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For over 120 years, it has been known that cancer can stimulate the immune response but the role of immunotherapy against cancer has only been clinically successful in the last two decades. Rosenberg et al showed that interleukin-2 (IL-2) can cause a significant antitumour effect on patients with metastatic melanoma and metastatic renal cell carcinoma in 1994. Only 7 per cent of patients achieved a complete remission with a further 10-13 per cent achieving a partial response. The use of cancer vaccines has also been widely investigated with limited efficacy. Sipuleucel-T is the only approved vaccine for treatment of castrate resistant metastatic prostate cancer showing an overall survival improvement against placebo. However, a further understanding of the role of the immune system in tumour control has recently led to the development of novel immunotherapeutics. The emergence of immune checkpoint inhibitors that directly enhance the function of T-cells in cancer control has been the cornerstone of a sea-change in cancer medicine.
Two pathways have been found to be effective targets for the checkpoint inhibitors resulting in direct enhancement of the function of T-cells in the tumour microenvironment: The cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathway and the programmed cell death 1 receptor (PD-1) or its ligands on tumour cells (PD-L1) pathway. T-cells activation begins when Antigen Presenting Cells (APCs) present peptide fragments of intracellular proteins bound to mixed histocompatibility complex (MHC), which is recognised through T-cell receptors (TCR). The activation of co-stimulatory molecule B7 is required to fully activate T-cells; however, this results in upregulation of CTLA-4 on T-cells, which in turn will compete with CD28 for binding to B7, thereby inhibiting over activation of the immune system. Ipilimumab is an anti-CTLA-4 antibody that blocks this inhibitory signal, thus enhancing T-cell antitumour activity. The second pathway uses the PD-1 receptor on T-cells which is another inhibitory receptor present on activated T-cells after antigen exposure. T-cells activity is downregulated when PD-1 binds to its ligand PD-L1 on tumour cells. Pembrolizumab and Nivolumab are antibodies directed against PD-1.
Evaluations of treatment response with checkpoint inhibitors may be challenging. There may be delayed responses where transient apparent radiologic worsening of disease may precede stabilisation or regression. Thus, it is prudent not to discontinue therapy too early. It is also observed that disease regression may continue after completion of treatment. In addition, clinical benefit was also observed in some patients who did not meet criteria for objective response. Immune-related response criteria have been proposed as a tool for response assessment because the use of traditional Response Evaluation Criteria in Solid Tumours (RECIST) criteria may result in early abandonment of treatment.
This review will mainly focus on the overview of immunotherapy in adjuvant and metastatic setting of melanoma, kidney cancers, and lung cancers.
Immunotherapy use in metastatic melanoma was first approved by the FDA over 20 years ago after Rosenberg et al showed that IL-2 can cause significant antitumour effect in this cohort of patient. Atkins MB et al evaluated 270 patients with metastatic melanoma treated with high dose IL-2 and found 6 per cent of patients had complete remission and 10 per cent had partial response, which was durable with median duration of response of nine months in responding patients.Dacarbazine chemotherapy was still the standard of care at that point with approximately 20 per cent objective response rate and complete response rate of five per cent with median response duration of five to six months.
Chemotherapy as the first-line treatment in metastatic melanoma has now been replaced by the superior checkpoint inhibitors. Ipilimumab (3mg/kg by intravenous infusion given every three weeks for four doses) was approved by FDA in March 2011. Two large Phase 3 trials showed significant prolonged overall survival in metastatic melanoma patients with durable response beyond three years. The first trial (n=676) assigned pateints to either ipilimumab plus a (gp100) vaccine or ipilimumab alone or gp100 alone. Overall survival was 10.0 versus 10.1 versus 6.4 months respectively with overall survival rates of 22, 24, and 14 per cent at 24 months. The objective response rate was 5.7 versus 10.9 versus 1.5 per cent respectively.
The second Phase 3 trial (n=502), which assigned patients to ipilimumab or placebo plus dacarbazine, showed a significant overall survival of 11.2 months versus 9.1 months respectively with survival rates of 18 versus 9 per cent at five years. Pooled analysis of long-term survival data from Phase 2 and Phase 3 trials of ipilimumab in unresectable or metastatic melanoma (n=1861) showed a median overall survival of 11.4 months and a durable survival of 21 per cent beyond three years.
The second generation immune checkpoint inhibitors, PD-1 inhibitors showed a significantly longer progression free survival (PFS) and overall survival compared to CTLA-4 inhibitor in the Phase 3 KEYNOTE 006 trial. Some 834 patients were assigned to either two weekly or three weekly pembrolizumab 10mg/kg or ipilimumab 3mg/kg every three weeks for four doses. Six month PFS for two weekly pembrolizumab schedule was 47.3 versus 26.5 per cent, HR 0.58, 95% CI 0.46-0.72 and three weekly pembrolizumab schedule was 46.4 versus 26.5 per cent, HR 0.58, 95% CI 0.57-0.72. One year overall survival rate for two weekly pembrolizumab was 74.1 versus 58.2 per cent, HR 0.63, 95% CI 0.47-0.83 and three weekly pembrolizumab was 68.4 versus 58.2 per cent, HR 0.69, 95% CI 0.52-0.90. Objective response rate was 33.7 and 32.9 versus 11.9 per cent respectively. Grade 3 to 5 adverse event were less with pembrolizumab compared to ipilimumab at a rate of 13 and 10 versus 20 per cent respectively.
Combination therapy of PD-1 inhibitor and CTLA-4 inhibitor has a higher efficacy than monotherapy but with increased toxicity. CHECKMATE 067 Phase 3 trial (n=945) assigned to nivolumab (1mg/kg every three weeks) plus ipilimumab (3mg/kg every three weeks) for four doses followed by nivolumab (3mg/kg every two weeks), or ipilimumab (3mg/kg every three weeks for four doses). The median PFS in the combination arm was superior compared to monotherapy ipilimumab with 11.5 versus 2.9 months, HR 0.42, 95% CI 0.31-0.57, and nivolumab monotherapy was 6.9 versus 2.9 months, HR 0.57, 95% CI 0.43-0.76.
Objective response rates for combination therapy, monotherapy nivolumab and monotherapy ipilimumab were 58, 44, and 19 per cent respectively, with complete response rate of 11.5, 8.9, and 2.2 per cent. Grade 3 and 4 adverse events were 55, 16, and 27 per cent respectively, with treatment discontinuation due to adverse event in 36.4, 7.7 and 14.8 per cent respectively. Overall, there were 24 per cent of patients with positive PD-L1 expression. Objective response rates and median PFS was more favourable in this subgroup of patients, however, those with negative PD-L1 responded to treatment as well. These results inform a new standard of care in metastatic melanoma.
Early stage cutaneous melanoma is mostly cured with standard surgical resection. A cohort of patients with high risk features will ultimately relapse with metastatic disease. High dose interferon alpha (IFNa) has been established as a standard of care in adjuvant setting for this cohort of patients defined as high risk node negative patients (stage 2b and 2c) including either tumour >4mm thickness or ulceration and patients with stage 3 disease. The use of high dose IFNa has been established by multiple large cooperative group trials. For instance, the Eastern Cooperative Oncology Group trial (ECOG 1684), 287 patients stage 2b and 3 were randomly assigned to one year of high dose IFNa with intravenous therapy at a dose of 20 million units/m2 five days per week for four weeks followed by 10 million units/m2 subcutaneously three times weekly for an additional 11 months versus observation. Median RFS in IFNa group was 21 months versus 12 months in the observation group with 11 per cent absolute increase in RFS at five years (37 versus 26 per cent). Mocellin et al published a meta-analysis of 14 randomised trial on adjuvant IFNa in high risk melanoma, which included a total of 8,122 patients.
Overall survival and disease free survival are significantly improved with IFNa compared to placebo or observation with (Hazard ratio [HR] for death 0.89, 95% CI 0.83-0.96) and (HR for recurrence 0.82, 95% CI 0.77-0.87) respectively. Treatment with high dose IFNa is associated with side effects including myelosupression (20-60 per cent), chronic fatigue (70-100 per cent), hepatotoxicity, psychological effect such as depression and impaired cognitive function, autoimmunity such as thyroid dysfunction, vitiligo and formation of autoantibody (15-30 per cent).
The use of ipilimumab as adjuvant treatment has been approved by the FDA in October 2015 based on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 Phase 3 trial. High risk patients (n=951) were randomly assigned to either ipilimumab or placebo. Ipilimumab was administered at a dose of 10mg/kg every three weeks for four doses, then every three months for three years. The median recurrence free survival for ipilimumab was 26 months compared to 17 months in the placebo group.
Furthermore, three year RFS was 46.5 per cent in ipilimumab versus 34.8 per cent in placebo with hazard ratio [HR] 0.75, 95% CI 0.64-0.90. Overall survival from this trial is still immature. Ipilimumab treatment is unfortunately associated with quite significant toxicity. Some 90 per cent of patients had immune-related side effects including 36.5 per cent with grade 3 events and 5.5 per cent with grade 4 events. Dermatologic (63 per cent), gastrointestinal (46 per cent), endocrine (38 per cent) and hepatic (25 per cent) toxicity were the most common side effects. It is worth noting that there were five treatment-related grade 5 adverse events due to colitis, myocarditis and multi-organ failure with Guillain-Barre syndrome. Only 50 per cent of the patients remain on treatment more than the initial 12 weeks of therapy and only 29 per cent continued more than one year. The dose used of 10mg/kg in this trial may account for the high level of toxicity when compared to 3mg/kg which is the standard dose used for metastatic setting.
There are no data comparing adjuvant IFNa and ipilimumab head to head at present but extrapolation of data from available Phase 3 trials showed at least RFS are comparable. One should, however, keep in mind that adjuvant ipilimumab is not without significant toxicity, which may be life-threatening especially with the higher dose of 10mg/kg. ECOG 1609, NCT01274338 is a second phase 3 trial comparing ipilimumab at 10mg/kg or 3mg/kg versus high dose interferon looking at overall survival and RFS which is on-going at present. This trial will be pivotal in selecting the appropriate adjuvant treatment option.
Phase 3 trials evaluating PD1 inhibitor either comparing to ipilimumab or IFNa or observation ARE ongoing: Pembrolizumab versus placebo with high risk stage 3 melanoma following complete resection (NCT02362594); pembrolizumab versus IFNa in patients with high risk stage 3 or 4 resected disease (S1404) and an adjuvant/pseudo-adjuvant trial with nivolumab versus ipilimumab in patients with stage 3 or 4 completely resected (NCT02388906).
RENAL CELL CARCINOMA
To date, all adjuvant trials either using cytokines or anti-angiogenic therapy for high risk renal cell carcinoma (RCC) post resection has been disappointing with no survival advantage. Hence, observation remains the standard of care. There are, however, no data on checkpoint inhibitors in this setting.
The rationale for immunotherapy in RCC is based on the observation that nephrectomy can rarely result in regression of metastasis. Secondly, up to 25 per cent of patients have infiltration of T-cells within their tumour. Lastly, clinical response seen in patients treated with cytokines could reflect the existence of immune response against RCC. Cytokines enhance the proliferation and function of T-lymphocytes. Objective response rate for either IFNa or IL-2 can be as high as five to 27 per cent. IL-2 therapy can provide durable partial (9 per cent) or complete (5 per cent) tumour responses. This is only seen in a small cohort of patients with significant toxicity.Durable complete remission is rare with IFNa. Flanigan et al and Mickisch et al showed patients with metastatic renal cell have longer survival with nephrectomy followed by interferon therapy than interferon therapy alone.
Checkpoint inhibition with nivolumab has been shown to improve overall survival compared to everolimus in the second line setting leading to FDA approval in November 2015. This phase 3 trial (CHECKMATE 025, n=821 patients) compared nivolumab (3mg/kg every two weeks) to everolimus (10mg/day). The median overall survival was 5.4 months longer with nivolumab (median, 25.0 versus 19.6 months, hazard ratio [HR] 0.73, 95% CI 0.57-0.93) but no difference in progression free survival (median, 4.6 versus 4.4 months, HR 0.88, 95% CI 0.75-1.03). The objective response rate was five times greater with nivolumab (25 versus 5 per cent, odds ratio 5.98, 95% CI 3.68-9.72), 1 per cent achieved complete remission and 24 per cent achieved partial response. Nivolumab is better tolerated with fewer patients having grade 3 or 4 toxicity (19 per cent vs 37 per cent) mainly fatigue (2 per cent) with nivolumab and anaemia (8 per cent) with everolimus. Eight per cent of nivolumab patients discontinued due to toxicity compared to 13 per cent on everolimus. It is worth noting that expression of PD-1 ligand on tumour cells is unhelpful in determining responders as survival benefits are comparable.
Combination of checkpoint inhibitors in melanoma showed superior efficacy and greater toxicity. Phase 1 combination trial in patients with metastatic RCC showed potential benefits with objective response of 45 per cent leading to a treatment-naïve multicentre Phase 3 trial CHECKMATE 214 for metastatic RCC.
Non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC)
NSCLC is generally believed to have very low immunogenicity given the poor results from IL-2, interferon, and vaccines therapy. For instance, the MAGRIT study investigating the MAGE-A3-specific vaccine GSK1572932A in 2,312 patients with resected NSCLC failed to extend disease-free survival with 60.5 months in MAGE-A3 group compared to 57.9 months in placebo group (hazard ratio [HR] 1.02, 95% CI 0.89-1.18; p=0.74). So far, there is no evidence for use of adjuvant immunotherapy in lung cancer. Results of ongoing work with other type of immunotherapy such as immune check point inhibitors are immature. For instance a Phase 3 KEYNOTE 091 evaluating pembrolizumab in the adjuvant setting in patients with or without adjuvant chemotherapy is open to accrual via Cancer Trials Ireland (previously ICORG)(NCT02504372).
However, there are increasing reasons to be optimistic. Petersen RP et al in 2006 and Shimizu K et al in 2010 showed tumour with higher proportion of tumour T-regulatory cells had a significantly higher risk of recurrence whereas Hiraoka K et al in 2006 reported that higher number of CD4+ and CD8+ T-cells infiltration in tumour cells are independent positive prognostic indicators for resected NSCLC, which was further supported by Al-Shibli KI et al in 2008 suggesting immune response may be implicated in lung cancer.
First-line platinum doublet chemotherapy results in overall survival and progression free survival of approximately 10 months and five months respectively with one year survival rate of up to 40 per cent in metastatic NSCLC. Recent mutational analysis leading to treatment personalisation in lung adenocarcinoma has led to improved overall survival up to 24 months using tyrosine kinase inhibitors. These represent a minority of patients (less than 15 per cent of Caucasian patients.
NCCN has recommended immunotherapy using nivolumab or pembrolizumab as second-line treatment for metastatic NSCLC based on data from CHECKMATE 057/CHECKMATE 017 and KEYNOTE 010 trials. Superior overall survival and durability of response and favourable toxicity compared to chemotherapy was demonstrated. Phase 3 Trial CHECKMATE 057 evaluated 582 metastatic non-squamous NSCLC patients and found median overall survival of 12.2 months in nivolumab arm (3mg/kg every two weeks) compared to 9.4 months in Docetaxel arm (75mg/m² every three weeks) (HR, 0.73; 95% CI, 0.59-0.89; P= 0.002) with excellent duration response of 17.2 months compared to 5.6 months respectively. Response rate was 19 per cent in nivolumab arm compared to 12 per cent in docetaxel arm. One-year survival rate is also better in nivolumab arm compared to docetaxel arm (51 per cent versus 39 per cent respectively) with less grade 3 to 5 adverse events (10 per cent versus 54 per cent respectively).
Phase 3 Trial CHECKMATE 017 included 272 patients with metastatic squamous NSCLC with similar regimens as CHECKMATE 057. The median overall survival was 9.2 months with nivolumab compared to 6.0 months with docetaxel; one-year survival rate 42 per cent versus 24 per cent respectively (HR 0.59, 95% CI 0.44-0.79). The response rate was 20 per cent in nivolumab compared to nine per cent in docetaxel (P=0.008). Grade 3 to 5 adverse events were similar. Phase 2/3 Trial KEYNOTE 010 included over 1,000 patients with either squamous or non-squamous NSCLC who were PD-L1 positive (≥1%) randomised to pembrolizumab (2mg/kg) or pembrolizumab (3mg/kg) or docetaxel (75mg/m²) every three weeks. Pembrolizumab arm had significantly better median overall survival for both doses (10.4 months for 2mg/kg arm, HR 0.71; 95% CI, 0.58-0.8; P=0.0008 and 12.7 months for 10mg/kg arm, HR 0.61; CI, 0.49-0.75; P<0.0001) compared to docetaxel (8.5 months). Pembrolizumab is also better tolerated in either dose compared to docetaxel with less grade 3 to 5 adverse event (13 per cent in 2mg/kg arm versus 16 per cent in 10mg/kg arm versus 35 per cent in docetaxel arm). Both CHECKMATE 057 and KEYNOTE 010 showed that PD-L1 non-expressers may benefit from checkpoint inhibitors however PD-L1 expressers had better responses from immunotherapy treatment. Atezolizumab is a PD-L1 inhibitor currently being investigated in several Phase 3 trials in advanced NSCLC where a Phase 2 POPLAR trial showed a survival advantage compared to docetaxel in second- or third-line setting.
At present, immunotherapy either with CTLA-4 inhibitor (ipilimumab) or PD-1 inhibitor (nivolumab/pembrolizumab) or in combination in small cell lung carcinoma is evolving with preliminary results showing objective response rates of 15 per cent to 30 per cent. More evidence was revealed at ASCO 2016.
Immunotherapy treatment has been the standard of care for early stage non-muscle invasive bladder tumour (T1) with transurethral resection of tumour followed by adjuvant intravesical Bacillus Calmette-Guerin (BCG). This is postulated to trigger local immune response leading to anti-tumour activity, however, the precise mode of action is unknown. In metastatic TCC, Phase 3 trial of PD-L1 inhibitor atezolizumab (NCT02302807) in second-line setting compared to chemotherapy has shown objective response rate of 15 per cent with durable response in 84 per cent of responders continuing to be seen at 11·7 months (95% CI 11·4-12·2). Grade 3 to 4 adverse event occurred in 16 per cent of patients. A phase 3 trial of pembrolizumab (KEYNOTE-045) versus paclitaxel, docetaxel, or vinflunine in second-line metastatic setting has completed accrual awaiting maturity (NCT02256436).
Prostate cancer is considered an immunogenic cancer as shown by the sipuleucel-T vaccine prolonging overall survival by 4.1 months in patients with metastatic castration-resistant prostate cancer (median 25.8 versus 21.7 months, HR 0.78, 95% CI 0.61-0.98). It was disappointing that the phase 3 trial using ipilimumab (10mg/kg every three weeks for four cycles) compared with placebo in 799 metastatic castrate resistant prostate cancer (MCRPC) patients, was negative. Overall survival was not improved (median 11.2 months with ipilimumab compared to 10 months with placebo) (HR 0.85, 95% CI 0.72-1.00, P= 0.053). Results are pending for another Phase 3 trial looking at ipilimumab in chemotherapy naïve MCRPC patients, which has completed accrual (NCT01057810).
Head and neck
Second-line treatment for metastatic squamous cell carcinoma of head and neck origin (HNSCC) is poor with objective response varying four to 10 per cent with median survival of seven months using either chemotherapy or Anti-EGFR monoclonal antibodies or in combination. The benefit of immunotherapy in patients with platinum refractory recurrent or metastatic setting was evaluated in CHECKMATE 141 Phase 3 trial. Some 240 patients were randomised to either nivolumab (3mg/kg every two weeks) or single agent chemotherapy of physician’s choice (methotrexate 40-60mg/m2, docetaxel 30-40mg/m2, or cetuximab 400-mg/m2 loading dose followed by 250mg/m2 weekly). The median overall survival was positive with 7.5 months in nivolumab arm compared to 5.1 months in chemotherapy arm (HR, 0.70; 97.73% CI, 0.51-0.96; P=.010) and objective response rate of 11.7 per cent versus 7.4 per cent respectively. Interestingly, patients with human papilloma virus (HPV) positive tumours derived more significant overall survival with median of 9.1 versus 4.4 months (HR 0.56, 95% CI 0.32-0.99). Preliminary results from phase 1/2 trial KEYNOTE 012 looking at fixed dose pembrolizumab 200mg every three weeks in 132 patients with metastatic HNSCC showed overall response rate of 18.2 per cent.
Colorectal cancers with mismatch repair (MMR) deficiency (Lynch syndrome and 15-20 per cent of sporadic cancer) express more mutations which can produce tumour specific antigens that serve as targets for immunotherapy.
Phase 2 trial of pembrolizumab (10mg/kg every two weeks) showed that the objective response rate was 40 per cent and progression free survival was 78 per cent in heavily pre-treated patients with MMR deficient where as 0 per cent and 11 per cent respectively for patients with MMR proficient. Another Phase 2 trial of nivolumab and nivolumab plus ipilimumab in metastatic colorectal cancer patients with MMR deficient is currently recruiting (NCT02060188) via Cancer Trials Ireland.
An on-going Phase 1 trial of nivolumab (3mg/kg administered at week one and week four then every two weeks) in heavily pre-treated patients where majority had three or more previous treatment regimens with relapsed or refractory Hodgkin’s lymphoma showed remarkable overall response of 87 per cent and complete response of 17 per cent. Some 78 per cent of patients had grade 1 to 3 adverse event but mostly mild.Updates were expected from ASCO 2016.
The KEYNOTE 012 phase 1b study of pembrolizumab in patients with metastatic triple negative breast cancer with PD-L1 expression showed overall response rate of 18.5 per cent and approximately 56 per cent experienced adverse effects. With limited options for triple negative breast cancer, the randomised Phase 3 trial KEYNOTE 119 of pembrolizumab versus treatment of physician’s choice in metastatic disease offers hope, and is available via Cancer Trials Ireland. (NCT02555657).
Two Phase 2 trials suggest activity in patients with PD-L1 expression treated with pembrolizumab. KEYNOTE 012 evaluating metastatic patients with up to five lines of treatment, showed objective response rate of 22 per cent. KEYNOTE 028 evaluating metastatic patients showed objective response rate of 30 per cent. A Phase 3 trial KEYNOTE 061 evaluating pembrolizumab versus paclitaxel in patients with metastatic gastric or gastroesophageal junction adenocarcinoma progressed after first-line platinum and fluoropyrimidine (NCT02370498) is open through Cancer Trials Ireland.
References available on request