FROM THE ANALYST’S COUCH

The immune checkpoint inhibitors: where are we now?Rachel M. Webster Isolted black couch with coloured pillows, image from iStock.

Immune checkpoint inhibitors have reignited enthusiasm for the development of immuno therapy drugs for cancer, having demonstrated high response rates and prolonged overall survival in cancer patients. Immune checkpoints control the balance of costimulatory and co-inhibitory signals that have essential roles in maintaining self-tolerance and in regulating the amplitude and duration of T-cell responses. Two notable immune checkpoint molecules, cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell-death protein 1 (PD1), are negative regulators of cytotoxic T-cell activation.

Currently available drugsThree immune checkpoint inhibitors are marketed: ipilimumab (Yervoy; Bristol-Myers Squibb), nivolumab (Opdivo; Bristol-Myers Squibb/Ono Pharmaceuticals), and pembrolizumab (Keytruda; Merck & Co.) — all for the treatment of malignant melanoma. The first to reach the market was the monoclonal CTLA4-specific antibody ipilimumab in 2011. This agent had a dramatic impact on medical practice for unresectable or metastatic malignant melanoma1. Data from a pooled analysis comprising 1,861 patients in clinical trials showed 3-year and 7-year overall survival of 22% and 17%, respectively. However, in the clinical study that led to its approval, response rates were low (11%) and the incidence of grade 3 and grade 4 adverse events high (46%, of which 15% were immune-related). Ipilimumab carries a black-boxed warning for immune-mediated adverse events and a risk evaluation and mitigation strategy (REMS) has been developed.

Nivolumab, a PD1-specific monoclonal antibody, became the first of a novel class of immune checkpoint inhibitors to gain regulatory approval when it was approved in Japan in July 2014 for malignant melanoma, on the basis of Phase II data under a prioritized review process. Interim Phase III data that have since been announced show a response rate in pretreated metastatic-melanoma of 32%, and 95% of responses were ongoing at the time of analysis. Nivolumab-related grade 3 and grade 4 adverse events were low (9%). In September 2014, a Biologic License

Application (BLA) was submitted to the US Food and Drug Administration (FDA) for nivolumab as a therapy for previously treated advanced malignant melanoma. The FDA has accepted nivolumab for priority review with a prescription drug user fee act (PDUFA) date set for 30 March 2015, and has granted it breakthrough therapy designation (BTD) status. The European Medicines Agency (EMA) have also granted accelerated review of the marketing authorization application for nivolumab in advanced malignant melanoma.

In September 2014, nearly two months ahead of its PDUFA date, pembrolizumab gained accelerated FDA approval for advanced

and unresectable malignant melanoma. It was awarded BTD status in April 2013 and, just three and a half years since the first-in-human trials, pembrolizumab became the first anti-PD1 therapy to reach the US market. Based on Phase I data, pembrolizumab is recommended for use in patients who have previously received ipilimumab and, if BRAF-mutation-positive, a BRAF inhibitor. Similar to nivolumab, response rates associated with pembrolizumab are high (24%) and durable (at the time of analysis, 86% of patients had responses that were ongoing). The most frequently reported adverse events were fatigue (7%), anaemia (5%) and dyspnoea (2%). ▶

Table 1 | Select immune checkpoint inhibitors in the pipeline

Drug (alterna­tive name)

Company Target First indication Development status

Opdivo (nivolumab)

Bristol-Myers Squibb

PD1 Malignant melanoma

Marketed (Japan)

Keytruda (pembrolizumab)

Merck & Co. PD1 Malignant melanoma

Marketed (USA)

MEDI4736 AstraZeneca PDL1 NSCLC Phase III

MPDL3280A Roche/Genentech PDL1 Urothelial bladder cancer or NSCLC

Phase III

Tremelimumab AstraZeneca CTLA4 Mesothelioma Phase II

Pidilizumab (CT-011)

CureTech PD1 Haematologic or solid tumours

Phase II

Lirilumab (BMS-986015)

Bristol-Myers Squibb

KIR Haematologic or solid tumours

Phase II

Indoximod (NLG-9189)

NewLink Genetics IDO1 Breast cancer Phase II

INCB024360 Incyte IDO1 Solid tumours Phase II

MEDI0680 (AMP-514)

AstraZeneca PD1 Solid tumours Phase I

MSB-0010718C Merck KGaA PDL1 Solid tumours Phase I

PF-05082566 Pfizer 4-1BB (also known as CD137)

Haematologic or solid tumours

Phase I

MEDI6469 AstraZeneca OX40 (also known as CD134)

Solid tumours Phase I

BMS-986016 Bristol-Myers Squibb

LAG3 Haematologic or solid tumours

Phase I

NLG-919 NewLink Genetics IDO1 Solid tumours Phase I

Urelumab (BMS-663513)

Bristol-Myers Squibb

4-1BB (also known as CD137)

Haematologic or solid tumours

Phase I

4‑IBB, tumour necrosis factor receptor superfamily member 9; CTLA4, cytotoxic T‑lymphocyte protein 4; IDO1, indoleamine 2,3‑dioxygenase 1; LAG3, lymphocyte activation gene 3 protein; KIR, killer cell immunoglobulin‑like receptor; NSCLC, non‑small‑cell lung cancer; OX40, tumour necrosis factor receptor superfamily member 4; PD1, programmed cell‑death protein 1; PDL1, programmed cell‑death ligand 1.

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FROM THE ANALYST’S COUCH

▶ Drug pipelineNivolumab is also in Phase III trials for non-small-cell lung cancer (NSCLC), squamous-cell carcinoma of the head and neck (SCCHN), renal-cell carcinoma (RCC) and glioblastoma multiforme, and pembrolizumab is in Phase III trials for NSCLC, SCCHN and urothelial bladder cancer.

Nivolumab is expected to be the first anti-PD1 therapy to gain approval for NSCLC2. In a Phase I study, nivolumab had a response rate of 24% and a median overall survival benefit of 14.9 months in heavily pretreated metastatic-NSCLC patients. A rolling submission to the FDA for nivolumab as a third-line treatment for squamous-cell NSCLC was initiated in May 2014; it is expected to be finalized before the end of 2014. In September 2014, the EMA accepted to review the market authorization application for nivolumab in NSCLC.

For pembrolizumab, Phase I data showed a response rate of 21% and median overall survival benefit of 12 months in heavily pretreated metastatic-NSCLC patients. The response rate is considerably higher in patients who overexpress programmed cell-death protein 1 (PDL1) compared with PDL1-negative patients (23% versus 9%). Pembrolizumab has also demonstrated encouraging response rates (31%) in PDL1-positive advanced gastric cancer patients, with less than 1% grade 3–5 treatment-related adverse events in a Phase Ib trial.

Further PD1 inhibitors in development include pidilizumab (CureTech), which is in Phase II development for solid tumours and haematologic malignancies, and MEDI0680 (AstraZeneca), which is in Phase I for mixed solid tumours.

Two therapies targeted at PDL1 are also in Phase III development for NSCLC — MEDI4736 (AstraZeneca) and MPDL3280A (Roche/Genentech) (TABLE 1; FIG. 1). These agents are also in early-stage trials for other solid-tumour indications, including SCCHN and urothelial bladder cancer.

Phase I data for MPDL3280A in NSCLC are promising, with a 23% response rate in heavily pretreated patients. Patients with moderate to stong PDL1 expression achieved a response rate of 46%. However, as seen with PD1 inhibitors in NSCLC, about 15% of PDL1-negative patients also responded. MPDL3280A was awarded BTD status for bladder cancer by the FDA in May 2014. In a Phase I study, it showed a 43% response rate in PDL1-positive pretreated metastatic urothelial bladder cancer patients. The response rate in PDL1-negative patients was 11%, and the majority of responses were ongoing at the time of analysis.

MEDI4736 is in Phase III development for locally advanced, unresectable stage III NSCLC. Preliminary Phase I efficacy data for MEDI4736 in NSCLC and SCCHN is encouraging, with durable responses.

Several other immune checkpoint inhibitors are in early-stage clinical trials (TABLE 1). Notably, numerous developers have checkpoint inhibitors in development that target novel targets such as LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), IDO1 (indoleamine 2,3-dioxygenase 1), 4-1BB (tumour necrosis factor receptor superfamily member 9) and OX40 (tumour necrosis factor receptor superfamily member 4).

Combinatorial approachesA number of drug combinations that include checkpoint inhibitors are being evaluated, including dual immune-checkpoint blockade (for example, anti-CTLA4 with anti-PD1), or checkpoint inhibitors with angiogenesis inhibitors, novel therapeutic vaccines, other small-molecule targeted agents (for instance, BRAF or MEK inhibitors) or chemotherapy.

The most advanced combination (now in Phase III) is that of ipilimumab and nivolumab for malignant melanoma and RCC. Phase I data for the combination

in unresectable or metastatic malignant melanoma showed a response rate of 53%, and 82% of responses were ongoing at time of analysis. However, the incidence of grade 3 or grade 4 adverse events for this combination is very high (63%). It remains to be determined to what extent the higher incidence of side effects and the likely high cost that this combination therapy will command could constrain its uptake.

A Phase III study for MEDI4736 in combination with the anti-CTLA4 agent tremelimumab (AstraZeneca) in SCCHN is scheduled to start before the end of 2014.

Market indicatorsThe immune checkpoint inhibitor market will experience considerable growth over the 2013–2020 forecast period, increasing from approximately US$1 billion in 2013 to in excess of $7 billion in 2020 (corresponding to 33% annual growth), across the seven major markets (United States, France, Germany, Italy, Spain, United Kingdom and Japan)3 (FIG. 1). Growth in sales will be fuelled by the expected market entry of nivolumab, pembrolizumab, MPDL3280A and MEDI4736 across multiple solid-tumour indications. In 2022, the anti-PD1 agents (including nivolumab and pembrolizumab) are expected to hold the highest market share, at 72%. Anti-CTLA4 agents and anti-PDL1 agents are expected to account for 20% and 8% of the immune checkpoint inhibitor market share, respectively. We anticipate that nivolumab will generate approximately $3 billion in 2020, a reflection of its robust uptake as a single agent and in combination with ipilimumab across multiple indications. Several developers are investing in and evaluating combinatorial approaches that involve immune checkpoint inhibitors through strategic collaborations. Combination approaches could provide an important route to market differentiation in what will probably be a crowded market4.1. Decision Resources Group: Malignant Melanoma.

Pharmacor Service. Onkos. 2013–2014.2. Decision Resources Group: NSCLC. Pharmacor Service.

Onkos. 2013–2014.3. Decision Resources Group: Pharmaview Service. 2014. 4. Decision Resources Group: Immunotherapies.

Pharmacor Service. Onkos. 2014.

Rachel Webster is at Decision Resources, 6th Floor, Aldermary House, 10–15 Queen Street,

London EC4N 1TX, United Kingdom. e-mail: rwebster@dresourcesgroup.com

doi:10.1038/nrd4476 Published online 27 October 2014

The author declares no competing financial interests.

Figure 1 | Major­market sales of select immune checkpoint inhibitors (estimated). Sales forecast in the seven major markets (United States, France, Germany, Italy, Spain, United Kingdom and Japan) from 2013 to 2020. Sales shown in US$ million.

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