Nivolumab (Opdivo), the first human IgG4 monoclonal antibody against PD-1, was initially approved by the FDA on 22 December 2014, based on the outcome of CheckMate-037 (Table 2
). This trial showed that ORR improved with fewer toxic effects with nivolumab against standard-of-care chemotherapy among patients with advanced, unresectable/metastatic melanoma who progressed following ipilimumab treatment, or a BRAF inhibitor if BRAF mutation positive [35
] (Category 1). On 1 October 2015, the FDA expanded its use in combination with ipilimumab (Yervoy in BRAFV600 wild-type unresectable melanoma or metastatic melanoma under certain circumstances such as high LDH and rapid progression of disease based on the CheckMate-067 andCheckMate-069 trials, which showed improved ORR with the combination immunotherapy [30
] (Category 1). The FDA again expanded the indication of this combination regimen to metastatic melanoma across BRAF mutation status on 23 January 2016 based on the improved progression-free survival (PFS) rate noted in the CheckMate-067 trial [30
] (Category 1). Thereafter, based on the improved recurrence-free survival (RFS) rate from CheckMate-238 trial on 20 December 2017, the FDA further expanded its indication in lymph node-positive or metastatic melanoma patients who had undergone complete resection [36
] (Category 1). This was the first indication of nivolumab in the adjuvant setting after direct comparison with ipilimumab and also one of the current first-line systemic therapy in patients with recurrent or metastatic melanoma regardless of BRAF V600 mutation status (Category 1).
Nivolumab later received FDA approval on 4 March 2015 for patients with squamous non-small-cell lung cancer (NSCLC) who progressed after platinum-doublet chemotherapy based on the result of the CheckMate-017 trial, with better ORR as well as survival benefit regardless of the PDL-1 expression level [37
] (Category 1). On 10 October 2015, the FDA further expanded its use in metastatic non-squamous NSCLC patients who progressed on first-line platinum-based chemotherapy in a similar setting; this study included patients with actionable mutations such as EGFR and ALK mutation who progressed after appropriate target therapy, per the CheckMate-057 trial, which resulted in increased survival and decreased immunotherapy-related toxicity [38
] (Category 1).
On 17 August, 2018, the FDA has also approved nivolumab for small-cell lung cancer (SCLC) patients who progressed on platinum therapy and at least one other line of therapy based on the CheckMate-032 trial, a phase 1/2 multi-center, multi-cohort study, which showed an increase in overall response rate and duration of response [39
] (Category 2A).
Nivolumab was also studied among advanced renal cell cancer (RCC) with prior anti-cancer therapy (mTOR) in CheckMate-025 with improved overall survival and fewer side effects [33
]. This led to its approval on 23 November 2015 (Category 1). In another trial, CheckMate-214, a phase 3 study, a combination of nivolumab and ipilimumab was compared against sunitinib (standard of therapy) for untreated intermediate- or poor-risk advanced RCC patients based on a better response rate and overall survival (OS) with the combination regimen; the FDA approved the combination regimen for this group of patients on 16 April 2018 as first-line therapy [40
] (Category 1). This combination immunotherapy is also approved as first-line therapy for the favorable-risk group (Category 2A), and the second-line therapy for relapse or stage IV disease (Category 2A).
The FDA granted accelerated approval to nivolumab on 17 May 2016 for Hodgkin’s lymphoma that has progressed or relapsed post-autologous stem cell transplantation (ASCT), post-transplantation brentuximab vedotin therapy. It is also approved after three or more lines of therapy that include ASCT (Category 2A based on the higher ORR noted with nivolumab in the CheckMate-205 and CheckMate-039 trials) [41
On 10 November 2016, nivolumab obtained another FDA indication for relapsed/refractory metastatic squamous cell cancer of head and neck (SCCHN) that has progressed on standard-of-care platinum-based therapy. This was based on the OS benefit from a phase-3, CheckMate-141 trial [42
] (non-nasopharyngeal—Category 1; nasopharyngeal—Category 2B).
Nivolumab was also studied among patients with locally advanced, unresectable or metastatic urothelial cancer who had progressed despite a platinum-based regimen in the CheckMate-275 trial. In this trial, improved ORR and OS benefit of 7 months irrespective of PD-L1 expression was observed. This formed the basis of its accelerated approval on 2 February 2017 for surgically unresectable or metastatic urothelial cancer [43
] (Category 2A).
Nivolumab was studied for metastatic colorectal cancer (mCRC) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) that had progressed on a combination of fluoropyrimidine, oxaliplatin, and irinotecan. The ORR and duration of response to nivolumab in the CheckMate-142 trial lead to its accelerated approval on 1 August 2017 for this group of patients [34
] (Category 2A). In the same cohort of patients, a combination of nivolumab and ipilimumab showed better ORR than with nivolumab alone, which led to accelerated approval of the combination regimen for this group of patients on 11 July 2018, provided patients could tolerate this combination [44
] (Category 2A).
Nivolumab was also studied for hepatocellular carcinoma (HCC) that was previously treated with sorafenib in the CheckMate-040 trial. The study was an open-label, phase 1/2, non-comparative dose escalation trial because sorafenib was the only approved drug for HCC at the time. Nivolumab was granted approval for this group of patients via an accelerated process on 22 September 2017, based on the ORR from this trial [45
] (Category 2A).
Pembrolizumab (Keytruda) is another human IgG4k monoclonal antibody against PD-1. It received its first approval on 4 September 2014, via an accelerated process based on the objective response rate of 24%, from the clinical trial NCT01295827, in metastatic melanoma patients who are refractory to CTLA-4 therapy and BRAF inhibitor if they have BRAF mutation [46
] (Category 2A), (Table 3
). The FDA further expanded its approval for previously untreated advanced melanoma regardless of BRAF mutation status on 18 December 2015 (Category 2A), based on the Keynote-006 trial, a phase 3 randomized trial comparing pembrolizumab against ipilimumab (then standard therapy), which resulted in a prolonged OS and PFS with less toxicity than ipilimumab [47
]. Based on Keynote-002, the FDA further expanded its use in ipilimumab refractory advanced Melanoma at the same time as it was shown to be superior to the investigator’s choice chemotherapy [48
] (Category 2A). On 19 February 2019, the FDA extended the use of pembrolizumab in the adjuvant treatment of lymph node(s)-positive melanoma following complete resection (Category 1) based on the phase 3, EORTC1325/Keynote-054 trial study demonstrating prolonged recurrence-free survival (RFS) [49
]. In the case of metastatic melanoma with limited resectability, if there is no disease after resection, it is still indicated as adjuvant therapy (Category 2A).
Pembrolizumab was approved by the FDA on 2 October 2015 for metastatic NSCLC patients who progressed after platinum-based therapy or EGFR- or ALK-targeted therapy and are positive for PDL-1, via accelerated approval based on the randomized, open-labeled, phase II/III study, Keynote-010 trial, showing improved ORR, PFS, and OS compared to Docetaxel in tumors with at least 1% expression of PDL-1 [50
]. There were fewer grade 3–4 adverse events in this study, and they noted signals for higher response rates and survival with higher PDL-1 expression > 50%. Earlier in the same year, nivolumab was also approved for advanced squamous cell lung cancer refractory to first-line therapy regardless of PDL-1 expression, as mentioned earlier in this paper. On 24 October 2016, the FDA expanded its approval as the first-line treatment for metastatic non-small-cell lung cancer with high PDL-1 expression (≥ 50%) but no EGFR or ALK mutation (Category 1 and preferred; category 2B if PDL-1 1–49%). This was based on Keynote-024, which was a randomized, open-label, phase 3 trial comparing pembrolizumab against platinum-based therapy for patients with untreated NSCLC with at least 50% PDL-1 expression but no EGFR or ALK mutation. Interim analysis of this trial showed significantly longer OS and PFS, with fewer treatment-related adverse events than with a platinum-based regimen. This trial was stopped early to allow patients who were still on chemotherapy the opportunity to receive pembrolizumab [51
]. On 10 May 2017, the FDA further expanded its approval as a first-line treatment in combination with pemetrexed and carboplatin for metastatic non-squamous NSCLC without EGFR or ALK mutation, irrespective of PDL-1 expression (Category 1 and preferred if PD-L1 expression 1–49%; Category 1 if PD-L1 expression is ≥ 50%). This approval was given via an accelerated process based on improved response rates and PFS from 8.9 months (pemetrexed + carboplatin) to 13 months with the triplet regimen, shown by the keynote-021 trial [52
]. This combination was granted full approval on 20 August 2018, based on consistent findings from the Keynote-189 trial [53
]. On 30 October 2018, the FDA expanded approval of pembrolizumab as a first-line therapy to metastatic squamous NSCLC in combination with carboplatin with paclitaxel/nab-paclitaxel irrespective of PD-L1 status based on the improved ORR, PFS and OS in a patient with pembrolizumab than without from Keynote-407 [54
] (Category 1 and preferred if PD-L1 expression 1–49%; Category 1 if PD-L1 expression ≥ 50%). On 11 April 2019, the FDA further expanded its approval of pembrolizumab in NSCLC as a first-line monotherapy for patients with stage 3 NSCLC who cannot undergo surgical resection as well as chemoradiation or metastatic NSCLC with PDL-1 expression ≥1% and no EGFR or ALK mutation. This was based on a phase 3 study, Keynote-042, which showed increased OS in comparison to chemotherapy [56
] (Category 1).
On 5 August 2016, pembrolizumab was also approved for recurrent or metastatic head and neck squamous cell cancer (HNSCC) patients who progressed on standard platinum-based therapy (non-nasopharyngeal—Category 1; nasopharyngeal and PD-L1 positive—Category 2B as per NCCN guideline). This approval via an accelerated process on based on the increased ORR (16%) and durability of response (DOR) regardless of human papilloma virus (HPV) status, demonstrated in Keynote-012 trial [57
]. On 11 June 2019, the FDA extended its indication as a first-line therapy for patients with metastatic or unresectable, recurrent HNSCC, either as monotherapy in patients whose tumor expresses PD-L1 (combined positive score ≥ 1%) or in combination with platinum and fluorouracil (only for nonnasopharyngeal–Category 2A). This was based on the increased OS noted with the pembrolizumab-based regimen either alone or in combination against those with the cetuximab-based regimen in Keynote-048 [58
Pembrolizumab was approved for refractory adult and pediatric classical Hodgkin’s lymphoma on 14 March 2017. This approval was given via an accelerated process based on the Keynote-087 trial, which was a single-arm phase 2 study (Category 2A). This showed an overall response rate of 69%—of which, 22% had complete remission and the median duration of response was 11 months [59
The FDA accelerated the approval of pembrolizumab on 18 May 2017 for unresectable or metastatic urothelial cancer patients who progressed on or after platinum-based therapy including those in the adjuvant setting. This was based on improved 3 month OS, with a lower rate of toxicity noted in the Keynote-045 trial [60
] (Category 2A). On the same day, it was also approved as first-line therapy for unresectable or metastatic urothelial cancer patients who are ineligible for cisplatin-containing chemotherapy based on the increased ORR noted in Keynote-052 trial [61
] (Category 2A). Patients with PD-L1 expression (combined positive score ≥ 10%) had a better response in this trial, and those with < 10% expression had inferior survival and so the FDA released a statement on 29 June 2018, limiting the use of this drug in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing therapy and tumors expressing PD-L1 > 10%, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status (Category 2A as per).
On 23 May 2017, pembrolizumab received accelerated approval for adult and pediatric patients with unresectable or metastatic solid tumors with biomarker selected for MSI-H or dMMR who have progressed after the first-line therapy and also do not have satisfactory alternative therapy, irrespective of the location of the primary tumor with tumor-agnotic approval. This approval was based on multiple clinical trials enrolling patients with MSI-H and dMMR solid tumor (Keynote-012, Keynote-016, Keynote-028, Keynote-158, and Keynote-164) showing an overall response rate of nearly 40% [62
] (Category 2A).
Pembrolizumab was approved as a third-line therapy for recurrent advanced or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma patients with PD-L1 expression (combined positive score ≥ 1%) who have progressed on or after two or more prior lines of therapy including fluoropyrimidine and a platinum-based regimen and, if appropriate, HER2/neu-targeted therapy. This approval was given via an accelerated process on 22 September 2017, based on the RR(13%) and DOR from the Keynote-059 trial [64
] (Category 2A). From the NCCN standpoint, pembrolizumab can be used in esophageal (squamous and adenocarcinoma) and EGJ adenocarcinoma (Category 2A for second-line or subsequent therapy for MSI-H or dMMR tumors [65
]; Category 2B for second-line with PD-L1 expression ≥ 10% [67
]; Category 2B for third-line or subsequent therapy) [64
Pembrolizumab was approved by the FDA on 12 June 2018 for recurrent or metastatic cervical cancer progressing after chemotherapy and PDL-1 positive patients. This approval was given via an accelerated process based on the evidence from cohort E of the Keynote-158 trial showing overall response rate of 14% [68
] (Category 2A).
On 13 June 2018, the FDA approved pembrolizumab for adult or pediatric patients with refractory or relapsed primary mediastinal large B-cell lymphoma (PMBCL); this approval was given via an accelerated process on based on the improved ORR (45%) noted in Keynote-170 [69
] (Category 2A).
The FDA approved pembrolizumab on 9 November 2018 for HCC patients who had previously been treated with sorafenib, based on RR (17%) and its durability from Keynote-224 [70
] (Category 2B, Child–Pugh Class A only).
The FDA granted accelerated approval to pembrolizumab on 19 December 2018, for adult and pediatric patients with recurrent or locally advanced or metastatic Merkel cell carcinoma (MCC) as first-line therapy, based on the ORR (56%) from the CITN-09/Keynote-017 trial [71
] (Category 2A).
The FDA has approved pembrolizumab in combination with axitinib as first-line treatment for patients with metastatic renal cell cancer (RCC), based on a phase 3 study, Keynote-426, which showed improved OS, PFS as well as ORR [72
] (poor and intermediate risk—Category 1; favorable risk—Category 2A).