Drug Profile
Pembrolizumab for the treatment of melanoma Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/08/15 For personal use only.
Expert Rev. Clin. Pharmacol. Early online, 1–12 (2015)
Sanjeev Srinivas Kumar* and Catriona Mairi McNeil Department of Medical Oncology, Chris O’Brien Lifehouse, 119-143 Missenden Road, Camperdown NSW 2050, PO BOX M33 Missenden Road NSW 2050, Australia *Author for correspondence: Tel.: +61 285 140 273 [email protected]
The immune system plays a vital role in regulating tumor growth, and the oncology community has witnessed an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. The utility of these strategies in advanced melanoma has been at the forefront of these developments. In particular, blockade of programmed cell death protein 1 (PD-1) in advanced melanoma has proven to be a most promising new anticancer strategy. Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. Its effect has been most convincingly demonstrated in the setting of advanced melanoma, with growing evidence of clinical responses across a broad spectrum of other solid and hematological malignancies. KEYWORDS: immunotherapy . lambrolizumab . melanoma . pembrolizumab . pharmacology
Melanoma is an aggressive malignancy with a median overall survival (OS) of 1.5–3-times ULN and any AST) or severe (bilirubin >3-times ULN and any AST) hepatic impairment [25]. Clinical efficacy Early phase studies
Following the publication of Phase I dose escalation trials of the anti-PD-1 Ab nivolumab in multiple advanced solid tumors, results from an international Phase I expansion study (KEYNOTE 001) of pembrolizumab intravenously at a dose of 10 mg/kg every 2 or 3 weeks or 2 mg/kg every 3 weeks in 135 patients with advanced melanoma were published [17]. This cohort included patients who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. The confirmed response rate across all dose cohorts was 38% (95% CI: 25–44), with the highest confirmed response rate observed in the cohort that received 10 mg/kg every 2 weeks (52; 95% CI: 38–66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI: 23–55] and 37% [95% CI: 26–49], respectively). Further reflecting the striking clinical activity of pembrolizumab, responses were documented in patients whose disease had indeed progressed while receiving other forms of immunotherapy, chemotherapy or BRAF-targeted therapy. In an open-label, international, multi-center expansion cohort of the Phase I KEYNOTE-001 study, patients with advanced melanoma whose disease had progressed after at least two doses of ipilimumab were randomly assigned to intravenous pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks, with a primary endpoint of ORR. Patients in this trial were generally heavily pretreated, with 72% having received at least two and 35% having received at least three previous treatments, including ipilimumab. In those with available data, 6% of patients had objectively responded and 21% had stable disease as their best overall response to previous ipilimumab treatment. In general, patients were not receiving pembrolizumab sequenced immediately after ipilimumab, with a mean interval between the last dose of ipilimumab and the first dose of informahealthcare.com
Drug Profile
pembrolizumab of around 33–34 weeks overall. In the 173 patients who received pembrolizumab, an ORR of 26% was observed at both doses – 21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0, 95% CI: 14–13; p = 0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths [26]. Therefore, both doses had similar and substantial anticancer activity and an acceptable safety profile in patients with advanced melanoma whose disease had progressed on ipilimumab, and in those with BRAF-mutant disease, who were previously treated with BRAF or MEK inhibitors, or both. This study was the largest reported of antiPD-1 therapy in patients with melanoma and the first reported randomized comparison of an anti-PD-1 agent. The Phase II KEYNOTE-002 study of pembrolizumab versus chemotherapy then confirmed the benefit of pembrolizumab over chemotherapy in patients who had progressed on prior ipilimumab. It also confirmed a lack of a dose–response relationship congruent with the results of the two randomized cohorts in KEYNOTE-001. In this trial, pembrolizumab demonstrated a manageable safety profile, with 14% of patients experiencing grade 3–4 toxicity, most of which were immunerelated [27]. Phase III studies
A recently published randomized, controlled Phase III study compared two dosing schedules of pembrolizumab (10 mg/kg every 2 or 3 weeks) to 4 doses of ipilimumab 3 mg/kg every 3 weeks, with primary endpoints of progression-free survival and OS [28]. Estimated 6-month progression-free survival rates for pembrolizumab every 2 and 3 weeks and ipilimumab were 47.3, 46.4 and 26.5%, respectively, with a hazard ratio of 0.58 (95% CI: 0.46–0.72, one-sided p 1% of pembrolizumab-treated patients were colitis (1.4 and 2.5%, respectively) and hepatitis (1.1 and 1.8%, respectively). There are currently no published or recruiting head-to-head trials of pembrolizumab versus nivolumab to directly compare the efficacy and safety of these competing anti PD-1 antibodies. Approval status of the drug
Pembrolizumab is the first PD-1 inhibitor to be approved by the US FDA for the treatment of patients with unresectable metastatic melanoma and disease progression following ipilimumab and if BRAFV600 mutation positive, a BRAF inhibitor. In the UK, pembrolizumab is the first treatment to be accepted under the new Early Access to Medicines Scheme created by the UK Medicines and Healthcare Regulatory Agency before being granted a European license. It was granted Therapeutic Goods Administration approval in Australia in April 2015. Conclusion
After years of disappointment in the management of advanced melanoma, we are seeing an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. Clinical trials of mAbs to PD-1 and PD-L1 have shown impressive response rates, coupled with response durability and a strikingly favorable toxicity profile previously unprecedented in patients with advanced melanoma. However, further studies are needed to dissect mechanisms of variable response rates to informahealthcare.com
Drug Profile
identify biomarkers of clinical response and toxicity and combine these agents with other available and investigative therapies. Expert commentary How long to treat for, & does re-treatment help?
PD-1/PD-L1 antibodies are administered on a continuous schedule, yet it remains unclear as to whether this continuous dosing is necessary. There is now emerging evidence that patients may demonstrate responses lasting beyond the cessation of anti-PD-1 therapy [7]. One patient who had benefited from nivolumab but who later experienced progression reinitiated nivolumab and later regained a response [33] similar to the benefits seen in some patients who have received re-induction ipilimumab. Further studies and assessment of longer term survival data in the current patient cohorts receiving antiPD-1 antibodies are required to answer these questions. Indeed, answering these questions would help alleviate growing concerns of therapeutic regulatory bodies about the costs associated with prolonged use of these agents. Sequencing of treatment
In patients with BRAFV600-mutant melanoma, the optimal sequence of immunotherapy and BRAF plus MEK inhibitors remains one of the most critical, yet unanswered questions. After initial tumor regression with response rates of up to 67% seen with BRAF plus MEK inhibition, most patients develop rapidly progressive disease after an average of 9 months of treatment [3]. This occurs coincident with the development of drug resistance, and disease escalation that in some patients outpaces further second-line immunotherapy, leading to a concern that perhaps V600-mutant melanoma may be best treated with upfront immunotherapy. Of note, the KEYNOTE 006 Phase III study of pembrolizumab compared with ipilimumab did not enroll patients with BRAFV600 mutations who did not receive previous anti-BRAF-targeted therapy if they had high lactate dehydrogenase levels and symptomatic or rapidly progressive disease, citing the rationale that targeted anti-BRAF agents can have a rapid clinical benefit in this population of patients [28]. Although the question of the most effective sequence of immunotherapy and BRAF or MEK inhibitors cannot be addressed without randomized, controlled trials, BRAFV600 status did not seem to influence the benefit of pembrolizumab over ipilimumab in this study. Other important areas of clinical investigation in terms of sequencing treatment include the role of combination immunotherapy with its high and sometimes rapid response rate, and the treatment of patients who have minimal disease progression or mixed responses. Synergy with radiotherapy & chemotherapy
Accumulating evidence suggests that tumors with a preexisting active immune microenvironment might have a better response to immunotherapy. In a number of preclinical and clinical studies, many cytotoxic agents elicit changes within tumors and doi: 10.1586/17512433.2015.1061430
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/08/15 For personal use only.
Drug Profile
Kumar & McNeil
their microenvironment that may make these malignant cells more sensitive to an efficient immune cell attack. Therefore, it is plausible that combining immunotherapy with standard anticancer therapies such as chemotherapy or radiotherapy will provide synergistic anti-tumor effects [34,35]. Phase I studies are currently underway that hypothesize that combining radiation therapy with immunomodulatory therapy will facilitate immune recognition of tumor-specific antigens, yielding a synergistic effect. Furthermore, these studies hypothesize that this combination could focus the immune system on tumor antigens and minimize the aberrant immune activation in normal tissues, consequently reducing the incidence of irAE’s. However, the safety profile and toxicities of combining immunotherapy with brain radiation treatment are largely unknown besides small case series [36], and require further investigation. The role of PD-L1 expression & TILs in predicting responders
There have been conflicting data regarding PD-L1 expression as a prognostic factor among patients with melanoma, and questions over whether PD-L1 expression may serve as a biomarker for response to anti-PD-1 therapy. A Danish study evaluated the relationship between PD-L1 expression and OS in 223 melanoma patients [37]. Tumor PD-L1 expression was measured using an immunohistochemistry assay with the 22C3 antibody, with PD-L1 positivity defined as staining in ‡1% of cells. Forty-nine percent of patients were PD-L1 positive, there was no significant association between PD-L1 expression and OS, and, in particular, there was no association between PD-L1 expression and survival among patients treated with ipilimumab, chemotherapy, IL-2, interferon or targeted therapy. The relationship between PD-L1 expression and clinical outcome with pembrolizumab was then assessed in patients recruited to the KEYNOTE 001 trial [38,39]. Once again, PD-L1 expression was assessed using the same techniques and criteria as the Danish study. PD-L1 expression was associated with a significantly higher response rate and significantly longer PFS and OS (84% at 1 year in PD-L1 positive, 69% in PD-L1 negative patients). However, although tumor PD-L1 positivity was associated with improved responses, durable anti-tumor activity was still observed in patients without PD-L1 expression, suggesting that PD-L1 expression should not exclude patients from treatment. Of interest, in the trial comparing the combination of nivolumab and ipilimumab to sequenced ipilimumab followed by nivolumab, PD-L1 expression (defined as ‡5% of cells) was demonstrated in 38% of patients, and did not correlate with differing OR rates in patients receiving concurrent treatment [9]. However, a higher ORR was demonstrated in PD-L1 positive compared to PD-L1 negative patients in the cohort receiving the sequenced regime, perhaps suggesting that combined immunotherapy may overcome the predictive effect of PD-L1 expression in responding to immunotherapy. To complicate this matter, an Australian study has now evaluated PD-L1 expression in immunotherapy-naive patients with advanced melanoma to determine longitudinal intra-patient doi: 10.1586/17512433.2015.1061430
PD-L1 concordance, and correlate PD-L1 status with clinicopathologic characteristics and outcomes. PD-L1 expression was found to be frequently discordant between primary tumors and metastases and between intra-patient metastases. PD-L1 was associated with higher TIL grade but not with other known prognostic features. A positive association was demonstrated between PD-L1 expression and higher TIL grade in locoregional metastases and melanoma-specific survival, but the effect was not observed for primary melanoma [40]. The same research group also illustrated the dynamic nature of PD-L1 expression by assessing PD-L1 and TIL expression as well as lymphocyte subsets at baseline and then at progression following treatment with BRAF inhibitors alone or the combination of BRAF and MEK inhibition [41]. Patient tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at progression, while patients who were PD-L1 negative at baseline alternatively demonstrated an increase in PD-L1. PD-1 expression also strongly correlated with TIL expression and lymphocyte subsets. Tumeh et al. [16] analyzed samples from 46 patients with metastatic melanoma obtained before and during antiPD-1 therapy with pembrolizumab using quantitative immunohistochemistry, multiplex immunofluorescence and nextgeneration sequencing for T-cell antigen receptors. They demonstrated that pre-existing CD8+ T cells located at the invasive tumor margin are associated with expression of the PD-1/PDL1 immune inhibitory axis and may predict response to therapy. Patients responding to treatment also showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumor size. Interpretation of all these data suggests that PD-L1 and TIL expression in melanoma at baseline could define different subgroups of patients, and could cautiously assist in the selection and sequence of more effective treatment combinations. Activity of pembrolizumab in the brain
While recent advances in the treatment of metastatic melanoma with agents targeting PD-1 have been particularly striking, there remains a significant need to develop therapies for patients with untreated brain metastases who were excluded from trials of pembrolizumab. The brain is a common site of metastatic spread in melanoma. Autopsy data have shown that up to 75% of patients who died from metastatic melanoma had brain metastases [42,43], and 20% of patients have them at first presentation with metastatic disease [44]. Current standard of care for cerebral metastases that require immediate local intervention, based on symptoms, location or size, is craniotomy with resection, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Surgery and SRS are directed to the tumor volume only, whereas WBRT delivers lower-dose radiotherapy to the whole brain, including areas of no overt tumor. Surgery is not limited by the size of the tumor; however, it is dependent on the lesion being surgically accessible. In appropriately selected patients (lesions
Pembrolizumab for the treatment of melanoma Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/08/15 For personal use only.
Expert Rev. Clin. Pharmacol. Early online, 1–12 (2015)
Sanjeev Srinivas Kumar* and Catriona Mairi McNeil Department of Medical Oncology, Chris O’Brien Lifehouse, 119-143 Missenden Road, Camperdown NSW 2050, PO BOX M33 Missenden Road NSW 2050, Australia *Author for correspondence: Tel.: +61 285 140 273 [email protected]
The immune system plays a vital role in regulating tumor growth, and the oncology community has witnessed an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. The utility of these strategies in advanced melanoma has been at the forefront of these developments. In particular, blockade of programmed cell death protein 1 (PD-1) in advanced melanoma has proven to be a most promising new anticancer strategy. Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. Its effect has been most convincingly demonstrated in the setting of advanced melanoma, with growing evidence of clinical responses across a broad spectrum of other solid and hematological malignancies. KEYWORDS: immunotherapy . lambrolizumab . melanoma . pembrolizumab . pharmacology
Melanoma is an aggressive malignancy with a median overall survival (OS) of 1.5–3-times ULN and any AST) or severe (bilirubin >3-times ULN and any AST) hepatic impairment [25]. Clinical efficacy Early phase studies
Following the publication of Phase I dose escalation trials of the anti-PD-1 Ab nivolumab in multiple advanced solid tumors, results from an international Phase I expansion study (KEYNOTE 001) of pembrolizumab intravenously at a dose of 10 mg/kg every 2 or 3 weeks or 2 mg/kg every 3 weeks in 135 patients with advanced melanoma were published [17]. This cohort included patients who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. The confirmed response rate across all dose cohorts was 38% (95% CI: 25–44), with the highest confirmed response rate observed in the cohort that received 10 mg/kg every 2 weeks (52; 95% CI: 38–66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI: 23–55] and 37% [95% CI: 26–49], respectively). Further reflecting the striking clinical activity of pembrolizumab, responses were documented in patients whose disease had indeed progressed while receiving other forms of immunotherapy, chemotherapy or BRAF-targeted therapy. In an open-label, international, multi-center expansion cohort of the Phase I KEYNOTE-001 study, patients with advanced melanoma whose disease had progressed after at least two doses of ipilimumab were randomly assigned to intravenous pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks, with a primary endpoint of ORR. Patients in this trial were generally heavily pretreated, with 72% having received at least two and 35% having received at least three previous treatments, including ipilimumab. In those with available data, 6% of patients had objectively responded and 21% had stable disease as their best overall response to previous ipilimumab treatment. In general, patients were not receiving pembrolizumab sequenced immediately after ipilimumab, with a mean interval between the last dose of ipilimumab and the first dose of informahealthcare.com
Drug Profile
pembrolizumab of around 33–34 weeks overall. In the 173 patients who received pembrolizumab, an ORR of 26% was observed at both doses – 21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0, 95% CI: 14–13; p = 0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths [26]. Therefore, both doses had similar and substantial anticancer activity and an acceptable safety profile in patients with advanced melanoma whose disease had progressed on ipilimumab, and in those with BRAF-mutant disease, who were previously treated with BRAF or MEK inhibitors, or both. This study was the largest reported of antiPD-1 therapy in patients with melanoma and the first reported randomized comparison of an anti-PD-1 agent. The Phase II KEYNOTE-002 study of pembrolizumab versus chemotherapy then confirmed the benefit of pembrolizumab over chemotherapy in patients who had progressed on prior ipilimumab. It also confirmed a lack of a dose–response relationship congruent with the results of the two randomized cohorts in KEYNOTE-001. In this trial, pembrolizumab demonstrated a manageable safety profile, with 14% of patients experiencing grade 3–4 toxicity, most of which were immunerelated [27]. Phase III studies
A recently published randomized, controlled Phase III study compared two dosing schedules of pembrolizumab (10 mg/kg every 2 or 3 weeks) to 4 doses of ipilimumab 3 mg/kg every 3 weeks, with primary endpoints of progression-free survival and OS [28]. Estimated 6-month progression-free survival rates for pembrolizumab every 2 and 3 weeks and ipilimumab were 47.3, 46.4 and 26.5%, respectively, with a hazard ratio of 0.58 (95% CI: 0.46–0.72, one-sided p 1% of pembrolizumab-treated patients were colitis (1.4 and 2.5%, respectively) and hepatitis (1.1 and 1.8%, respectively). There are currently no published or recruiting head-to-head trials of pembrolizumab versus nivolumab to directly compare the efficacy and safety of these competing anti PD-1 antibodies. Approval status of the drug
Pembrolizumab is the first PD-1 inhibitor to be approved by the US FDA for the treatment of patients with unresectable metastatic melanoma and disease progression following ipilimumab and if BRAFV600 mutation positive, a BRAF inhibitor. In the UK, pembrolizumab is the first treatment to be accepted under the new Early Access to Medicines Scheme created by the UK Medicines and Healthcare Regulatory Agency before being granted a European license. It was granted Therapeutic Goods Administration approval in Australia in April 2015. Conclusion
After years of disappointment in the management of advanced melanoma, we are seeing an exciting resurgence in clinical research to develop effective immunotherapeutic strategies. Clinical trials of mAbs to PD-1 and PD-L1 have shown impressive response rates, coupled with response durability and a strikingly favorable toxicity profile previously unprecedented in patients with advanced melanoma. However, further studies are needed to dissect mechanisms of variable response rates to informahealthcare.com
Drug Profile
identify biomarkers of clinical response and toxicity and combine these agents with other available and investigative therapies. Expert commentary How long to treat for, & does re-treatment help?
PD-1/PD-L1 antibodies are administered on a continuous schedule, yet it remains unclear as to whether this continuous dosing is necessary. There is now emerging evidence that patients may demonstrate responses lasting beyond the cessation of anti-PD-1 therapy [7]. One patient who had benefited from nivolumab but who later experienced progression reinitiated nivolumab and later regained a response [33] similar to the benefits seen in some patients who have received re-induction ipilimumab. Further studies and assessment of longer term survival data in the current patient cohorts receiving antiPD-1 antibodies are required to answer these questions. Indeed, answering these questions would help alleviate growing concerns of therapeutic regulatory bodies about the costs associated with prolonged use of these agents. Sequencing of treatment
In patients with BRAFV600-mutant melanoma, the optimal sequence of immunotherapy and BRAF plus MEK inhibitors remains one of the most critical, yet unanswered questions. After initial tumor regression with response rates of up to 67% seen with BRAF plus MEK inhibition, most patients develop rapidly progressive disease after an average of 9 months of treatment [3]. This occurs coincident with the development of drug resistance, and disease escalation that in some patients outpaces further second-line immunotherapy, leading to a concern that perhaps V600-mutant melanoma may be best treated with upfront immunotherapy. Of note, the KEYNOTE 006 Phase III study of pembrolizumab compared with ipilimumab did not enroll patients with BRAFV600 mutations who did not receive previous anti-BRAF-targeted therapy if they had high lactate dehydrogenase levels and symptomatic or rapidly progressive disease, citing the rationale that targeted anti-BRAF agents can have a rapid clinical benefit in this population of patients [28]. Although the question of the most effective sequence of immunotherapy and BRAF or MEK inhibitors cannot be addressed without randomized, controlled trials, BRAFV600 status did not seem to influence the benefit of pembrolizumab over ipilimumab in this study. Other important areas of clinical investigation in terms of sequencing treatment include the role of combination immunotherapy with its high and sometimes rapid response rate, and the treatment of patients who have minimal disease progression or mixed responses. Synergy with radiotherapy & chemotherapy
Accumulating evidence suggests that tumors with a preexisting active immune microenvironment might have a better response to immunotherapy. In a number of preclinical and clinical studies, many cytotoxic agents elicit changes within tumors and doi: 10.1586/17512433.2015.1061430
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/08/15 For personal use only.
Drug Profile
Kumar & McNeil
their microenvironment that may make these malignant cells more sensitive to an efficient immune cell attack. Therefore, it is plausible that combining immunotherapy with standard anticancer therapies such as chemotherapy or radiotherapy will provide synergistic anti-tumor effects [34,35]. Phase I studies are currently underway that hypothesize that combining radiation therapy with immunomodulatory therapy will facilitate immune recognition of tumor-specific antigens, yielding a synergistic effect. Furthermore, these studies hypothesize that this combination could focus the immune system on tumor antigens and minimize the aberrant immune activation in normal tissues, consequently reducing the incidence of irAE’s. However, the safety profile and toxicities of combining immunotherapy with brain radiation treatment are largely unknown besides small case series [36], and require further investigation. The role of PD-L1 expression & TILs in predicting responders
There have been conflicting data regarding PD-L1 expression as a prognostic factor among patients with melanoma, and questions over whether PD-L1 expression may serve as a biomarker for response to anti-PD-1 therapy. A Danish study evaluated the relationship between PD-L1 expression and OS in 223 melanoma patients [37]. Tumor PD-L1 expression was measured using an immunohistochemistry assay with the 22C3 antibody, with PD-L1 positivity defined as staining in ‡1% of cells. Forty-nine percent of patients were PD-L1 positive, there was no significant association between PD-L1 expression and OS, and, in particular, there was no association between PD-L1 expression and survival among patients treated with ipilimumab, chemotherapy, IL-2, interferon or targeted therapy. The relationship between PD-L1 expression and clinical outcome with pembrolizumab was then assessed in patients recruited to the KEYNOTE 001 trial [38,39]. Once again, PD-L1 expression was assessed using the same techniques and criteria as the Danish study. PD-L1 expression was associated with a significantly higher response rate and significantly longer PFS and OS (84% at 1 year in PD-L1 positive, 69% in PD-L1 negative patients). However, although tumor PD-L1 positivity was associated with improved responses, durable anti-tumor activity was still observed in patients without PD-L1 expression, suggesting that PD-L1 expression should not exclude patients from treatment. Of interest, in the trial comparing the combination of nivolumab and ipilimumab to sequenced ipilimumab followed by nivolumab, PD-L1 expression (defined as ‡5% of cells) was demonstrated in 38% of patients, and did not correlate with differing OR rates in patients receiving concurrent treatment [9]. However, a higher ORR was demonstrated in PD-L1 positive compared to PD-L1 negative patients in the cohort receiving the sequenced regime, perhaps suggesting that combined immunotherapy may overcome the predictive effect of PD-L1 expression in responding to immunotherapy. To complicate this matter, an Australian study has now evaluated PD-L1 expression in immunotherapy-naive patients with advanced melanoma to determine longitudinal intra-patient doi: 10.1586/17512433.2015.1061430
PD-L1 concordance, and correlate PD-L1 status with clinicopathologic characteristics and outcomes. PD-L1 expression was found to be frequently discordant between primary tumors and metastases and between intra-patient metastases. PD-L1 was associated with higher TIL grade but not with other known prognostic features. A positive association was demonstrated between PD-L1 expression and higher TIL grade in locoregional metastases and melanoma-specific survival, but the effect was not observed for primary melanoma [40]. The same research group also illustrated the dynamic nature of PD-L1 expression by assessing PD-L1 and TIL expression as well as lymphocyte subsets at baseline and then at progression following treatment with BRAF inhibitors alone or the combination of BRAF and MEK inhibition [41]. Patient tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at progression, while patients who were PD-L1 negative at baseline alternatively demonstrated an increase in PD-L1. PD-1 expression also strongly correlated with TIL expression and lymphocyte subsets. Tumeh et al. [16] analyzed samples from 46 patients with metastatic melanoma obtained before and during antiPD-1 therapy with pembrolizumab using quantitative immunohistochemistry, multiplex immunofluorescence and nextgeneration sequencing for T-cell antigen receptors. They demonstrated that pre-existing CD8+ T cells located at the invasive tumor margin are associated with expression of the PD-1/PDL1 immune inhibitory axis and may predict response to therapy. Patients responding to treatment also showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumor size. Interpretation of all these data suggests that PD-L1 and TIL expression in melanoma at baseline could define different subgroups of patients, and could cautiously assist in the selection and sequence of more effective treatment combinations. Activity of pembrolizumab in the brain
While recent advances in the treatment of metastatic melanoma with agents targeting PD-1 have been particularly striking, there remains a significant need to develop therapies for patients with untreated brain metastases who were excluded from trials of pembrolizumab. The brain is a common site of metastatic spread in melanoma. Autopsy data have shown that up to 75% of patients who died from metastatic melanoma had brain metastases [42,43], and 20% of patients have them at first presentation with metastatic disease [44]. Current standard of care for cerebral metastases that require immediate local intervention, based on symptoms, location or size, is craniotomy with resection, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Surgery and SRS are directed to the tumor volume only, whereas WBRT delivers lower-dose radiotherapy to the whole brain, including areas of no overt tumor. Surgery is not limited by the size of the tumor; however, it is dependent on the lesion being surgically accessible. In appropriately selected patients (lesions
