Impact case study database

Background. Over the last 10 years, clinical development of immunotherapies has led to significant advances in cancer treatment:

1. Immune checkpoints are critical regulators of the immune system, preventing it from targeting cells indiscriminately. Cancers frequently exploit these checkpoints to subvert the immune system and evade detection. Inhibiting these immune checkpoints therefore helps restore immune function in cancer patients. This case study focuses on:

• Ipilimumab—an inhibitor of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4);

• Avelumab—which inhibits programmed death-ligand 1 (PD-L1);

• Nivolumab and pembrolizumab—which inhibit the programmed death 1 (PD-1) receptor.

2. Oncolytic virus therapies use genetically modified viruses, designed to specifically target cancer cells. This case study focuses on Talimogene laherparepvec (T-VEC)—a modified form of herpes simplex virus type-1 which has been genetically engineered to stimulate the immune system to attack and destroy the tumour.

Immune checkpoint inhibitors in melanoma. CTLA-4 and PD-1 inhibit antitumour immunity through complementary and non-redundant mechanisms. Therefore, it was thought that there could be a clinical benefit in combining inhibitors that target these two checkpoints, which was further supported by preclinical and early phase studies. Professor James Larkin—ICR Honorary Faculty and Reader from 2015 (Professor from 2018)—working with Bristol-Myers Squibb, developed and led a randomised double-blind phase 3 study of nivolumab (a PD-1 inhibitor) plus ipilimumab (a CTLA-4 inhibitor), compared to nivolumab or ipilimumab alone, in patients with metastatic melanoma. The trial involved 137 sites in Australia, Europe, Israel, New Zealand, and North America, and a total of 945 patients. The study found median progression-free survival for nivolumab plus ipilimumab was 11.5 months, compared to 6.9 months for nivolumab alone, and 2.9 months for ipilimumab alone (Ref. 1). The five-year survival outcomes from this trial were published in 2019—overall survival at five years was 52% for nivolumab plus ipilimumab, 44% for nivolumab alone, and 26% for ipilimumab alone. For context, advanced melanoma has historically had a five-year survival rate of less than 10%.

In an effort to improve the outcomes of patients with stage 3 melanoma and patients with surgically resected stage 4 melanoma (who are generally excluded from phase 3 trials of adjuvant therapy), Professor Larkin also jointly led the phase 3 CheckMate 238 trial, and showed that treatment with nivolumab is superior to the standard of care in high-risk patients with resected stage 3B–C or 4 melanoma. Nivolumab also had a lower rate of grade 3 or 4 adverse events, compared to adjuvant therapy with ipilimumab. This trial was designed, overseen, and analysed through collaboration between Professor Larkin, other senior academic authors, and Bristol-Myers Squibb (Ref. 2).

Immune checkpoint inhibitors in renal cancer. Following previous studies that showed activity of avelumab (a PD-L1 inhibitor) in renal-cell carcinoma, it was hypothesised that the combination of avelumab and axitinib (a VEGF-targeted antiangiogenic therapy) might have clinical benefit, as the drugs have complementary mechanisms of action. The JAVELIN Renal 101 phase 3 trial—sponsored by Pfizer—was developed to test this hypothesis. Professor Larkin and other investigators worked with Pfizer on the trial design, the collection and analysis of data, and interpretation of results. The trial (Ref. 3) demonstrated that:

• Patients with PD-L1-positive tumours had a median progression-free survival of 13.8 months with avelumab plus axitinib, compared to 7.2 months with the standard of care.

• In the overall population, patients had a median progression-free survival of 13.8 months with avelumab plus axitinib, compared to 8.4 months with the standard of care, and a higher objective response rate.

Immune checkpoint inhibitors in head and neck cancer. Patients with relapsed squamous cell carcinoma of the head and neck (HNSCC) that progress within six months of first-line chemotherapy have a poor prognosis—and previously had limited therapeutic options to prolong survival. It was known that the recurrence of HNSCC is facilitated by immune evasion and, therefore, it was hypothesised that immune checkpoint inhibitors could be effective in these cancers. The ICR’s Professor Harrington was involved in the CheckMate 141 clinical trial, which found that nivolumab increased survival of patients with recurrent or metastatic HNSCC cancer (Ref. 4). The trial was designed and overseen by the academic authors, including Professor Harrington, in collaboration with Bristol-Myers Squibb. Professor Harrington also led a study into the effect of nivolumab on patient-reported outcomes from the CheckMate 141 trial, which showed that patients on nivolumab gave consistently better patient-reported outcomes ratings throughout. Due to the importance of improving quality of life for these patients, these data support nivolumab as a new standard of care in this setting (Ref. 5).

Professor Harrington co-led the KEYNOTE-040 study which showed that pembrolizumab provides a clinically meaningful survival benefit in patients with recurrent or metastatic HNSCC that progressed during or after platinum-based therapy. This therapy was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) based on the results of this trial. The indication was not pursued by NICE due to results from KEYNOTE-048 (see below). With the activity of immune checkpoint inhibitors in HNSCC demonstrated, it was hypothesised a combination of immune checkpoint inhibitors and chemotherapy in the first-line setting would be synergistic, as chemotherapy leads to immunogenic cell death and antigen shedding. Professor Harrington led the UK arm of the KEYNOTE-048 phase 3 trial—funded by Merck—which found that, in previously untreated recurrent or metastatic HNSCC, the pembrolizumab with chemotherapy combination improved overall survival compared to cetuximab with chemotherapy (13.0 months compared to 10.7 months) (Ref. 6). Professor Harrington played a leading role in conceiving, designing, and planning the study alongside Professor Barbara Burtness (Yale), Dr Jonathan D Cheng (Merck), and Dr Fan Jin (Merck).

Talimogene laherparepvec (T-VEC) in melanoma. Professor Harrington treated melanoma patients with T-VEC in the initial phase 1 trial (Hu Clin. Cancer Res. 2006), which then led to a phase 2 clinical trial in patients with melanoma, in which Professor Harrington was the UK Principal Investigator (Senzer et al. J. Clin. Oncol. 2009). Professor Harrington then led the UK arm of a landmark phase 3 trial—the first to show the benefit of viral immunotherapy for patients with unresected stage 3B to 4 melanoma (Ref. 7). In this trial, patients treated with T-VEC had a 21% reduced risk of death and, 4.4-month longer median overall survival compared to the control group. This culminated in global approval of the treatment.