Examining New Approaches to Management of Immune-Related AEs in Lung Cancer

With the rise of immunotherapy, patients with lung cancer are experiencing improved outcomes that have allowed for prolonged survival, but it is important to ensure that the adverse effects (AEs) associated with these novel agents are effectively managed so that their achieved efficacy does not come at the cost of quality of life (QoL).

“Corticosteroid use is related to AEs, and it’s important to keep in mind that prophylactic therapy for pneumocystis and gastritis is necessary for patients receiving more than 20 mg a day for more than 30 days. Approximately one-quarter of these patients will not respond, or will recur, after the use of systemic steroids,” Mario E. Lacouture, MD, said in a presentation during the 16th Annual New York Lung Cancers Symposium®. “It’s important to think about the different pathways when considering alternate agents. [If you are dealing with] the Th1 [inflammatory pathway], you would use an [interleukin (IL)-6 inhibitor. For Th2, you would consider an IL-4 inhibitor. If it’s mediated by B cells, you would consider rituximab [Rituximab].”

In his presentation, Lacouture, who is the director of the Oncodermatology Program at Memorial Sloan Kettering (MSK) Cancer Center, an attending physician of Dermatology, and a professor in the Department of Dermatology at Weill Cornell Medicine, outlined novel approaches to managing immune-related AEs (irAEs), how to use the skin as a tool to better understand these toxicities, and how known data can be translated to other organ systems in terms of event management.¹

Impact of irAEs on Organs, QoL, and Dosing

Prior to prescribing immune checkpoint inhibitors, it is important to be aware of the spectrum of toxicity associated with them. Trials examining CTLA-4 and PD-1/PD-L1 inhibitors have spotlighted the colitis or pneumonitis that is often reported in participants, but nearly all organs can be affected by irAEs.²

“It appears that PD-1 inhibitors, and the concurrent administration of cytotoxic chemotherapy or radiation, are associated with a greater risk of pneumonitis. We see rates of pneumonitis that are greater than 5% in [patients enrolled to] the phase 3 PACIFIC trial [NCT02125461], as well as [in those included] in the phase 3 CheckMate-227 [NCT02477826], KEYNOTE-407 [NCT02775435], and KEYNOTE-042 [NCT02220894] trials,” Lacouture noted. “Therefore, these patients with pre-existing disease should have a higher degree of attention. As it pertains to dermatologic toxicities [with] PD-L1 inhibitors and chemotherapy, those in the phase 3 IMpower133 trial [NCT02763579] appeared to have a greater risk of dermatologic toxicity.”

Impact on QoL

Many efforts have been made to evaluate the impact of toxicities from checkpoint inhibitors on patients with cancer. According to Lacouture, there is no better population to evaluate the psychosocial impact of these AEs, or their impact on QoL, than in those who are receiving these agents in the adjuvant or neoadjuvant setting.

In the multinational, randomized, double-blind, phase 3 EORTC 18071 trial (NCT00636168), a total of 951 patients with stage III cutaneous melanoma were randomized to receive either adjuvant ipilimumab (Yervoy; n = 475) at 10 mg/kg or placebo (n = 476) following complete resection.³ Participants received treatment every 3 weeks for 4 doses and then every 3 months for up to 3 years.

Health-related QoL (HRQoL) was examined with the EORTC QLQ-C30 QoL instrument at baseline, at weeks 4, 7, 10, and 24; it was then examined every 12 weeks thereafter for up to 2 years, irrespective of progressive disease. Ninety-four percent of patients completed the HRQoL questionnaire at baseline, 51% did so at week 24, and 51% did so at week 108.

Results showed that the mean HRQoL scores differed by more than 10 points at week 10 between the treatment arms with respect to diarrhea (7.67 for placebo and 18.17 for ipilimumab) and insomnia (15.17 for placebo and 25.60 for ipilimumab).

“After 4 administrations of ipilimumab, the decrease in QoL was significantly higher,” Lacouture said. “This negative impact on QoL was maintained up to 2 years after patients had received their therapy. As such, [we need to remember this] when advising patients. [We need to] inform them that AEs may be persistent or long lasting. This is especially important for those with early disease.”

Impact on Dosing

Another important factor is the impact of immunotherapies on consistent dosing, Lacouture added.

In the phase 3 CheckMate-067 trial (NCT01844505), which enrolled 945 patients with previously untreated, histologically confirmed stage III or stage IV melanoma who had received nivolumab (Opdivo) plus ipilimumab (n = 314), nivolumab alone (n = 316), or ipilimumab alone (n = 315), it was found that treatment-related AEs of any grade led to discontinuation of treatment more frequently with the combination than with either monotherapy.⁴

“With PD-1 or PD-L1 inhibitors as single agents, approximately 19% of patients will have an interruption, and about 9% will have a discontinuation resulting from an IRAE,” Lacouture said. “With CTLA-4 inhibitors, which are rarely used as single agents anymore, data from early days showed that up to one-third of patients would have an interruption and 15% would discontinue. The combination of ipilimumab/nivolumab will triple these findings, with almost 60% of patients experiencing dose interruption and more than one-third requiring discontinuation due to an AE.”

Taking Into Consideration the Timeline and Severity of irAEs

Timeline

When considering the timeline of IRAEs, it has been observed that dermatologic toxicities are usually the first to present, appearing within 3 weeks of treatment, according to Lacouture, and these AEs are more commonly observed when PD-L1 inhibitors are combined with chemotherapy.

A retrospective safety review on data from 3 trials looked at patients with advanced melanoma who received at least 1 dose of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab at 3 mg/kg every 2 weeks.⁵ Results showed that the median time to onset of grade 3 or 4 treatment-related select AEs ranged from 3.1 weeks for skin toxicities (n = 33), to 16.3 weeks for renal toxicities (n = 7).

“Toxicities appeared up to 1 year since initiation of therapy. However, again, it is important to remember that these toxicities may appear even 2 or 3 years after patients had initiated therapy,” Lacouture said. “Another interesting observation is that when you combine cytotoxic chemotherapy with a checkpoint inhibitor, and then the cytotoxic agents are stopped, we are seeing a resurgence of toxicities perhaps because the chemotherapy is, in a way, treating some of these toxicities by blocking T- or B-cell function.”

Severity

A comprehensive review of IRAEs with immune checkpoint blockade showed that when comparing several organs involved, grade 1 to 2 effects mainly affected the skin and the gut, whereas grade 3 to 5 toxicities were mainly restricted to the digestive tract.⁶

“With regard to mild to moderate toxicities experienced with CTLA-4 inhibitors, skin and gastrointestinal (GI) AEs are very common, as well as with PD-1 or PD-L1 inhibitors,” Lacouture noted. “But then you see that grade 3 to 5, or severe to life-threatening to fatal AEs are less frequent. However, pulmonary pneumonitis is the most common fatal irAE that has been reported across a meta-analysis of trials.”

Dermatologic Evaluation Sheds Light on Various Phenotypes

AEs are often categorized by organ type, Lacouture added, but it is important to recognize that these effects are then subject to examination by a specialist, such as a dermatologist, and then several phenotypes may appear.

In a retrospective analysis of 285 patients with 427 immune-related cutaneous AEs (irCAEs) such as pruritus (32%), maculopapular rash (28%), psoriasiform rash (5%), and others (34%), the class of checkpoint inhibitors was linked with the irCAE phenotype (P = .007), and maculopapular rash was predominant in those who received combination treatment.⁷

“Various phenotypes…appear to also be dependent on whether a CTLA-4 inhibitor was added to a PD-1 or PD-L1 inhibitor,” Lacouture added.

Of the 120 events of maculopapular rash reported, 64 patients had received a CTLA-4 with or without a PD-1/PD-L1 inhibitor and 56 patients had just received a PD-1/PD-L1 agent. Moreover, of the 138 patients who experienced pruritus, 83 just received a PD-1/PD-L1 agent and 55 had the addition of a CTLA-4 agent. Among the 21 patients who reported bullous, 18 had just received a PD-1/PD-L1 agent and just 3 patients had the addition of a CTLA-4 agent.

Why Are Dermatologic AEs so Common in Lung Cancer?

In a cohort study of 73 patients with non–small cell lung cancer who received treatment with a PD-1 inhibitor, 34.2% developed autoimmune skin AEs which were more frequently experienced by those in complete or partial remission (68.2%) vs those who experienced disease progression or stable disease (19.6%).⁸

“They collected tumor tissue, as well as tissue from the sin, and they saw that at least the T-cell infiltrates appear to be similar in both tissues at the time of the [effect]. The T-cell receptor repertoire was also analyzed and [results] showed similar clones for the T-cell receptor as it pertains to their targets in both the skin and in the lung cancer,” Lacouture explained. “This is also recapitulated by larger meta-analyses that have demonstrated that those with lung cancer have a higher risk of pneumonitis and those with melanoma have a higher risk of skin toxicity.”

Moving Beyond Corticosteroids to Manage irAEs

Many guidelines have been issued by ASCO, ESMO, SITC, and the National Comprehensive Cancer Network to inform the appropriate use of systemic corticosteroids. However, according to Lacouture, it is important to remember that even after these agents are given, additional therapies are needed.

“We suspect that from our analysis of dermatologic events that approximately 20% of patients will not respond to corticosteroids; these are corticosteroid-refractory patients,” Lacouture said. “Also, corticosteroids, as we all know, are associated with their own set of AEs.” These AEs include changes in mood or sleep, body mass index increase, infection, myopathy, and dyspepsia, among others.

Patients who are refractory to corticosteroids should be considered for treatment with other biologic or targeted immunomodulating agents, according to Lacouture. “In 2% of over 2700 patients with lung cancer who were treated at MSK, additional therapies were needed after corticosteroids, and this provided a resolution of AEs in about 50% of patients. One-quarter of these patients did not improve, and one-quarter succumbed to their disease.”

Some of the agents that were utilized included infliximab (Remicade), vedolizumab (Entyvio), intravenous immunoglobulin, and mycophenolate mofetil, Lacouture said.⁹

Among the patients who had a steroid-refractory or -resistant neuromuscular event (n = 5), 20% improved following the start of their second immunosuppressant, as did 30% of those with steroid-refractory or -resistant pneumonitis (n = 10), 83% of those with hepatitis (n = 6), 67% of those with colitis (n = 27), and 50% of those with immune thrombocytopenic purpura (n = 2).

Targeting Cutaneous AEs: Taking a Closer Look at Specific Cases

In a patient with advanced melanoma and grade 3 bullous pemphigoid related to treatment with a PD-1 inhibitor in combination with a CTLA-4 agent who was resistant to cetirizine, diphenhydramine, mycophenolate mofetil, rituximab (Rituxan), prednisone, and pregabalin (Lyrica), a single subcutaneous injection of omalizumab (Xolair) at a dose of 300 mg resulted in partial response with reduction of the effect to grade 1 severity.¹⁰

Another patient who had renal cell carcinoma and experienced grade 3 eczematous rash and pruritus after having received treatment with nivolumab, was treated with dupilumab (Dupixent), which blocks the IL-4 receptor and is a mediator of the Th2 pathway. After 4 weeks, the pruritus went from an 8 to a 2, according to Lacouture.⁷

Determining the Role of Endoscopic Evaluation for Immune-Related Colitis

David Faleck, MD, a gastroenterologist at MSK, has stated that endoscopic evaluation may be needed to confirm the diagnosis of immune-related colitis, as 15% to 30% of patients may have an alternative diagnosis.

Moreover, Falek has noted that the role of endoscopy is important to prognosticate. Some of these patients may have microscopic colitis, which would benefit from treatment with budesonide, whereas others may have severe colitis and require infliximab.

“Endoscopy may also help to guide therapy because steroids may be effective in only about 60% of cases,” Lacouture said. “As such, identifying which patients are at higher risk may allow for just taking the next step and moving to a more effective type of therapy.”

Leveraging Targeted Therapies to Tackle irAEs

A recent review paper indicated that first-line management of irAEs may largely consist of corticosteroids with or without mycophenolate mofetil, but second-line management should be based on histology of the target tissue, as well as biomarkers in the blood such as cells or antibodies, and an inhibitor that corresponds with the pathway involved, Lacouture explained.¹¹

If the dominant mechanism of injury was determined to be lymphocytic upon immunohistopathological analysis, then potential targets would include antitumor necrosis factor (TNF), IL-6, IL-17, or integrins. If determined to be mixed innate and lymphoid, then targets would include TNF, IL-6, IL-1, IL-12/IL-23, and JAK–STAT. If pauci-immune, then targets include IL-1 and JAK–STAT, whereas if eosinophilic, then the targets would be IL-5 and mTOR. If determined to be antibody mediated, the target may be CD20, and if complement mediated, then the potential targets would include C5a, IVIG, and plasmapheresis.

“The impact of irAEs is increasing with the use of adjuvant or neoadjuvant [approaches] with combination therapies, as we have seen with the use of cytotoxic agent, and as patients are living longer, these QoL issues will become even more important,” Lacouture concluded.

References

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3. Coens C, Suciu S, Chiarion-Sileni V, et al. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017;18(3):393-403. doi:10.1016/S1470-2045(17)30015-3
4. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356. doi:10.1056/NEJMoa1709684
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8. Berner F, Bomze D, Diem S, et al. Association of checkpoint inhibitor–induced toxic effects with shared cancer and tissue antigens in non–small cell lung cancer. JAMA Oncol. 2019;5(7):1043-1047. doi:10.1001/jamaoncol.2019.0402
9. Luo J, Beattie JA, Fuentes P, et al. Beyond steroids: immunosuppressants in steroid-refractory or resistant immune-related adverse events. J Thorac Oncol. 2021;16(10):1759-1764. doi:10.1016/j.jtho.2021.06.024
10. Barrios DM, Phillips GS, Geisler AN, et al. IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies. Ann Oncol. 2021;32(6):736-745. doi:10.1016/j.annonc.2021.02.016
11. Esfahani K, Elkrief A, Calabrese C, et al. Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol. 2020;17(8):504-515. doi:10.1038/s41571-020-0352-8