was present in 291 (36%) of 804 patients. Indeed, the investigators emphasise, on the basis of a post-hoc analysis, that there was a numerical improvement in event-free survival in this subgroup of patients. Furthermore, it was hypothesised radiotherapy-induced immunogenic cell death would boost PD-L1 expression during treatment, culminating in an enhanced response to pembrolizumab. However, because tumour draining lymph nodes are mandatorily included in the radiation field, it might very well be that concurrent radiotherapy counteracts rather than promotes a synergistic antitumoural T-cell response, through its ablative effect on the tumour draining lymph nodes and peripheral lymphocytes.4
The results of the KEYNOTE-412 trial are supported by another large phase 3 trial, the JAVELIN Head and Neck 100 trial, published in 2021.5 Similar in design, this study did not show an improved outcome for patients treated with avelumab (an anti-PD-L1 monoclonal antibody) plus chemoradiotherapy versus chemoradiotherapy alone. An exploratory analysis also showed a potential progression- free survival benefit for a subgroup of patients with high tumour PD-L1 expression. The negative overall results of these two studies support one another, with the current KEYNOTE-412 study also removing doubts an anti- PD-1-based approach, instead of an anti-PD-L1-based approach, would lead to a different result.
It is now time to reflect on these data. A predictive biomarker-driven approach for patient stratification seems more appropriate than ever. Additionally, many studies in localised HNSCC, understandably, aim to avoid delay of standard of care local treatment in order to prevent cancer progression. This leaves a short
window for experimental treatment preceding local ablative therapy. However, more time might be needed to mount an effective antitumour response in the case of ICI therapy. Because HNSCC is an immunologically heterogeneous disease, a better understanding of response and resistance patterns to immunotherapy is of great importance for a more personalised treatment approach. The investigators of the KEYNOTE-412 study should be applauded for their formidable effort and contribution to the field. The promise of checkpoint inhibitor therapy for organ preserving treatment strategies of localised head and neck cancer remains. However, to unlock its full potential new study designs and approaches are needed.
I declare support for attending meetings and travel from Pfizer and Ipsen, and participation on an advisory board from Janssen and Astellas (fees paid to institution).
Jens Voortman j.voortman@amsterdamumc.nl
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081HV Amsterdam, Netherlands
1 Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375: 1856-67.
2 Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019; 394: 1915-28
3 Machiels J-P, Tao Y, Licitra L, et al. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol 2024; 25: 572-87.
4 Van Pul KM, Fransen MF, van de Ven R, et al. Immunotherapy goes local: the central role of lymph nodes in driving tumor infiltration and efficacy. Front Immunol 2021; 12: 643291.
5 Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 2019; 4: 450-62.
CrossMark
Mitotane: a friend or a foe before cabozantinib treatment in adrenocortical cancer?
Published Online April 9, 2024 https://doi.org/10.1016/ S1470-2045(24)00151-7
See Articles page 649
Adrenocortical carcinoma is a rare cancer with a dismal prognosis, which affects 1-2 people per million annually, worldwide.1 Because of the small number of patients within single centres and the scarcity of preclinical models until recently,2 advancements in treatment options have been limited. Mitotane, a cell-specific adrenolytic, has been the mainstay of treatment, together with etoposide, doxorubicin, and cisplatin chemotherapy.3 Early studies
with tyrosine kinase inhibitors (TKIs) have not shown a strong signal of response in patients with adrenocortical carcinoma as monotherapy.1 Cabozantinib is a multi- kinase inhibitor with major targeting of c-Met, AXL, RET, and VEGFR2. Anti-tumour activity with cabozantinib has been seen in preclinical studies in an adrenocortical carcinoma cell line and a xenograft mouse model.4 A previous retrospective compilation across several
institutions of 16 patients treated with cabozantinib with previous exposure to mitotane suggested it might be an effective monotherapy in advanced adrenocortical carcinoma after treatment failure.5 In that study, recruited patients had low concentrations of mitotane at study entry. Three of 16 patients had a partial response, five patients had stable disease, and eight patients had progressive disease.
In The Lancet Oncology, Matthew T Campbell and colleagues present the first prospective randomised phase 2 study of cabozantinib in 18 patients with adrenocortical carcinoma, in which 4-month progression-free survival was 72.2% (95% CI 46-5-90.3).6 Despite the small sample size, this is a major accomplishment in the field. Because mitotane induces CYP34A, it can decrease concentrations of cabozantinib and other TKIs.7 The authors reasoned that patients who had concurrent or previous mitotane use would not have a response to cabozantinib. However, in the previous retrospective review of 16 patients treated with cabozantinib, 15 received mitotane previously as standard of care and stopped treatment within 3 months of cabozantinib initiation had a variable positive response.5 In the study by Campbell and colleagues, patients who received mitotane previously (before or within 6 months of study start) had a better progression-free survival than those who had never received mitotane despite having lower concentrations of cabozantinib.6 This finding contrasts with the authors’ hypothesis. The number of patients is small, and thus it could be argued that there was selection bias for patients with less aggressive tumour types; however, it could be possible that a lower plasma concentration of cabozantinib with less drug toxicity, in addition to the potential benefits of previous or continued mitotane therapy, might be a positive rather than a negative predictor. Cabozantinib tends to have substantial adverse effects, so perhaps lower concentrations make the drug more feasible for a multidrug combination. The exact mechanism of mitotane action remains unclear. There is a delay between starting treatment and reaching therapeutic concentrations (ie, weeks to months) and there is a variable decay curve after stopping the drug. The authors show that cabozantinib alters the suppressive function of T cells in tumours, suggesting an effect on the immune milieu.6 A 2019 study suggested that mitotane changes the tumour microenvironment,8 suggesting a rationale to improve response to immunotherapy,
which is being investigated in an ongoing clinical trial (NCT05634577). Perhaps previous mitotane exposure might predispose patients to an improved response to subsequent cabozantinib therapy.
Sebastian Kaulitzki/Science Photo Library/Getty images
Pan-genomic profiling of adrenocortical carcinoma samples demonstrated that large subsets have driver mutations in the Wnt/B-catenin pathway or in TP53 pathways, which are not targetable at present.9 However, 40% of adrenocortical carcinoma tumours have unknown drivers. Additional reports have identified abnormalities in the mismatch repair pathway, for which immunotherapy would be suitable, in around 14% of tumours.1º Advances in the field in the past 6 years, such as transitioning from one preclinical model to multiple, transitioning from one adrenocortical carcinoma cell line (H295R) to five adrenocortical carcinoma cell lines, and the first patient derived xenograft preclinical models,2 should enable potential combination or sequential therapies to be investigated to expand the treatment armamentarium. Testing and revising existing hypotheses is crucial for the advancement of the field and defining more personalised therapy for patients with adrenocortical carcinoma. I declare no competing interests.
Margaret E Wierman margaret.wierman@cuanschutz.edu
Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Center,Aurora, CO 80045, USA
1 Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018; 179: G1-46.
2 Sedlack AJH, Hatfield SJ, Kumar S, et al. Preclinical models of adrenocortical cancer. Cancers 2023; 15: 2873.
3 Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012; 366: 2189-97.
4 Phan LM, Fuentes-Mattei E, Wu W, et al. Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma. Cancer Res 2015; 75: 4131-42.
5 Kroiss M, Megerle F, Kurlbaum M, et al. Objective response and prolonged disease control of advanced adrenocortical carcinoma with cabozantinib. J Clin Endocrinol Metab 2020; 105: 1461-68.
6 Campbell MT, Balderrama-Brondani V, Jimenez C, et al. Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial. Lancet Oncology 2024; published online April 9. https://doi. org/10.1016/S1470-2045(24)00095-0.
7 Corso CR, Acco A, Bach C, Bonatto SJR, de Figueiredo BC, de Souza LM. Pharmacological profile and effects of mitotane in adrenocortical carcinoma. Br J Clin Pharmacol 2021; 87: 2698-710.
8 Head L, Kiseljak-Vassiliades K, Clark TJ, et al. Response to immunotherapy in combination with mitotane in patients with metastatic adrenocortical cancer. J Endocr Soc 2019; 3: 2295-304.
9 Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 2016; 29: 723-36.
10 Pozdeyev N, Fishbein L, Gay LM, et al. Targeted genomic analysis of 364 adrenocortical carcinomas. Endocr Relat Cancer 2021; 28: 671-81.