Immunotherapy: management of toxicity

The basis underlying the toxicities of immune checkpoint inhibitors is their promotion of T-cell activity in a physiological manner. “The amplification of the immune system results in autoimmunity,” explained Ross Soo, MD, FRACP, National University Cancer Institute, Singapore.

Common AEs include fatigue, anorexia and arthralgia. Terms that denote immune-related adverse events (irAEs) typically end in -itis or -opathy. CTLA-4 inhibitors, PD-1/PD-L1 inhibitors and their combinations can give rise to fever, chills and lethargy [1]. Skin eruptions are usually of a maculopapular type, and gastrointestinal events include diarrhoea and colitis, with ulceration. Elevations in liver function tests can occur. Potential endocrine complications include hypophysitis, thyroiditis, and adrenal insufficiency. Rarely, neuropathy, nephritis, pneumonitis, Guillain-Barré syndrome, sarcoids, and myasthenia gravis can be observed. The incidence of specific AEs varies slightly according to the mechanism of action of the immunotherapeutic used.

Improved tolerability of PD-1/ PD-L1 agents

For patients receiving CTLA-4 inhibitor therapy, irAEs can occur within days or months, or even after discontinuation of the treatment, which is why the follow-up of these patients should continue for several months after their cessation of treatment. Early AEs associated with CTLA-4 therapy include pruritus and skin rash, while hypophysitis and liver toxicity count among the late toxicities. “The risk of AEs naturally increases when these drugs are administered in combination with other agents,” said Dr. Soo. A meta-analysis in more than 1,200 patients across 22 trials rated the incidences of all-grade irAEs and grade ≥ 3 irAEs with CTLA-4 inhibitor therapy at 72 % and 25 %, respectively [2].

Compared to anti-CTLA-4 treatments, PD-1/PD-L1 inhibitor therapy is generally less likely to cause irAEs. Also, anti-PD-1 antibodies often show considerably higher tolerability than their chemotherapeutic comparators in clinical studies. In the CheckMate 017 trial, any treatment-related AEs occurred in 86 % with docetaxel, but only in 58 % with nivolumab. For grade 3/4 events, the respective percentages were 55 % and 7 % [3]. Similar numbers were obtained in the CheckMate 057 study that investigated the same agents in patients with a different histology [4]. Notably, (febrile) neutropenia hardly emerges with PD-1 inhibitor therapy, and there are also substantial advantages in terms of non-haematological toxicity (e.g., fatigue, nausea, peripheral neuropathy). AEs of nivolumab tend to cluster within the first three months of treatment [5]. After that, the incidence decreases markedly. Resolution of AEs is seen in significant percentages.

What to do when irAEs appear?

The first step that should be taken in the management of irAEs is the identification of alternative causes. Close monitoring is necessary. If no clear-cut alternative cause can be found, all events of an inflammatory nature should be considered as immune-related. “Just by googling product inserts, physicians can obtain simple information on how to manage toxicities,” Dr. Soo said. Moreover, several review articles that outline the management of a range of toxicities and suggest treatment algorithms are available [6–9].

Low-grade AEs are controlled with symptomatic/topical measures (Figure). If low-grade events persist or severe AEs occur, systemic corticosteroids should be considered. Potent immunosuppressive drugs are an option in cases of lack of response to systemic steroids. “Patient education has an important role,” Dr. Soo pointed out. Information leaflets on various agents are provided by the pharmaceutical industry.

Figure: General principles of irAE management

Figure: General principles of irAE management

Overall, increasing expertise in handling immune checkpoint inhibitors has contributed to improved management. “Treatment discontinuation rates due to treatment-related AEs in clinical studies were low,” Dr. Soo emphasised.

Source: Educational session “New challenges in immunotherapy for lung cancer”, 18th December 2015

REFERENCES

  1. Weber JS et al., Toxicities of immunotherapy for the practitioner. J Clin Oncol 2015; 33(18): 2092-2099
  2. Bertrand A et al., Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Medicine 2015; 13: 211
  3. Brahmer J et al., Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2): 123-135
  4. Borghaei H et al., Nivolumab versus docetaxel in advanced non-squamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627-1639
  5. Reckamp K et al., WCLC 2015
  6. Gangadhar TC & Vonderheide RH, Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol 2014; 11(2): 91-99
  7. Fecher LA et al., Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist 2013; 18(6): 733-743
  8. Howell M et al., Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer. Lung Cancer 2015; 88(2): 117-123
  9. Naidoo J et al., Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015; 26(12): 2375-2391

More posts

Immunotherapy: management of toxicity

The basis underlying the toxicities of immune checkpoint inhibitors is their promotion of T-cell activity in a physiological manner. “The amplification of the immune system results in autoimmunity,” explained Ross Soo, MD, FRACP, National University Cancer Institute, Singapore.  Common AEs include fatigue, anorexia and arthralgia. Terms that denote immune-related adverse events (irAEs) typically end in -itis or -opathy.

PD-L1 expression is a nightmare in terms of complexity

here are two issues that are tied to the topic of biomarkers in immunotherapies. First, all attempts to define biomarkers have focused primarily on response as a marker of efficacy. We have to be aware, however, that immunotherapies are not targeted therapies, and fast tumor shrinkage is not necessarily observed with this kind of treatment. The efficacy of an immunotherapy is defined by long-lasting tumor stabilization.

Immunotherapy: anti-tumour activity despite extensive pretreatment

The anti-PD-1-antibodies pembrolizumab and nivolumab have been shown to be active in lung cancer. Pembrolizumab is a high-affinity, humanised, monoclonal IgG4κ antibody against PD-1 that prevents the interaction of the receptor with PD-L1 and PD-L2. The KEYNOTE-001 trial demonstrated significant anti-tumour activity of pembrolizumab in advanced NSCLC, with improved outcomes in terms of PD-L1 Tumor Proportion Scores (TPS) ≥ 50 %.

Risks and chances in patients with oligometastatic disease

Against the background of improved systemic therapies, there are rising expectations with regard to the potential cure of NSCLC patients who have a limited number of haematogeneous metastases. “Most studies define oligometastasis as one to three, or one to five lesions,” explained Suresh Senan, MRCP, FRCR, PhD, VU University Medical Centre, Amsterdam, The Netherlands.

Disease progression on EGFR TKI therapy: what to do after erlotinib, gefitinib and afatinib?

The most common mechanism of acquired resistance is the T790M mutation within exon 20 of the EGFR gene (Figure 1). Indolent slow tumour growth typically occurs when this mutation emerges. “Repeated imaging may be necessary to identify progression,” explained Pasi A. Jänne, MD, PhD, Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, USA, during a symposium at the ESMO Asia Congress.

EGFR-mutation-positive NSCLC: expanding the data pool for established treatment options

Non–small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations represents a defined molecular subset of lung cancer that can be targeted with EGFR tyrosine kinase inhibitor (TKI) therapies. Erlotinib, gefitinib and afatinib have been approved as first-line treatment options for EGFR-mutation-positive NSCLC.