Immunotherapy using agents targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is one of the biggest success stories of cancer treatment in recent decades; these immune checkpoint inhibitors can produce durable, long-term benefits without the toxicities associated with previously-used immunotherapy, such as interleukin-2 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies. However, many obstacles remain. The challenges associated with PD-1/PD-L1-targeted agents, together with a number of novel approaches, were discussed at the European Society of Medical Oncology (ESMO) Virtual Congress 2020, held on 19–21 September 2020.
In an oral presentation, Prof. Lieping Chen of the Yale Cancer Centre, Yale University, New Haven, CT, USA, summarised the current status of cancer immunotherapy. Despite the excellent activity of PD-1/PD-L1-targeted agents, only a minority of patients (around 25%) respond to treatment, and the reasons for this have not been fully established. Current evidence suggests that a large proportion of patients who do not respond to immunotherapy do not have PD-L1-expressing tumours. We therefore need to elucidate other immune targets.1
Combined therapeutic approaches involving pembrolizumab (Keytruda®, Merck KGaA, Darmstadt, Germany) continue to show promise. The LEAP-005 phase II study (ClinicalTrials.gov Identifier: NCT03797326) is evaluating the combination of lenvatinib (Lenvima®, Eisai, Tokyo, Japan), an anti-angiogenic tyrosine kinase inhibitor, plus pembrolizumab in patients with previously-treated advanced solid tumours, including triple-negative breast cancer, ovarian cancer, gastric cancer, colorectal cancer, glioblastoma multiforme and biliary tract cancer. Data presented at ESMO showed that at a median follow-up of 8.6 months, overall response rates were 29% in triple-negative breast cancer, 32% in ovarian cancer, 21.9% in colorectal cancer, 9.7% in gastric cancer, 9.7% in biliary tract cancer and 16.1% in glioblastoma multiforme. Safety findings observed with the combination were consistent with previously-reported data.2 As a result of these promising findings, the trial is expanding to include 100 patients in each cohort.
Targeting both PD-L1 and CTLA-4 is known to be an effective approach and it has been demonstrated in the combination of nivolumab plus ipilimumab. However, the development of this combination has been hampered by safety concerns.3 Attempts to reduce toxicity have led to the development of bispecific antibodies that target PD-L1 and CTLA-4. These only bind to tumour-infiltrating lymphocytes expressing both PD-1 and CTLA-4, and therefore, their effects are more likely to remain localised to the tumour microenvironment, minimising toxicity. Data on two promising bispecific antibodies were presented at ESMO 2020.
AK104 (Akeso Biopharma, Guangdong, China) is being evaluated in a phase I study (ClinicalTrials.gov Identifier: NCT03261011) in patients with solid tumours. Data were reported on 15 patients with mesothelioma, a particularly aggressive and hard to treat tumour. The overall response rate was 15%, with grade 3–4 adverse events (AE) in 17% and discontinuation due to an AE in 6%.4 These are better safety findings than those of CheckMate-743, which evaluated nivolumab plus ipilimumab in the same treatment setting.5 AK104 is also being investigated in combination with chemotherapy for the treatment of advanced gastric cancer (ClinicalTrials.gov Identifier: NCT03852251).
MGD 019 (MacrogGenics, Rockville, Maryland, United States) is a dual-affinity re-targeting antibody that targets both PD-1 and CTLA-4. In a phase I study (ClinicalTrials.gov Identifier: NCT03761017) involving 43 patients with advanced solid tumours, MGD 019 was well tolerated, and among the 18 evaluable patients, four objective responses were reported, including a confirmed complete response (CR) in metastatic castration-resistant prostate cancer, a confirmed partial response (PR) in microsatellite stable colorectal cancer, a confirmed PR in metastatic type AB thymoma and an unconfirmed PR in serous fallopian tube carcinoma.6 These are encouraging findings, as anti-tumour activity was seen in malignancies that tend not to respond to immune checkpoint inhibition. All four cases of CR were seen with 6 mg/kg dosage, which had an acceptable safety profile and will be taken forward to a phase II study.
While new approaches with established immune targets show promise, it is important to identify and investigate novel immune targets. Targeting the tumour microenvironment may provide a novel strategy for immunotherapy. Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule that is mainly expressed in myeloid cells, including monocytes, macrophages, dendritic cells and granulocytes. It is also enriched in tumour cells and stroma cells in the tumour microenvironment of a number of malignancies and promotes tumour immune evasion.7 Preliminary data from the first-in-human phase I study (ClinicalTrials.gov Identifier: NCT03564691) of MK-4830 (Merck KGaA, Darmstadt, Germany), an antibody targeting ILT4, showed that MK-4830 alone (n=50) or in combination with pembrolizumab (n=34) had promising efficacy among heavily pre-treated patients (50% had previously received three or more lines of therapy) with advanced solid tumours, including pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma, advanced non-small cell lung cancer and gastric cancer. There was one CR and eight PRs, including five responses in patients who had not responded to prior anti-PD-1 therapy. The incidence of treatment-related AEs was consistent with those reported for pembrolizumab.8 The authors concluded that these initial data support the further development of MK-4830 as monotherapy or in combination with pembrolizumab in patients with advanced solid tumours.
Another promising new therapeutic target is 4-1BB (CD137), a key costimulatory immunoreceptor that regulates immune responses.9 In a phase I study (ClinicalTrials.gov Identifier: NCT03330561), PRS-343 (Pieris Pharmaceuticals, Boston, MA, US), a bispecific molecule that binds human epidermal growth factor receptor 2 (HER2) and 4-1BB, was investigated in 74 patients with HER2+ advanced or metastatic solid tumours (including gastric and gastroesophageal junction adenocarcinoma, breast cancer, colorectal cancer and gynaecological cancer). Of 33 patients who were evaluable for response, the objective response rate was 12% and the disease control rate was 52% (CR: 3%; PR: 9%; stable disease: 40%).10 Based on these data, a phase II trial has been planned to investigate PRS-343 in combination with ramucirumab and paclitaxel in patients with gastric and gastroesophageal junction cancer. PRS-343 is also being investigated in combination with atezolizumab (Tecentriq®, Roche, Basel, Switzerland) in HER2-positive solid tumours (ClinicalTrials.gov Identifier: NCT03650348).
Finally, ESMO 2020 brought a report of clinical responses with the combination of immune checkpoint inhibitors and tumour-infiltrating lymphocyte-based adoptive cell therapy combined with immunotherapy. In a phase I/II study (ClinicalTrials.gov Identifier: NCT03296137), treatment with ex vivo expanded tumour-infiltrating lymphocytes, preceded by a single dose of ipilimumab before tumour removal and combined with four doses of nivolumab before and after cell infusion, yielded a PR in four and stable disease in 17 of 25 patients with 12 different cancer diagnoses.11
In summary, immunotherapy has dramatically improved survival and quality of life for patients with cancer, but it is becoming more challenging to increase the efficacy of established immune checkpoint inhibitors and combination therapies. The clinical trials presented at ESMO, though still in early stages,11,12 provide hope of a new generation of more effective therapeutic approaches.
- Chen L, Present and future of cancer immunotherapy. Available at: www.esmo.org/meetings/past-meetings/esmo-virtual-congress-2020/daily-reporter/daily-reporter-news/present-and-future-of-cancer-immunotherapy (accessed 27 October 2020).
- Lwin Z, Gomez-Roca C, Saada-Bouzid E, et al. LEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours. Ann Oncol. 2020;31(Suppl 4):S1170.
- Kooshkaki O, Derakhshani A, Hosseinkhani N, et al. Combination of ipilimumab and nivolumab in cancers: from clinical practice to ongoing clinical trials. Int J Mol Sci. 2020;21:4427.
- Millward M, Frentxas S, Gan HK, et al. Safety and antitumor activity of AK104, a bispecific antibody targeting PD-1 and CTLA-4, in patients with mesothelioma which is relapsed or refractory to standard therapies. Ann Oncol. 2020;31(Suppl 4):S705–S6.
- Bristol Mysers Squbb press release. Opdivo® (nivolumab) Plus Yervoy® (ipilimumab) Demonstrates Durable Survival Benefit vs. Chemotherapy in Patients with Previously Untreated Malignant Pleural Mesothelioma. Available at: https://news.bms.com/news/details/2020/Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Demonstrates-Durable-Survival-Benefit-vs.-Chemotherapy-in-Patients-with-Previously-Untreated-Malignant-Pleural-Mesothelioma/default.aspx (accessed 27 October 2020).
- Sharma MR, Sanborn RE, Cote GM, et al. A phase 1, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 ×CTLA-4 DART® molecule in patients with advanced solid tumors. Ann Oncol. 2020;31(Suppl 4):S704–5.
- Gao A, Sun Y, Peng G. ILT4 functions as a potential checkpoint molecule for tumor immunotherapy. Biochim Biophys Acta Rev Cancer. 2018;1869:278–85.
- Siu LL, Wang D, Hilton J, et al. Initial results of a phase I study of MK-4830, a first-in-class anti–immunoglobulin-like transcript 4 (ILT4) myeloid-specific antibody in patients (pts) with advanced solid tumours. Ann Oncol. 2020;31(Suppl 4):S462–S504.
- Hinner MJ, Aiba RSB, Jaquin TJ, et al. Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-anticalin fusion PRS-343. Clin Cancer Res. 2019;25:5878–89.
- Ku G, Bendell JC, Tolcher AW, et al. A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies. Ann Oncol. 2020;31(Suppl 4):S462–S504.
- Kverneland AH, Borch TH, Chamberlain C, et al. Clinical potential of adoptive cell therapy with tumour infiltrating lymphocytes therapy in combination with checkpoint inhibitors in non-melanoma patients. Ann Oncol. 2020;31(Suppl 4):S706.
- Moehler M, Shitara K, Garrido M, et al. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1l) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. Ann Oncol. 2020;31(Suppl 4):S1191.
Disclosures: Katrina Mountfort is a freelance medical writer for Touch Medical Media Ltd., Goring-on-Thames, UK.
Support: Commissioned, edited and supported by Touch Medical Media.
Published: 29 October 2020
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