Case Description

We present a case of an 85-year-old male with Muir-Torre syndrome, a variant of Lynch syndrome (LS) associated with visceral malignancies as well as secondary sebaceous neoplasms. The patient presented with a germline mutation in the MSH2 gene. Other pertinent medical history was significant for coronary artery disease with percutaneous coronary intervention to the left anterior descending artery, resulting in mildly reduced left ventricular ejection fraction (LVEF) at 50%, as well as typical atrial flutter with ablation to the cavotricuspid isthmus. His oncologic history was significant for metachronous CRC diagnosed at age 52 years, initially treated with 5-FU–based chemotherapy, but with recurrence approximately 20 years later requiring partial colectomy and anastomosis. He also developed multiple urothelial cancers starting at age 65 years, as well as several skin cancers, including sebaceous carcinoma. As expected, his family history is also consistent with LS, including other family members with both colorectal and noncolorectal cancers.

In March 2020, a screening upper endoscopy was performed, which revealed a 3-cm polyp in the gastric fundus with pathology showing moderately differentiated, intestinal-type gastric adenocarcinoma with lymphovascular and submucosal invasion. Based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, the patient underwent diagnostic laparoscopy with peritoneal washings to rule out radiologically occult disease.¹¹ A biopsy from the peritoneum was positive for metastatic adenocarcinoma, consistent with the patient’s known gastric primary. Genetic analysis confirmed MLH1 and MSH2 mutations via immunohistochemical staining.

Following the diagnosis of invasive gastric adenocarcinoma in the setting of high microsatellite instability, the patient was started on the PD-1 receptor–targeted immunotherapy pembrolizumab (200-mg infusions every 3 weeks). Shortly after receiving the second infusion of pembrolizumab, the patient experienced significant chest pain and progressive shortness of breath, requiring multiple hospital admissions. During his initial presentation, his troponin levels were noted to be elevated at 1,414 ng/L and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 1,076 pg/mL. His 12-lead EKG showed sinus rhythm with premature ventricular contractions and nonspecific ST-T abnormalities. He underwent a transthoracic echocardiogram, which showed LVEF of 47% with regional wall motion abnormalities.

A cardiac MRI showed delayed enhancement in a nonvascular distribution predominately involving the basilar lateral wall, with small areas of delayed enhancement scattered throughout the left ventricle. Due to findings of the cardiac MRI, invasive testing with endomyocardial biopsy was deferred. Furthermore, the patient’s last coronary angiogram had been completed 1 year prior, with placement of a drug-eluting stent to the mid left anterior descending coronary artery. Overall, this was felt to be consistent with grade 4 myocarditis related to immunotherapy, and less likely acute coronary syndrome (Figures 1 and 2). The patient also had evidence of grade 1 myositis and possible signs of grade 1 hepatitis, as noted by elevations in creatine kinase (607 ng/L) and ALT/AST (259/385 U/L) levels. Inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate, at the time were not assessed. It should be noted that the elevation in liver enzymes was thought by rheumatology to be related to muscle injury rather than true liver inflammation or grade 1 hepatitis.

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Cardiac MRI images with colorized T2 mapping short axis orientation at (A) mid left ventricle and (B) apical left ventricle, showing patchy areas of increased T2 signal in a nonvascular distribution (orange color indicating edema, pink color indicating normal myocardium). Myocardial delayed enhanced images of the left ventricle in (C) short axis and (D) horizontal long axis orientations, showing patchy delayed enhancement (red arrows) in nonvascular distribution of myocardium damaged from myocarditis.

Citation: Journal of the National Comprehensive Cancer Network 21, 9; 10.6004/jnccn.2023.7029

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Bright blood cine: short axis orientation of mid ventricle showing relative thickening and hypokinesis centered in inferoseptal region where this is a significant amount of edema.

Citation: Journal of the National Comprehensive Cancer Network 21, 9; 10.6004/jnccn.2023.7029

Pembrolizumab was discontinued, and the patient was started on immunosuppressive therapy with intravenous methylprednisolone at 1,000 mg for 3 days followed by a 60 mg of oral prednisone daily, tapered by 10 mg every 7 days. After his initial hospital discharge, he experienced recurrent chest pain on 3 separate occasions, each time presenting with elevated troponin and NT-proBNP levels, thought to be flares of ICI-related myocarditis during his steroid taper. Prior elevation in creatine kinase and liver enzymes had returned to baseline levels and there was no concern for concurrent muscle or hepatic injury. After careful consideration of the available treatment options for refractory myocarditis, the patient was treated with the tumor necrosis factor–inhibitor infliximab. A single dose of 5 mg/kg was used with concurrent pulsed methylprednisolone at 1,000 mg for 3 days and transitioned to a slow prednisone taper. He had no further episodes of chest pain or biochemical evidence of recurrent myocarditis. Troponin and NT-proBNP levels eventually stabilized to a new baseline of approximately 100 ng/L and 400 pg/mL, respectively, in addition to creatine kinase and liver enzymes remaining within normal limits. He underwent frequent monitoring by the cardiology department, with scheduled echocardiograms every 3 months and serial NT-proBNP and troponin measurements. Additionally, he was started on beta-blockade with metoprolol succinate at 50 mg daily to protect against tachyarrhythmias.

The patient had 2 repeat upper endoscopies within 7 months of the initial complications from pembrolizumab. Although he had only completed 2 doses, biopsies from the first esophagogastroduodenoscopy (EGD) showed gastric oxyntic-type mucosa and superficial fragments of neoplastic intestinal-type epithelium with no invasive carcinoma identified. However, the biopsy results from the second EGD (7 months after stopping pembrolizumab) showed recurrent focal invasive well-differentiated adenocarcinoma arising in a background of high-grade dysplasia, with morphology composed of foveolar-type epithelium with scattered goblet cells. CT imaging of the abdomen and pelvis from that time showed a 2.2-cm lesion near the proximal stomach, representing the patient's known local recurrent tumor, and no radiographic evidence of peritoneal or mesenteric disease.

Due to the patient’s disease recurrence, a risk/benefit discussion was conducted regarding his prognosis with and without ICI therapy. Systemic chemotherapy was considered; however, due to the numerous prior cycles of chemotherapy for previous malignancies that the patient had undergone, as well as their associated side effects and his advanced age, he opted not to pursue this option. Large, powered studies suggest an overall survival of roughly 3 to 6 months in unselected untreated metastatic gastric cancer.¹² Following careful consideration of potential significant risks, the patient’s prior pathologic and radiographic response to anti–PD-1 therapy, and prior data suggesting a meaningful benefit in MSI-H gastric cancer treated with ICI, the decision was made to proceed with an alternative ICI therapy. Due to the significant benefit previously achieved with pembrolizumab after only 2 doses, the anti–PD-1 biosimilar nivolumab was started at a 50% dose reduction (480 mg decreased to 240 mg), with infusions administered at an interval of every 4 weeks. Dose reduction of nivolumab was chosen to mitigate the risk of recurrent myocarditis or other irAEs. Although nivolumab has not been extensively studied in MSI-H gastric cancer, results from the NCI-MATCH trial showed an objective response rate (ORR) of 36% and promising results toward progression-free and overall survival for patients with relapsed or refractory dMMR noncolorectal cancers.¹³

The patient was closely observed by medical oncology and cardio-oncology for potential severe adverse reactions. At the time of initiation with dose-reduced nivolumab, troponin and NT-proBNP levels were 150 ng/L and 582 pg/mL, respectively, and continued to decrease to the baseline levels mentioned previously. He tolerated nivolumab without significant side effects or irAEs. The patient received 13 cycles of dose-reduced nivolumab over 1 year. The patient remains disease-free almost 1 year after completing therapy, with no radiographic evidence of residual disease. Additionally, surveillance EGD showed no visible masses, and biopsies revealed only mild acute and chronic inflammation, negative for intestinal metaplasia or dysplasia. Images from the EGDs over the course of his diagnosis and treatment are shown in Figure 3. A timeline of the course of events is shown in Figure 4.

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EGD pictures from the anterior wall of the gastric cardia at (A) initial diagnosis, showing a 3.8-cm tubular mass with histology revealing moderately differentiated gastric adenocarcinoma; (B) recurrence 9 months after initial treatment with pembrolizumab, showing a 2.0-cm polypoid mass with histology revealing well-differentiated gastric adenocarcinoma; and (C) resolution 1 year after secondary challenge using dose-reduced nivolumab, with histology showing mild acute and chronic inflammation, negative for malignancy.

Abbreviation: EGD, esophagogastroduodenoscopy.

Citation: Journal of the National Comprehensive Cancer Network 21, 9; 10.6004/jnccn.2023.7029

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Timeline of events, including prior oncologic history, clinical course of invasive gastric adenocarcinoma, and complications of treatment resulting in myocarditis.

Abbreviations: CR, complete response; CRC, colorectal cancer; EGD, esophagogastroduodenoscopy; ESD, endoscopic submucosal dissection; HGD, high-grade dysplasia; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; LS, Lynch syndrome; LVEF, left ventricular ejection fraction; LVI, lymphovascular invasion; NT pro-BNP, N-terminal pro-B-type natriuretic peptide; RWMA, regional wall motion abnormalities; SCC, squamous cell carcinoma; TCC, transitional cell carcinoma; TTE, transthoracic echocardiogram.

Citation: Journal of the National Comprehensive Cancer Network 21, 9; 10.6004/jnccn.2023.7029

Discussion

This case represents an approach that includes a shared decision to rechallenge patients with ICI following immune-related life-threatening complications in highly selective cases in which considerable benefit may be expected. Multiple clinical practice guidelines report on management of ICI-related adverse events.^14–17 The specific management of irAEs in the acute setting ultimately depends on the type and extent of organ involvement and should be carefully considered on a case-by-case basis. However, there is no specific guidance regarding secondary considerations for rechallenge in patients with MSI-H malignancies who develop life-threatening irAEs from PD-1 receptor inhibitors.

The general recommendations from the Society for Immunotherapy of Cancer (SITC) for patients who encounter grade 3 or 4 irAEs are to risk adjust the possibility of re-treatment based on the expected benefit from immunotherapy against the risk of potential toxicity.^14,18,19 However, the panel makes very specific recommendations for patients who develop myocarditis due to the significant overlap with myositis and potentially fatal neurotoxicity. Myocarditis can develop as a spectrum of multisystem irAEs, with concurrent irAEs present in 9.8% of patients.²⁰ An individual who develops any grade of muscle, cardiac, or neurologic involvement from immunotherapy should be tested for concurrent toxicity with a shared set of diagnostics.²¹ Due to the high mortality rates associated with myocarditis, the panel states that permanent discontinuation of immunotherapy should be strongly considered.¹⁴ Of note, SITC does not comment on the utility of dose reduction as a potential alternative strategy for those who develop irAEs, irrespective of the underlying severity.

The Multinational Association of Supportive Care in Cancer (MASCC) is another international society that provides general recommendations for patients who experience irAEs from ICIs. The consensus from MASCC regarding myocarditis is permanent discontinuation of any ICI due to the high risk of recurrence.¹⁵ ASCO has similar recommendations for the diagnosis and management of toxicity reactions, with guidelines regarding grade 4 toxicities (except for endocrinopathies controlled by hormone replacement) recommending permanent discontinuation of ICIs.¹⁶

The importance of a thorough risk assessment for secondary challenge is especially critical for cancers harboring a dismal prognosis. Cancers with MSI-H are recalcitrant to adjuvant chemotherapy and may in fact worsen outcomes in earlier stages of disease (stages II and III) as shown in post hoc analysis of the MAGIC and CLASSIC randomized controlled trials.^22,23 A meta-analysis from 4 randomized controlled trials showed improved OS in resected MSI-H resectable gastric cancer, but no observable increase in disease-free survival (DFS) for those treated with additional adjuvant chemotherapy.²⁴ MSI-H status also confers prognostic benefits compared with MSI-L/MSS resectable gastric cancer (5-year DFS, 71.8% vs 52.3%; 5-year OS, 77.9% vs 52.3%), as shown in the pooled meta-analysis from the MAGIC, CLASSIC, ARTIST, and ITACA-S trials.²⁵ The utility of traditional chemotherapy in patients with advanced or metastatic disease should be explored and MSI status should not preclude their use, particularly in those who have contraindications to or side effects from immunotherapy. Although our patient declined systemic chemotherapy for reasons stated previously, 5-FU–based or platinum-based chemotherapy should also be considered due to the improved outcomes compared with untreated patients with metastatic disease.¹²

Evidence for continued immunotherapy for MSI-H–detected cancer comes from results the KEYNOTE-158 and KEYNOTE-177 trials.^7,26 Specifically, the KEYNOTE-177 trial showed significant improvements for MSI-H CRC toward median progression-free survival (PFS) (16.5 vs 8.2 months) with pembrolizumab compared with 5-FU–based chemotherapy.²⁷ Further evidence for the use of immunotherapy in advanced MSI-H or dMMR tumors has been demonstrated from a subanalysis of the CheckMate 649 and ATTRACTION-4 trials.^28,29 Patients with advanced, resistant, or recurrent MMR-deficient gastric or gastroesophageal cancer who received nivolumab + oxaliplatin-based chemotherapy experienced a median survival of 44.8 months compared with 8.8 months with chemotherapy alone.²⁸ Results of these studies suggest a survival benefit for immunotherapy with or without traditional chemotherapy and the risks and benefits should considered carefully on an individual basis.

In 2019, a JAMA Oncology study of case safety reports from the WHO database VigiBase analyzed the rate of irAE recurrence after ICI rechallenge.¹⁷ Results of the study showed 0 of 3 patients with prior ICI-related myocarditis experienced recurrence after secondary rechallenge. Moreover, a patient with recurrent endometrial cancer who developed myocarditis from the PD-1 inhibitor sintilimab was successfully rechallenged with an alternative agent, zimberelimab.³⁰ However, based on our review of the literature, there have been no published reports of patients who developed grade 4 myocarditis from ICI therapy who were subsequently rechallenged with dose reduction of same class agents.

Conclusions

We present a case of a patient with metastatic gastric adenocarcinoma and Muir-Torre/LS secondary to a confirmed mutation in the MSH2 gene. Following the early administration of pembrolizumab, the patient developed several irAEs, including grade 4 myocarditis as defined by ASCO as symptomatic life-threatening disease with radiographic and biologic evidence of myocarditis, requiring treatment with corticosteroids and infliximab.³¹ He was later safely rechallenged with nivolumab at 50% dose reduction and achieved a complete response after treatment for 1 year. This case highlights a therapeutic strategy for cautious rechallenge of select patients who develop severe irAE from ICIs, through careful consideration and a shared decision-making process that highlights the risk/benefit ratio.