Treatment of platinum non-responsive metastatic malignant peritoneal mesothelioma with combination chemoimmunotherapy

Abstract

Malignant peritoneal mesothelioma (MPeM) is a rare cancer associated with minimal durable disease control with chemotherapy and poor overall survival. The efficacy of combined cytotoxic chemotherapy and immune-checkpoint inhibitors (ICI) in MPeM has not previously been studied. We describe the clinical course of two patients with metastatic peritoneal mesothelioma who both relapsed with platinum non-responsive disease after initial cytoreductive surgery and chemotherapy. In both cases, addition of pembrolizumab to platinum and pemetrexed treatment resulted in a substantial partial and a near-complete disease response. Notably, both patients possessed tumors without validated biomarkers of ICI response, including low tumor mutational burden and negative PD-L1. The unique genomic landscape of each patient may have enabled increased tumor immunorecognition and ICI efficacy. In addition, chemotherapy priming of the tumor microenvironment may have improved ICI response. This report supports future research to characterize the benefit of combination chemotherapy and ICI in peritoneal mesothelioma.

Case Presentation:

Patient 1

A 28-year-old male presented with diffusely metastatic epithelioid-type peritoneal mesothelioma (MPeM) with papillary and solid patterns involving 50–60% of his small bowel, both diaphragms and the anterior rectal wall with diffuse omental and serosal nodularity. Next generation sequencing (NGS) with a 468 gene panel (320X coverage) revealed microsatellite-stable (MSS) disease with a tumor mutational burden (TMB) of 1.8 mutations/megabase, including loss of function pathogenic mutations in BAP1 (V99M: c.295G>A) and NF2 (R34:1c.1021C>T), as well as broad copy number loss on chromosome arms 14q and 19q. Germline sequencing (targeting 88 cancer-predisposing genes including BAP1, BRCA1 and BRCA2) showed no pathogenic variant. The patient’s disease was initially unresectable, and he received four treatments of cisplatin and pemetrexed with an initial decrease in peritoneal carcinomatosis. He underwent a large debulking surgery with a preoperative and postoperative peritoneal cancer index (PCI) score of 27 and 5, respectively (completeness of cytoreduction score of 1). The patient also received normothermic postoperative intraperitoneal chemotherapy (NIPEC) with alternating cisplatin and mitomycin for three total cycles.

The patient exhibited disease recurrence with increased bulky carcinomatosis after 3 years of active surveillance and received eight cycles of pemetrexed/cisplatin without response (Fig.1A). His disease was evaluated with laparoscopic biopsy and found to be unresectable due to small bowel and sigmoid colon serosal metastases and extensive mesenteric adenopathy. Genetic sequencing of obtained biopsies (using the same sequencing platform) was consistent with the initial sequencing results obtained at diagnosis. The patient resumed carboplatin (500 mg/m²) and pemetrexed (460 mg) for two cycles without response.

Figure 1:

Radiographic burden of disease in patient 1 approximately 1.5 months before pembrolizumab addition to treatment (A). Resolution of pelvic ascites and thickened peritoneum in patient 1 after seven months of chemoimmunotherapy (B). Radiographic burden of ascites, and peritoneal infiltration in patient 2 four days before addition of pembrolizumab (C). Resolution of pelvic ascites and thickened peritoneum in patient 2 after 5.5 months of chemoimmunotherapy (D). Arrows highlight extent of disease.

Pembrolizumab (200 mg) was then added to the pemetrexed/carboplatin every three weeks (Q3W) for thirteen total treatments over eight months. After pembrolizumab addition, the patient exhibited markedly improved functional status with resumption of normal bowel movements and decreased abdominopelvic ascites, abdominal nodularity, and peritoneal thickening (Figure 1B). The patient suffered from platinum-associated tinnitus before pembrolizumab, but otherwise exhibited no severe side effects while taking therapy. One year after the aborted CRS and eight months after immune checkpoint inhibitor (ICI) initiation, he was surgically explored and noted to have near complete resolution of the disease witnessed previously in the bowel and mesentery. He underwent a successful tumor debulking (CC0) of several nodules along with a transverse colectomy and ileal wedge resection. Excised tissue was sequenced with the same genetic test and possessed an identical mutational landscape to the previously sequenced tissue noted above. Comparative pathological assessment of tumor samples obtained pre- and post-ICI revealed a localization of tumor-associated CD4 and CD8+ positive lymphocytes to the periphery of the tumor nodules with accumulation of immune cells in the tumor-stroma interface in post-ICI tumor samples (Figure 2). This post-ICI immune cell organization was not seen in pre-ICI samples. Programmed-death-ligand-1 (PD-L1) expression was consistently negative in both the pre-ICI and post-ICI samples (Figure 2). Notably, five months after his final dose of pembrolizumab, the patient suffered from auto-immune colitis confirmed on gastrointestinal biopsy. His symptoms abated after treatment with a steroid taper. He remains in good health off any treatment since his surgery with no evidence of disease on a scan 71 months after initial diagnosis and 28 months after initiation of ICI.

Figure 2:

Patient 1 peritoneal mesothelioma tissue resected three months before initiation of chemoimmunotherapy (top row) and 1.5 months after chemoimmunotherapy initiation (bottom row) with respective cell type staining as indicated by bold text. Arrows designate examples of positive staining.

Patient 2:

A 61-year-old male patient was diagnosed with well-differentiated, papillary MPeM metastatic to the peritoneum, duodenum and abdominal soft tissue. Next generation sequencing using the same panel as the Patient 1 determined a TMB of 2 mutations/Mb, including pathogenic loss of function mutations in BAP1 (deletion), PBRM1 (deletion), and ARID1B (X515 splicing mutation: c.1543–2A>T). The patient was also noted to have an APC germline mutation (c.3920T>A), although the variant has no validated association with peritoneal mesothelioma. The patient underwent his first CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin. Subsequently, the patient underwent active surveillance with CT imaging every 6 months until he was found to have increased abdominal distention and CT evidence of new soft tissue densities abutting the duodenum, SMV, bowel and mesentery, as well as a new right lung lesion. The patient underwent an additional CRS (5.5 years after his previous surgery) with removal of multiple small tumor nodules and subsequent HIPEC using cisplatin. After the second CRS, the patient continued CT surveillance for one year until progression was noted on CT with peritoneal and serosal thickening along the bowel wall extending to the mesentery.

After his second progression of disease, the patient received cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) Q3W for four cycles with radiographic disease progression witnessed on his first scan, 12 weeks after starting therapy (Figure 1C). Pembrolizumab (200 mg Q3W) was added to the patient’s treatment regimen and provoked a dramatic radiographic response with decreased abdominopelvic ascites and peritoneal infiltration starting after two cycles and continuing throughout therapy (Fig 1D). Similar to Patient 1, Patient 2 experienced signs of tinnitus on cisplatin and was changed to carboplatin (4 mg/area under the curve, AUC) after two cycles. His carboplatin dose was subsequently lowered to 3 mg/AUC for cycle 5, and subsequently to 260 mg (flat dosing) which was continued for the duration of therapy. The patient continued with combination pembrolizumab/carboplatin/pemetrexed therapy with a continued disease response for 14 months. After that time, the patient exhibited radiographic abdominal disease progression. The patient strongly desired a treatment break and was taken off therapy. After continued progression off therapy, the patient eventually passed in the hospital on hospice care 19 months after his initial treatment with combination carboplatin, pemetrexed and pembrolizumab.

Discussion:

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive malignancy seen in less than 3 cases per million persons.[1] Although both MPeM and malignant pleural mesothelioma (MPM) are associated with exposure to asbestos, gene expression patterns between the two diseases are different, suggesting that peritoneal mesothelioma progresses in a distinct manner. BAP1 is often mutated in both MPeM and MPM, yet MPeM shows a lower occurrence of copy number alterations and NF2 mutations. [2–3]

The prognosis for patients with MPeM is poor, with a one and two-year overall survival of 47% and 20%, respectively.[4] Cytoreductive surgery (CRS) with perioperative intraperitoneal or systemic chemotherapy is indicated for patients who show no extraperitoneal disease spread and acceptable performance status. Unresectable disease is treated with first-line cisplatin and pemetrexed chemotherapy which has been associated with a median overall survival of 13 months and an overall response rate (ORR) of 26%.[5] Few late-line treatment options exist for patients with unresectable MPeM.

Sole ICI therapy has shown minimal success in prospective trials accruing patients with MPeM (Table 1). In a phase IIB double-blinded, randomized control trial of tremelimumab ICI versus placebo in patients with mesothelioma (including 26 patients with MPeM), only 4.5% demonstrated an objective response (no complete responses), and tremelimumab did not improve overall survival. [6] A separate phase II trial of single-agent pembrolizumab in MPeM and MPM showed similar findings. [7]

Table 1:

Prospective clinical trials examining immune checkpoint inhibitor therapy in Malignant Peritoneal Mesothelioma

Authors	Year	Trial Description	Treatment Description	Number pleural mesothelioma patients	Number peritoneal mesothelioma patients	Number Patients with Objective Response/Total Patients (%)
Maio et al.6	2017	Phase IIB double-blinded, placebo-controlled RCT	IV tremelimumab (until PD) versus placebo	543	26	17/382 (4.5%)*
Desai et al.7	2018	Phase II single-arm trial	IV pembrolizumab (until PD)	56	8	1/8 (12%)+
Calabro et al.10	2018	Phase II single arm trial	IV tremelimumab and durvalumab (4 cycles) followed by maintenance durvalumab (9 cycles)	38	2	11/40 (28%)*
Pratap and Raghav et al.12	2020	Phase II single-arm trial	IV atezolizumab and bevacizumab (until PD)	0	20	7/20 (35%)+

RCT (randomized control trial), IV (intravenous), PD (progressive disease).

^*Response shown for all patients with pleural and peritoneal mesothelioma

⁺Responses shown for only patients with MPM

Combination ICI-based therapy has shown promising success in MPM, a disease where ICI is approved. In a randomized, phase III study, combination PD-1 (nivolumab) and CTLA-4 (ipilimumab) blockade in patients with untreated MPM significantly extended overall survival (median 18.1 months) versus chemotherapy (median 14.1 months: HR for death 0.74, 95% Confidence Interval 0.60–0.91).[8] Patients with untreated MPM given combination durvalumab/cisplatin/pemetrexed also exhibited a promising median OS of 21.1 months, with a 1-year overall survival rate of 70%. [9]

Although MPM and MPeM exhibit epidemiological and genomic dissimilarities [1–3], several studies suggest that combination ICI treatments may also benefit patients with MPeM. Thirty-five percent (7/20) of patients with MPeM treated with combination tremelimumab and durvalumab ICI exhibited objective responses [10]. A retrospective cohort study of 29 patients with MPeM demonstrated an overall response rate (ORR) of 19.2% (5/26 patients) after treatment with various single agent ICI (N=9) or combination nivolumab and ipilimumab (n=20) treatments. [11] Although a similarly promising ORR of 35% has been seen in early results of combination atezolizumab and bevacizumab in patients with MPeM, no study has reported the efficacy of combination ICI and cytotoxic chemotherapy in multiple patients with MPeM. [12]

We present patients with metastatic MPeM who demonstrate a near complete response (patient 1) and a dramatic partial response durable for fourteen months (patient 2) after addition of pembrolizumab to failing pemetrexed and platinum therapy. Our report suggests that chemoimmunotherapy can be effective in MPeM. Several valuable observations are supported by this case series.

Notably, both patients exhibited remarkable disease responses after ICI despite an absence of traditional predictive biomarkers for ICI efficacy, including high TMB, microsatellite-instability (MSI-H) or PD-L1 positivity. Despite low TMB and PD-L1 negativity, post-ICI treatment tumor samples from Patient 1 showed evidence of immune cell mobilization; a pattern associated with immune-related response (Figure 2). [13] Although patient 2 did not have evaluable tissue for immunohistochemistry, his sequencing results similarly revealed low TMB and microsatellite-stable disease.

Patients with MPM treated with combination chemoimmunotherapy similarly showed no association between TMB, PD-L1, and survival.[9] PD-L1 status, in particular, also seems to have low association with sole ICI response in MPeM; no correlation between response and tumor PD-L1 status was found in patients with pleural and peritoneal mesothelioma treated with dual CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) therapies. [10]

The genomic landscape of our patients’ tumors may have enabled an enhanced ICI effect. BAP1-loss, seen in both patients, is associated with increased tumor-associated cytokine signaling and leukocyte infiltration compared to BAP1-intact tumors.[3] Co-BAP1-NF2 mutations, as seen in patient 1, are more rare in MPeM, but are more prevalent in pleural mesothelioma, potentially representing a distinct mesothelioma subtype that may be uniquely responsive to ICI.[3] Patient 2’s tumor exhibited an ARID1B-deletion also associated with improved ICI sensitivity in non-small-cell lung cancer. [14] NF2 and ARID1B mutations represent plausible, promising predictive biomarkers for ICI benefit; future research is needed to validate genetic determinants of ICI response in MPeM.

We cannot confirm ICI-chemotherapy synergy in our patients because of a lack of a single-ICI control comparator. However, using historical prospective phase IIB trial data, ICI monotherapy shows low efficacy (4.5% ORR in a phase IIB trial) in heavily-pretreated MPeM without documented responses that lasted over 1 year. [6] Responses in our patients were also unlikely to be solely due to chemotherapy; both of our patients progressed on platinum/pemetrexed treatments until pembrolizumab addition. Administration of chemotherapy prior to ICI may induce tumor microenvironment changes that improve ICI efficacy. Prior studies show that chemotherapy increases tumor-associated cytotoxic T-lymphocytes, lowers pro-tumor T-regulatory cells, and enhances tumor neoantigen presentation through stimulation of class-I human leukocyte antigen expression.[15] In particular, platinum chemotherapies have been shown to inhibit the signal transducer and activator of transcription 6 (STAT6)-regulated expression of the immunosuppressive programmed death ligand 2 (PD-L2), leading to improved ICI-tumor responses. [15]

Our case series has several implications for future clinical practice. In patients with MPeM and few treatment options, addition of ICI may allow for a potential “rescue” effect of therapy when other lines have been exhausted. Promising response rates as high as 35% in patients with MPeM treated with durvalumab and tremelimumab [10] suggest that combinations of multiple ICI and chemotherapy agents, if tolerable, may produce improved outcomes. As evidenced by our patients, ICI may be effective even if the patient does not possess high TMB, microsatellite-instability, or PD-L1 positive status. Current studies are ongoing to evaluate platinum-based chemotherapy and bevacizumab with or without atezolizumab in MPeM (NCT05001880). Results from this study, as well as future correlative analyses are needed to characterize the complex genetic and immune system interactions in MPeM, as well as prospectively evaluate chemoimmunotherapy efficacy in patients with MPeM.