{"id":4245,"date":"2017-01-25T11:05:07","date_gmt":"2017-01-25T16:05:07","guid":{"rendered":"http:\/\/blogs.shu.edu\/cancer\/?p=4245"},"modified":"2021-07-02T08:51:43","modified_gmt":"2021-07-02T12:51:43","slug":"pd-l1-expression-correlates-with-outcomes-in-patients-with-melanoma","status":"publish","type":"post","link":"https:\/\/blogs.shu.edu\/cancer\/2017\/01\/25\/pd-l1-expression-correlates-with-outcomes-in-patients-with-melanoma\/","title":{"rendered":"PD-L1 Expression correlates with outcomes in patients with melanoma"},"content":{"rendered":"

Keytruda (pembrolizumab)<\/a> and Opdivo (nivolumab)<\/a> are monoclonal antibodies that disrupt the PD-1 (Opdivo) \/ PD-L1 (Keytruda) pathway; they are approved by the FDA for the treatment of patients with unresectable melanoma, as well as other cancers including non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma (Opdivo), and Hodg\u00a0 kin lymphoma (Opdivo). Keytruda is limited to patients with NSCLC with a tumor proportion score (TPS) of greater than 50% for PD-L1 staining.<\/p>\n

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Figure 1. Human cancer immunotherapy with anti-PD-1 and anti-PD-L1\/L2 antibodies: Antigen-presenting cells (APC) take up antigens (Ag) released from cancer cells and present to T cells. Cancer cells can also present Ag to activated T cells in the context of MHC. Upon T cell activation, PD-1 receptors are expressed on T cells and inhibit immune responses by engagement of PD-L1 and PD-L2 ligands on APC and PD-L1 on cancer cells. Therefore, monoclonal antibody (mAb)-mediated specific blockade of the PD-1\/PD-L1\/PD-L2 pathway can enhance anti-tumor immunity. In addition to binding to PD-1, PD-L1 and PD-L2 also bind B7-1 and repulsive guidance molecule B, respectively. In addition to T cells and APC, PD-1 and PD-L1 can be induced on other immune cells. http:\/\/www.cell.com\/trends\/molecular-medicine\/fulltext\/S1471-4914(14)00183-X<\/a><\/p><\/div>\n

Does PD-L1 expression matter in lung cancer?<\/em><\/strong><\/p>\n

In NSCLC patients that failed following prior chemotherapy, Keytruda has superior overall survival compared to chemotherapy -10.4 months (Keytruda 2 mg\/kg every 3 weeks) versus 8.5 months (p < 0.001) and 12.7 months (10 mg\/kg every 3 weeks) versus 8.5 months (p < 0.001). The subgroup of patients with a TPS > 50% had a better survival than with chemotherapy \u2013 14.9 months (Keytruda 2 mg\/kg every 3 weeks) versus 8.2 months (p < 0.001) and 17.3 months (10 mg\/kg every 3 weeks) versus 8.2 months (p < 0.001).<\/p>\n

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Figure 2. Response in patients with NSCLC from Keytruda package insert. A total of 1033 patients were randomized: 344 to the KEYTRUDA 2 mg\/kg arm, 346 patients to the KEYTRUDA 10 mg\/kg arm, and 343 patients to the docetaxel arm. The study population characteristics were: median age 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG performance status 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with non-squamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic 23 aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease. https:\/\/www.merck.com\/product\/usa\/pi_circulars\/k\/keytruda\/keytruda_pi.pdf<\/a><\/p><\/div>\n

Patients receiving Opdivo had superior overall survival compared to patients treated with chemotherapy \u2013 12.2 months versus 9.4 months (p = 0.0015). PD-L1 expression was not evaluated. The results with Opdivo were in line with the response seen in all patients treated with Keytruda, not just those with a TPS of greater than 50%.<\/p>\n

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Figure 3. and 7% of patients \u226575 years. The majority of patients were white (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US\/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former\/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%). https:\/\/packageinserts.bms.com\/pi\/pi_opdivo.pdf<\/a><\/p><\/div>\n

Does PD-L1 expression matter in melanoma?<\/em><\/strong><\/p>\n

In the KEYNOYE-001 trial<\/a>, patients with unresectable melanoma who had higher PD-L1 expression (as assessed using the MEL Score) had better responses to Keytruda than patients whose tumors did not express PD-L1. However, even patients with melanomas that did not express PD-L1 showed some benefit.<\/p>\n

Between December 2011 and September 2013, 655 patients with advanced melanoma were enrolled in KEYNOTE-001<\/em>. Among these 655 patients, biopsy samples from 451 patients that were collected in the 60 days before the first dose of pembrolizumab was administered were evaluable for PD-L1 expression. Of 451 evaluable patients, 344 (76%) had PD-L1\u2013positive tumors and 107 (24%) had PD-L1\u2013negative tumors.<\/em>\u00a0<\/em>The pattern of change in tumor size compared with baseline seemed to vary by MEL score. Among evaluable patients at week 12, 35%, 38%, 57%, 78%, 84%, and 86% showed reductions from baseline tumor measurements for MEL scores 0 to 5, respectively. Of note, patients with MEL scores of 4 or 5, 33% and 22%, respectively, showed a reduction of \u2265 50% at week 12. Qualitatively, patients with MEL scores of 0 or 1 were less likely to have a decrease from baseline tumor size overall, whereas more patients with MEL scores of 2 to 5 had a 100% decrease from baseline.<\/em><\/p>\n

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Figure 4. Efficacy according to melanoma (MEL) score for programmed death-ligand 1 (PD-L1) expression. (A) Objective response rate (ORR) and associated 95% CIs. (B) Kapan-Meier estimates of progression-free survival (PFS) and associated 95% CIs at 9 months. (C) Kaplan-Meier estimates of overall survival (OS) and associated 95% CIs at 12 months. Response was assessed per RECIST, version 1.1, by independent central review. MEL score \u2265 2 is considered PD-L1 positive. http:\/\/ascopubs.org\/doi\/full\/10.1200\/JCO.2016.67.2477<\/a><\/p><\/div>\n

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Figure 5. Efficacy by PD-L1 positivity. (A) Kaplan-Meier estimate of progression-free survival (PFS) assessed per RECIST, version 1.1, by independent central review. (B) Kaplan-Meier estimate of overall survival (OS). Melanoma score \u2265 2 is considered PD-L1 positive. NR, not reached; PD-L1, programmed death-ligand 1. http:\/\/ascopubs.org\/doi\/full\/10.1200\/JCO.2016.67.2477<\/a><\/p><\/div>\n

The authors concluded that:<\/p>\n

Given the data described here, PD-L1 expression is correlated with clinical outcome in patients with advanced melanoma. Whereas there is some uncertainty regarding the optimal level of PD-L1 expression, a level that corresponds to MEL scores of 3 to 5 seems to best capture the population that is most highly responsive to PD-1 blockade. Conversely, MEL scores of 0 or 1 represents the least responsive population, and a MEL score of 2, which represents the largest proportion of patients (29%), seems to be intermediate, with many patients experiencing a response to therapy. Furthermore, tumors with the highest levels of PD-L1 staining exhibited deeper responses (33% and 22% of patients showed reductions of \u2265 50% at week 12 with MEL scores of 4 and 5, respectively).\u00a0<\/em><\/p>\n

Important questions remain regarding the relationship between PD-L1 expression and the therapeutic effects of anti\u2013PD-1 and anti\u2013PD-L1 antibodies. It is clear that even with a MEL score of 0 in the assay used in this study, durable responses were still observed<\/strong>; response rates were even higher in the other MEL score groups. The high prevalence of PD-L1 positivity observed in this study, along with the durable responses observed in PD-L1\u2013negative tumors, suggest that pembrolizumab treatment should not be limited to patients with PD-L1\u2013positive tumors. Ongoing clinical trials with correlative studies will further delineate the role of PD-L1 expression in melanoma.<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

Keytruda (pembrolizumab) and Opdivo (nivolumab) are monoclonal antibodies that disrupt the PD-1 (Opdivo) \/ PD-L1 (Keytruda) pathway; they are approved by the FDA for the treatment of patients with unresectable melanoma, as well as other cancers including non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma (Opdivo), and Hodg\u00a0 kin lymphoma (Opdivo). […]<\/p>\n","protected":false},"author":2252,"featured_media":3979,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[711,28,1],"tags":[893,617,1130,89,179,749,218],"class_list":["post-4245","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-active-immunotherapy","category-checkpoint-inhibitors","category-uncategorized","tag-keytruda","tag-lung-cancer","tag-melanoma","tag-nivolumab","tag-nsclc","tag-opdivo","tag-pembrolizumab"],"post_mailing_queue_ids":[],"_links":{"self":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4245","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/users\/2252"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/comments?post=4245"}],"version-history":[{"count":4,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4245\/revisions"}],"predecessor-version":[{"id":4878,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/posts\/4245\/revisions\/4878"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media\/3979"}],"wp:attachment":[{"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/media?parent=4245"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/categories?post=4245"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.shu.edu\/cancer\/wp-json\/wp\/v2\/tags?post=4245"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}