CHICAGO -- Cancer patients who develop autoimmune symptoms after treatment with immune checkpoint inhibitors such as pembrolizumab (Keytruda) or nivolumab (Opdivo) are best managed carefully, without biologics except as a last resort, a specialist said here.
Corticosteroids and conventional DMARDs (disease modifying anti-rheumatic drugs) such as sulfasalazine or hydroxychloroquine should be tried first, said Anne Bass, MD, of the Hospital for Special Surgery in New York City, speaking at the .
Only when patients show moderate to severe arthritis that doesn't respond to high-dose steroids should tumor necrosis factor (TNF) inhibitors be brought in, Bass said.
Management of patients developing inflammatory autoimmune disease as a result of checkpoint inhibitor treatment is already a significant issue for oncologists and will only become more so as these agents become more widely used. Pembrolizumab and nivolumab, for example, were first approved in 2014 for advanced melanoma, subsequently gaining indications for lung cancer and a range of other solid and hematologic cancers, with more expected.
Checkpoint inhibitors -- which include the CTLA-4 inhibitor ipilimumab (Yervoy) and the PD-L1 inhibitor class that includes atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio), along with the PD-1 inhibitors pembrolizumab, nivolumab, and cemiplimab (Libtayo) -- block tumor cells' ability to shut down immune attack. In particular, the PD-1/PD-L1 inhibitors prevent tumor cells from forcing CD8-positive effector T cells to commit suicide when they come in contact. Thus, the drugs "reinvigorate" these immune cells as they infiltrate tumors, with near-miraculous results in some patients with refractory cancers.
However, an inevitable side effect is invigoration of immune cells elsewhere in the body as well. Bass noted that, in patients who do not develop autoimmune symptoms, their tumors don't respond to the drug either. Recent data show approximately double the rate of patient survival for those who develop immune-related adverse events compared with those who don't.
One implication is that clinicians need to walk a fine line: treating these events too effectively might compromise the checkpoint inhibitor's anticancer effect.
Some of these adverse events can be fatal -- mainly myocarditis and myositis -- but these are rare, Bass said. The risk does mean patients should be monitored closely, but it's not a reason to withhold checkpoint inhibitors.
That brings up another clinical question regarding checkpoint inhibitors, which is whether they should even be used in patients with preexisting autoimmune disease. Bass said immune-related adverse events in these patients are no more common than in other patients, although there is a strong risk of autoimmune disease flare. But remember that those events correlate with improved survival.
The upshot, Bass said: "Yes, your patients can receive checkpoint inhibitors" -- but it's advisable to stop immunosuppression when starting those agents and be especially careful with polymyositis patients.
Most of the immune-related events with checkpoint inhibitors come in the form of rash and gastrointestinal symptoms. The latter are the most likely to become high grade, with rates of diarrhea and colitis reaching 19% with ipilimumab/nivolumab combination treatment, according to .
She spent much of her talk here on arthritis as a checkpoint-inhibitor side effect, because it's the most common disabling event. Unfortunately, it was largely missed in the initial trials of these agents, in part because patients were also on steroids and also because investigators tended to focus on grade 3/4 events.
Consequently, incidence estimates vary widely, from 1% to 43% for arthralgia and 1% to 7% for overt arthritis, and other aspects are also not well understood, such as risk factors, differences from other forms of arthritis, and responses to treatment.
A registry now underway at the Hospital for Special Surgery should provide better data, Bass suggested. The institution is a leading center for rheumatologic disease research and treatment and, as it's located directly adjacent to Memorial Sloan Kettering Cancer Center, is well situated as the home for it. Thus far, 36 patients developing arthritis with checkpoint inhibitors have been enrolled. Bass discussed some of the data from this group, but numbers are too small as of yet to draw conclusions.
Of greater interest, perhaps, is gene expression data collected by other groups that point to the risk that aggressive treatment of immune-related adverse effects may undermine checkpoint inhibitors' clinical effectiveness.
Bass showed charts depicting genes that nivolumab upregulates on one hand, and the genes upregulated in the context of rheumatoid arthritis. These overlapped markedly. Moreover, anti-rheumatic drugs downregulate those genes -- suggesting, therefore, that an effective treatment of checkpoint inhibitor-induced arthritis is likely to suppress the genes necessary for the checkpoint inhibitor to have its intended effect.
So what's the best approach? Bass said there's not much evidence to go on yet. Steroids have been used most commonly as initial treatment and she said that's a reasonable place to start. But it's much less clear for patients who don't respond to steroids. One drug not to use is tocilizumab (Actemra), she suggested, citing a study from an institution that used it in all patients with checkpoint inhibitor-related arthritis resistant to steroids. Those patients showed markedly poorer survival.
Indirect evidence also indicates that JAK inhibitors such as tofacitinib (Xeljanz) are likely to compromise the cancer treatment. That leaves drugs acting on the TNF pathway, but evidence that they are effective against the arthritis while also letting the checkpoint inhibitors do their work remains largely nonexistent.
Bass's suggested algorithm was to start with steroids (prednisone 10-20 mg or equivalent) and, if mild arthritis persists, then add hydroxychloroquine or sulfasalazine. For patients with more severe arthritis not responding to higher dose steroids (up to 80 mg prednisone), physicians should "strongly consider" TNF inhibitors. Some patients may require combination therapy, she advised.
And the old arthritis standby, methotrexate? It can also be used, Bass said, but beware of its slow onset of action.
Disclosures
Bass said she had no relevant financial interests.
Primary Source
American College of Rheumatology
Bass A "Checkpoint inhibitor-associated autoimmunity" ACR-SOTA 2019.