Moving Immunotherapy to the Adjuvant Setting

An article by John Haanen released in occasion of ESMO Immuno-Oncology Congress 2017, 7-10 December, Geneva, Switzerland.

Moving Immunotherapy to the Adjuvant Setting

Increasingly, monoclonal antibodies that act as T-cell checkpoint inhibitors are transforming the treatment of patients with advanced cancers, with five drugs now approved for treatment across many cancers including metastatic melanoma and non-small cell lung cancer (NSCLC) (1). Although the first immune checkpoint inhibitor (ICPi) approved was ipilimumab, which is an antibody that targets the negative immune checkpoint cytotoxic lymphocyte antigen-4 (CTLA-4) on T-cells, it is drugs that act to block the programmed death 1 (PD-1) receptor or its main ligand, PD-L1 that are now the standard of care for many cancers (1). These drugs have profoundly changed the treatment of advanced cancers, mostly for unresectable metastatic disease.

Ipilimumab was the first ICPi approved for treatment in the adjuvant setting by the US Food and Drug Administration (FDA), specifically in patients with cutaneous melanoma with involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy (2). The next logical step is to explore the potential of other ICPis, such as PD-1/PD-L1 inhibitors, both in the adjuvant setting and as neoadjuvant treatment ahead of surgery, across a range of cancers. In this short review, we describe some of the main studies of adjuvant immunotherapy for several types of cancer.    

Melanoma

The choice of adjuvant therapies for melanoma remains limited, but recent findings with PD-1 blockade suggest immunotherapy will become an adjuvant treatment option. CheckMate 238, a phase III trial of patients with resected stage IIIB, IIIC, or IV melanoma, randomised 906 patients to nivolumab (3 mg/kg every 2 weeks) or high-dose ipilimumab (10 mg/kg every 3 weeks for four doses and then every 12 weeks) (3). Treatment was administered for up to 1 year or until disease recurrence. Initial results show that recurrence-free survival (RFS) was superior with nivolumab than ipilimumab (66.4%, 95% CI 61.8 to 70.6 and 52.7%, 95% CI 47.8 to 57.4, respectively, at 18 months) achieved with a markedly lower rate of Grade 3 or 4 adverse events (14.4% vs. 45.9% respectively); 42.6% of ipilimumab-treated patients discontinued. These results with ipilimumab reflect the findings of the registration trial EORTC 18071, and again identify a major issue with toxicity with the high-dose schedule.

There are ongoing studies using lower doses of ipilimumab. A phase II trial of adjuvant nivolumab (3 mg/kg every 2 weeks) with low-dose ipilimumab (1 mg/kg every 6 weeks) in patients with completely resected stage III (lymph node positive) or resected stage IV disease will report the toxicity profile and RFS and overall survival (OS) using this reduced dose ipilimumab combination (NCT02656706). A large, phase III trial (CheckMate 915) is assessing an intermediate dose of ipilimumab (5 mg/kg) in combination with nivolumab (10 mg/kg) compared to nivolumab alone in patients after complete resection of stage IIIb/c/d or stage IV melanoma (NCT03068455). Pembrolizumab is currently being evaluated in two large phase III trials, specifically in a placebo-controlled trial of high-risk stage III melanoma following complete resection (KEYNOTE-054), and in comparison with high-dose interferon or high-dose ipilimumab in high-risk stage III or IVA disease following complete resection (NCT02506153). If these phase III trials prove positive, it is likely that the standard of care for patients with node positive stage III melanoma will include PD-1 blockade.

There are a number of ongoing studies assessing neoadjuvant therapy for resectable melanoma. One of the first is a phase II trial that compares nivolumab and ipilimumab; this has completed enrolment, but findings are not expected until 2019 (4). The study has two arms that compare nivolumab alone and nivolumab plus ipilimumab combination. The monotherapy neoadjuvant phase administers nivolumab (3 mg/kg) every 2 weeks on weeks 1, 3, 5 and 7 prior to surgical excision, followed by every 2 weeks postoperatively for 6 months. The combination neoadjuvant therapy is low-dose nivolumab (1 mg/kg) and low-dose ipilimumab (3 mg/kg) every 3 weeks on weeks 1, 4 and 7 prior to surgical excision, followed by nivolumab (3 mg/kg) every 2 weeks postoperatively for 6 months. In contrast, the OpACIN-neo phase II trial is attempting to identify an optimal neo-adjuvant combination scheme of ipilimumab plus nivolumab by comparing three different schedules of 6 weeks ipilimumab plus nivolumab (two courses 3 weeks apart) prior to surgery in stage IIIB and IIIC melanoma with no post-surgery treatment (NCT02977052). The dosing schedules are ipilimumab 3 mg/kg plus nivolumab 1 mg/kg, ipilimumab 1 mg/kg plus nivolumab 3 mg/kg and one dose of ipilimumab 3 mg/kg followed by 1 dose of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg followed by one dose of nivolumab 1 mg/kg. An interim analysis is planned after 13 patients have been accrued to each arm (5).

Non-small Cell Lung Cancer

The results of the KEYNOTE-024 trial, which assessed the efficacy of pembrolizumab as first-line treatment versus platinum-based chemotherapy in untreated patients with advanced non-small cell lung cancer (NSCLC) with high-level tumour cell PD-L1 expression (≥ 50%) (6), supported the approval of pembrolizumab as the first immunotherapy for first-line treatment (7). The indication is as monotherapy in tumours without EGFR mutations or ALK rearrangements. Pembrolizumab significantly improved progression-free survival (PFS) by approximately 4 months compared to chemotherapy (10.3 vs. 6.0 months, hazard ratio (HR) =0.50) and pembrolizumab is now regarded as the standard of care first line in this selected group of metastatic lung cancer patients. Adjuvant immunotherapy using PD-1 pathway interventions after surgical resection and standard of care adjuvant chemotherapy is being investigated in several randomised trials: KEYNOTE 091/PEARLS (NCT02504372), IMpower10 (NCT02486718), BR 31 (NCT02273375), and ANVIL (NCT02595944). Due to the nature of the disease-free survival (DFS) endpoint, results are not expected before 2021.

More recently, the PD-L1 inhibitor, durvalumab showed enhanced PFS compared with placebo when administered as consolidation therapy 1 to 42 days after platinum-based chemoradiotherapy in patients with stage III, locally advanced, unresectable NSCLC (PACIFIC trial) (8). This trial did not select patients using a biomarker, and the survival advantage was apparent irrespective of PD-L1 expression. A small ongoing phase II study (n=22) to assess neoadjuvant nivolumab for resectable NSCLC has reported initial findings (9). Patients with stage IB - IIIA NSCLC received two doses of nivolumab 3 mg/kg over 4 weeks before surgery. Nivolumab was well-tolerated and no surgeries were delayed. Of great interest was the observation that 9/21 (43%) had a major pathologic response as defined by less than 10% viable tumour cells in the resection specimen. With a median post-operative follow-up of 9 months, 18 patients (86%) remain alive and recurrence free. Pre-treatment tumour exome sequencing showed a correlation between both tumour mutation and predicted neoantigen loads with pathologic responses. Checkpoint blockade is being further evaluated in resectable, locally advanced NSCLC in randomised trials (CheckMate 816 [NCT02998528]), as well as in unresectable, locally advanced NSCLC after chemoradiation.

Urothelial Cancer

The treatment options for locally advanced or metastatic urothelial carcinoma, particularly for those who progressed on platinum-based therapy or who are not cisplatin-eligible in the first-line metastatic setting, have increased markedly in the last year with five PD-1/PD-L1 inhibitors approved by the US FDA and three by the European Medicines Agency. The potential for the use of these immunotherapies in the adjuvant and neoadjuvant setting is now the subject of a number of clinical trials (Table 1) (10). 

Renal Cell Carcinoma

Treatment options for advanced renal cell carcinoma (RCC) have changed markedly in recent years, with the addition of both novel targeted therapies and ICPis. Adjuvant immunotherapy is currently under investigation; several phase III trials are ongoing (11). CheckMate 914 is comparing the combination of nivolumab and ipilimumab with placebo in patients with localised RCC who underwent radical or partial nephrectomy and who are at high risk of relapse (NCT03138512). IMmotion010 is an ongoing phase III placebo-controlled trial of atezolizumab given for 1 year as adjuvant therapy in RCC at high risk of metastasis following nephrectomy (NCT03024996) and will report in 2024. KEYNOTE 564 is a phase III, placebo-controlled trial to assess pembrolizumab after surgery given on 3-week cycles for up to 17 cycles in patients with resected intermediate or high risk RCC with clear cell component (NCT03142334). This trial is expected to report in late 2022. PROSPER, a phase III trial, is comparing perioperative nivolumab to placebo in high-risk RCC with expected primary completion in July 2022 (NCT03055013). RAMPART is a phase III trial of adjuvant therapy in patients with resected RCC at high or intermediate risk of relapse. The three arms are (i) active monitoring for 1 year; (ii) durvalumab for 1 year; (iii) durvalumab for 1 year plus tremelimumab (anti-CTLA-4 antibody).

Moving Immunotherapies From Salvage Therapy to Earlier Disease Treatment

The use of ICPis in the adjuvant/neoadjuvant setting raises a number of questions, including the degree of toxicity (an important consideration after potentially curative surgery), duration of treatment, choosing appropriate comparators, and in some cancers with treatable mutations, the sequencing of therapies. For ipilimumab in melanoma, the high level of toxicity (including 2 deaths) and the inferior efficacy to nivolumab, position nivolumab ahead of ipilimumab in the adjuvant setting. Most of the ongoing trials across various cancers are designed with a duration of adjuvant treatment of 1 year, largely inferred from the treatment of stage 4 disease. The long-term survival patterns data will be closely analysed to determine if this duration is sufficient or required. With many hundreds of ongoing trials with ICPis across many cancer types, it is likely that these questions will be answered and if positive, then reactivation of host T-cells through T-cell checkpoint inhibition will adopt a central role in cancer management beyond the treatment of advanced cancer alone. 

References

1. Topalian SL. Targeting immune checkpoints in cancer therapy. JAMA 2017; 318(17):1647-1648.
2. Opdivo® prescribing information, 2017.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017; 377:1824-1835. 
4. Neoadjuvant immunotherapy for melanoma. MD Anderson Cancer Centre. Accessed 11 November 2017.
5. Rozeman EA, Van Akkooi A, Routier E, et al. Multicenter phase 2 study to identify the optimal neo-adjuvant combination scheme of ipilimumab (IPI) and nivolumab (NIVO) (OpACIN-neo). J Clinical Oncol 2017; 35 (15_suppl): TPS9600.
6. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 2016; 375:1823-1833.
7. Ilie M, Hofman P. Immunotherapy supplanting chemotherapy for upfront treatment of advanced non-small cell lung cancer: what’s next? J Thorac Dis 2017; 9(5): E519–E521.
8. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer. N Engl J Med 2017; 377(20):1919-1929.
9. Chaft JE, Forde PM, Smith KN, et al. Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers. J Clin Oncol 2017; 35 (15_suppl): 8508-8508.
10. Yu SS, Ballas LK, Skinner EC, et al. Immunotherapy in urothelial cancer, part 2: adjuvant, neoadjuvant, and adjunctive treatment. Clin Adv Hematol Oncol 2017; 15(7):543-551.
11. Massari F, Di Nunno V, Ciccarese C, et al. Adjuvant therapy in renal cell carcinoma. Cancer Treat Rev 2017; 60:152-157.

Table 1. Selected Ongoing Neoadjuvant and Adjuvant Immunotherapy Trials in Bladder Cancer (9)