immune-mediated cholangitis); w. pruritus (urticaria, urticaria papular and pruritus genital); x. rash (rash erythematous, rash follicular, rash macular, rash maculo‑papular, rash papular, rash pruritic, rash vesicular and genital rash); y. severe skin reactions (exfoliative rash, pemphigus, and Grade ≥ 3 of the following: dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo‑papular, rash pruritic, rash pustular, skin necrosis and toxic skin eruption); z. vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); aa. lichenoid keratosis (lichen planus and lichen sclerosus); bb. musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); cc. myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis); dd. arthritis (joint swelling, polyarthritis and joint effusion); ee. tenosynovitis (tendonitis, synovitis and tendon pain); ff. nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous); gg. oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema). Description of selected adverse reactions Data for the following immune‑related adverse reactions are based on patients who received pembrolizumab across four doses (2 mg/kg bw every 3 weeks, 10 mg/kg bw every 2 or 3 weeks, or 200 mg every 3 weeks) in clinical studies (see section 5.1). The management guidelines for these adverse reactions are described in section 4.4. Immune-related adverse reactions (see section 4.4) Immune-related pneumonitis Pneumonitis occurred in 324 (4.2%) patients, including Grade 2, 3, 4 or 5 cases in 143 (1.9%), 81 (1.1%), 19 (0.2%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.9 months (range 2 days to 27.2 months). The median duration was 2.0 months (range 1 day to 51.0+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (3.9%). Pneumonitis led to discontinuation of pembrolizumab in 131 (1.7%) patients. Pneumonitis resolved in 190 patients, 6 with sequelae.

 In patients with NSCLC, pneumonitis occurred in 160 (5.7%), including Grade 2, 3, 4 or 5 cases in 62 (2.2%), 47 (1.7%), 14 (0.5%) and 10 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.9% with a history of prior thoracic radiation. In patients with cHL, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in KEYNOTE-087 (n=210) and KEYNOTE-204 (n=148), respectively. Immune-related colitis Colitis occurred in 158 (2.1%) patients, including Grade 2, 3 or 4 cases in 49 (0.6%), 82 (1.1%) and 6 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 4.3 months (range 2 days to 24.3 months). The median duration was 1.1 month (range 1 day to 45.2 months). Colitis led to discontinuation of pembrolizumab in 48 (0.6%) patients. Colitis resolved in 130 patients, 2 with sequelae. In patients with CRC treated with pembrolizumab as monotherapy (n=153), the incidence of colitis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4. Immune-related hepatitisHepatitis occurred in 80 (1.0%) patients, including Grade 2, 3 or 4 cases in 12 (0.2%), 55 (0.7%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 3.5 months (range 8 days to 26.3 months). The median duration was 1.3 months (range 1 day to 29.0+ months). Hepatitis led to discontinuation of pembrolizumab in 37 (0.5%) patients. Hepatitis resolved in 60 patients.Immune-related nephritis Nephritis occurred in 37 (0.5%) patients, including Grade 2, 3 or 4 cases in 11 (0.1%), 19 (0.2%) and 2 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 4.2 months (range 12 days to 21.4 months). The median duration was 3.3 months (range 6 days to 28.2+ months). Nephritis led to discontinuation of pembrolizumab in 17 (0.2%) patients. Nephritis resolved in 20 patients, 5 with sequelae. In patients with non-squamous NSCLC treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), the incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.Immune-related endocrinopathiesAdrenal insufficiency occurred in 74 (1.0%) patients, including Grade 2, 3 or 4 cases in 34 (0.4%), 31 (0.4%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of adrenal insufficiency was 5.4 months (range 1 day to 23.7 months). The median duration was not reached (range 3 days to 40.1+ months). Adrenal insufficiency led to discontinuation of pembrolizumab in 13 (0.2%) patients. Adrenal insufficiency resolved in 17 patients, 11 with sequelae. Hypophysitis occurred in 52 (0.7%) patients, including Grade 2, 3 or 4 cases in 23 (0.3%), 24 (0.3%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 5.9 months (range 1 day to 17.7 months). The median duration was 3.6 months (range 3 days to 48.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 14 (0.2%) patients. Hypophysitis resolved in 15 patients, 8 with sequelae. Hyperthyroidism occurred in 394 (5.2%) patients, including Grade 2 or 3 cases in 108 (1.4%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 23.2 months). The median duration was 1.6 months (range 4 days to 43.1+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 4 (0.1%) patients. Hyperthyroidism resolved in 315 (79.9%) patients, 11 with sequelae. In patients with RCC and melanoma treated with pembrolizumab monotherapy in the adjuvant setting (n=1,480), the incidence of hyperthyroidism was 10.9%, the majority of which were Grade 1 or 2. Hypothyroidism occurred in 939 (12.3%) patients, including Grade 2 or 3 cases in 687 (9.0%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.4 months (range 1 day to 25.9 months). The median duration was not reached (range 2 days to 63.0+ months). Hypothyroidism led to discontinuation of pembrolizumab in 6 (0.1%) patients. Hypothyroidism resolved in 200 (21.3%) patients, 16 with sequelae. In patients with cHL (n=389) the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. In patients with HNSCC treated with pembrolizumab as monotherapy (n=909), the incidence of hypothyroidism was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab in combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients treated with pembrolizumab in combination with axitinib or lenvatinib (n=1,456), the incidence of hypothyroidism was 46.2% (all Grades) with 0.8% Grade 3 or 4. In patients with RCC and melanoma treated with pembrolizumab monotherapy in the adjuvant setting (n=1,480), the incidence of hypothyroidism was 17.7%, the majority of which were Grade 1 or 2. Immune-related skin adverse reactions Immune‑related severe skin reactions occurred in 130 (1.7%) patients, including Grade 2, 3, 4 or 5 cases in 11 (0.1%), 103 (1.3%), 1 (< 0.1%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 3.0 months (range 2 days to 25.5 months). The median duration was 1.9 months (range 1 day to 47.1+ months). Severe skin reactions led to discontinuation of pembrolizumab in 18 (0.2%) patients. Severe skin reactions resolved in 93 patients, 2 with sequelae. Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 and 4.4). Complications of allogeneic HSCT in cHL Of 14 patients in KEYNOTE‑013 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients reported acute GVHD and 1 patient reported chronic GVHD, none of which were fatal. Two patients experienced hepatic VOD, one of which was fatal. One patient experienced engraftment syndrome post-transplant. Of 32 patients in KEYNOTE‑087 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 16 patients reported acute GVHD and 7 patients reported chronic GVHD, two of which were fatal. No patients experienced hepatic VOD. No patients experienced engraftment syndrome post-transplant. Of 14 patients in KEYNOTE‑204 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 8 patients reported acute GVHD and 3 patients reported chronic GVHD, none of which were fatal. No patients experienced hepatic VOD. One patient experienced engraftment syndrome post-transplant. Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC In a clinical study of previously untreated patients with RCC receiving pembrolizumab in combination with axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and AST increased (13%) were observed. The median time to onset of ALT increased was 2.3 months (range: 7 days to 19.8 months). In patients with ALT ≥ 3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with either pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% had no recurrence of ALT > 3 times ULN, and of those patients with recurrence of ALT > 3 times ULN, all recovered. There were no Grade 5 hepatic events. Laboratory abnormalities In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.4% for lymphocytes decreased, 7.4% for sodium decreased, 5.8% for haemoglobin decreased, 5.3% for phosphate decreased, 5.3% for glucose increased, 3.3% for ALT increased, 3.1% for AST increased, 2.6% for alkaline phosphatase increased, 2.3% for potassium decreased, 2.1% for potassium increased, 1.9% for neutrophils decreased, 1.8% for platelets decreased, 1.8% for calcium increased, 1.7% for bilirubin increased, 1.5% for calcium decreased, 1.4% for albumin decreased, 1.3% for creatinine increased, 1.2% for glucose decreased, 0.8% for leucocytes decreased, 0.7% for magnesium increased, 0.5% for sodium increased, 0.4% for haemoglobin increased, and 0.2% for magnesium decreased. In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 44.0% for neutrophils decreased, 29.4% for leucocytes decreased, 26.9% for lymphocytes decreased, 22.1% for haemoglobin decreased, 13.2% for platelets decreased, 11.0% for sodium decreased, 7.7% for phosphate decreased, 6.8% for ALT increased, 6.8% for potassium decreased, 6.1% for glucose increased, 5.6% for AST increased, 3.5% for calcium decreased, 3.2% for potassium increased, 2.9% for creatinine increased, 2.2% for albumin decreased, 2.1% for alkaline phosphatase increased, 2.0% for bilirubin increased, 2.0% for calcium increased, 1.3% for prothrombin INR increased, 1.2% for glucose decreased and 0.5% for sodium increased. In patients treated with pembrolizumab in combination with axitinib or lenvatinib, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 23.0% for lipase increased (not measured in patients treated with pembrolizumab and axitinib), 12.0% for lymphocyte decreased, 11.4% for sodium decreased, 11.2% for amylase increased, 11.2% for triglycerides increased, 10.4% for ALT increased, 8.9% for AST increased, 7.8% for glucose increased, 6.8% for phosphate decreased, 6.1% for potassium decreased, 5.1% for potassium increased, 4.5% for cholesterol increased, 4.4% for creatinine increased, 4.2% for haemoglobin decreased, 4.0% for magnesium decreased, 3.5% for neutrophils decreased, 3.1% for alkaline phosphatase increased, 3.0% for platelets decreased, 2.8% for bilirubin increased, 2.2% for calcium decreased, 1.7% for white blood cells decreased, 1.6% for magnesium increased, 1.5% for prothrombin INR increased, 1.4% for glucose decreased, 1.2% for albumin decreased, 1.2% for calcium increased, 0.4% for sodium increased, and 0.1% for haemoglobin increased. Immunogenicity In clinical studies in patients treated with pembrolizumab 2 mg/kg bw every three weeks, 200 mg every three weeks, or 10 mg/kg bw every two or three weeks as monotherapy, 36 (1.8%) of 2,034 evaluable patients tested positive for treatment‑emergent antibodies to pembrolizumab, of which 9 (0.4%) patients had neutralising antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development. Paediatric population The safety of pembrolizumab as monotherapy has been evaluated in 161 paediatric patients aged 9 months to 17 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg bw every 3 weeks in the Phase I/II study KEYNOTE-051. The cHL population (n=22) included patients 11 to 17 years of age. The safety profile in paediatric patients was generally similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (33%), vomiting (30%), headache (26%), abdominal pain (22%), anaemia (21%), cough (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. Seventy-six (47.2%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (3.1%) patients had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. Long-term safety data of pembrolizumab in adolescents with Stage IIB, IIC and III melanoma treated in the adjuvant setting are currently unavailable. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: in Belgium: Agence Fédérale des Médicaments et des Produits de Santé. Division Vigilance. Boîte Postale 97, B-1000 Brussels Madou.  Website: www.notifieruneffetindesirable.be, e-mail: adr@afmps.be, in Luxembourg: Centre Régional de Pharmacovigilance de Nancy ou Division de la pharmacie et des médicaments de la Direction de la santé. Site internet: www.guichet.lu/pharmacovigilance. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme B.V. Waarderweg 39. 2031 BN Haarlem. The Netherlands. 8. MARKETING AUTHORISATION NUMBER(S) EU/1/15/1024/002 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 17 July 2015. Date of latest renewal: 24 March 2020. 10. DATE OF REVISION OF THE TEXT 10/2022. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. DELIVERY: on medical prescription.