Stacy Stein, MD, and co-investigators, research omalizumab to treat oxaliplatin hypersensitivity reactions for patients with gastrointestinal cancers.
Background: Oxaliplatin hypersensitivity reactions (HSRs) are immunoglobulin E (IgE)-mediated and prevent maximum benefit from this drug. This study was designed to determine whether oxaliplatin HSRs could be prevented or reduced with omalizumab (Xolair), an anti-IgE antibody.
Patients/Methods: This was a single-arm prospective pilot study. Patients receiving oxaliplatin-based chemotherapy for gastrointestinal cancers who were experiencing grade 1/2 HSRs were eligible. Patients received omalizumab 300 mg subcutaneously every 2 weeks, alternating with oxaliplatin-based chemotherapy. Nine patients enrolled. The primary end point was reduction of repeat HSR over the next 2 cycles. The sample size of 12 patients would achieve 79% power to detect a decrease from HSR rate of 70% (the null hypothesis) to 35% using a 1-sided binomial test. The study would be considered positive if fewer than 6 HSR events over 2 cycles occurred on omalizumab.
Results: Nine patients received 58 cycles of omalizumab. The mean number of treatments was 6 (range, 1-12). Eight of 9 patients (88%) completed 2 or more cycles and 7 (78%) completed 4 or more cycles; the overall rate of HSR was 12%. Five of 7 evaluable patients had stable disease, including 1 with near partial response.
Conclusions: Omalizumab reduces or abrogates oxaliplatin HSRs and allows months of additional therapy with apparent clinical benefit.
Keywords: gastrointestinal malignancies, oxaliplatin, hypersensitivity reaction, omalizumab
Trial registration: Role of Omalizumab in Reducing the Incidence of Oxaliplatin-induced Hypersensitivity Reaction
ClinicalTrials.gov Identifier: NCT02266355
Oxaliplatin is a third-generation platinum alkylating agent that has demonstrated efficacy against a variety of tumor types, both in adjuvant and metastatic regimens.1-6 Oxaliplatin is widely used in treatment of gastrointestinal (GI) cancers, including the FOLFOX regimen (folinic acid, fluorouracil [5FU], and oxaliplatin) for colorectal cancer and gastroesophageal cancer and the FOLFIRINOX regimen (leucovorin calcium, 5FU, irinotecan hydrochloride, and oxaliplatin) for pancreatic cancer. Unfortunately, oxaliplatin use is limited by the development of drug-related neuropathy and drug hypersensitivity reaction (HSR). The incidence of oxaliplatin-induced HSRs is 10% to 19%, emerging after a median of 7 cycles of continuous treatment or on the second cycle after reintroduction.7-11 When HSRs occur, there is no clear protocol for selecting which patients should be rechallenged with oxaliplatin and how best to rechallenge. Patients who develop HSR while they are still deriving benefit from oxaliplatin therapy may have a worse prognosis than those who do not need to discontinue oxaliplatin.
HSRs to chemotherapeutic agents have been defined as unforeseen reactions that are inconsistent with a treatment’s known toxicities. Oxaliplatin-induced HSR has been reported to occur with an overall incidence of 10% to 19%.12,13 The most common symptoms of HSRs include flushing, urticarial rash, and dyspnea without bronchospasm. Grade 3/4 reactions—which, according to Common Terminology Criteria for Adverse Events (CTCAE) version 4, involve symptomatic bronchospasm with or without urticarial rash, edema/angioedema, and hypotension requiring urgent intervention—are rare, occurring in 1.6% of patients receiving platinum-based chemotherapy. They have been described in case reports. Patients with a personal history of allergies to environmental factors or other drugs appear to be at increased risk to develop HSRs to platinum agents. There are also reports that a link may exist between the type and number of metastatic sites and the risk for HSR.7 In addition, young women may be at great risk for HSR.
Several desensitization protocols are in the literature for continued oxaliplatin use in patients with HSR. The protocols usually involve administering gradually increasing oxaliplatin concentrations at increasing rates of infusion until the full therapeutic dose is given.12,13 These protocols are complicated, time consuming, and labor intensive, potentially involving hospitalization and specially trained nursing staff. In addition, the protocol is not truly a desensitization and needs to be repeated with every subsequent oxaliplatin infusion. Often histamine 1 (H1) antagonists and steroids are given as premedication prior to each infusion.
Omalizumab (Xolair) is a recombinant humanized monoclonal anti–immunoglobulin E (IgE) antibody that is approved as an add-on therapy for moderate to severe persistent allergic asthma. Omalizumab binds soluble IgE, thus preventing IgE from binding to the high-affinity receptor on mast cells and basophils. This then leads to downregulation of the high-affinity IgE receptor on the surfaces of these cells and precludes their activation. Omalizumab has been used for a variety of indications, including moderate to severe allergic asthma, asthma with concurrent parasitic infections, seasonal and perennial allergic rhinitis, atopic dermatitis, food allergies, and chronic idiopathic urticaria. Safety, efficacy, and dose response of omalizumab was
evaluated in 10 phase 1/2 studies.14-24
The exact mechanism of how oxaliplatin causes HSR is unknown; it may be that it occurs via an IgE-dependent activation of mast cells and basophils with subsequent release of preformed inflammatory mediators. This results in itching, chest pain, rash, and, rarely, anaphylaxis. These symptoms usually occur during or shortly after the drug infusion. Therefore, we hypothesized that omalizumab could be a therapeutic tool to prevent HSRs to oxaliplatin and could allow for the continued use of an effective chemotherapy drug.
The study was conceived in 2013 and a letter of intent for the protocol was approved by Genentech on September 4, 2014. The study was approved by the Yale University institutional review board on November 13, 2014, and activated for accrual on April 27, 2015. Genentech provided omalizumab as an investigational agent and partial financial support for the trial.
Eligible subjects had a clinically evident oxaliplatin-induced HSR (defined as symptoms of flushing, urticaria, pruritus, rash, and/or dyspnea without bronchospasm emerging during or shortly after infusion) while undergoing treatment with an oxaliplatin-containing regimen for GI cancer. Patients who enrolled had metastatic GI malignancies and were receiving either the FOLFOX, FOLFOXIRI (folinic acid, 5FU, oxaliplatin, irinotecan), or FOLFIRINOX chemotherapy regimen. Eligible patients were required to have at least stable disease or response to the regimen. Any line of therapy was included. Patients had an ECOG performance status of 0 to 2. Patients who had a severe reaction to oxaliplatin, defined as hemodynamic instability, significant respiratory symptoms, or potential airway compromise, were excluded from participation. Patients with a history of HSR to omalizumab were also excluded.
Omalizumab (300 mg subcutaneously) was administered in clinic every 2 weeks during the duration of chemotherapy. The first injection was given at least 7 days after the development of the initial reaction and at least 7 days before the next scheduled oxaliplatin dose. Once anti-IgE therapy was initiated, regular doses of oxaliplatin were administered at a usual infusion rate (2 hours). Patients who had previously received oxaliplatin at a slower infusion rate, or at increasing concentrations, were allowed to continue with their prior infusion plan. All patients received cetirizine and dexamethasone 8 mg the evening before and morning of treatment. They then received dexamethasone 20 mg as premedication in the clinic. In the event of minor reactions, oxaliplatin infusion duration was allowed to be increased. Subjects were evaluated during and after oxaliplatin infusion for the development of clinically evident HSRs.
Rescue medications were available for all patients during their chemotherapy infusion as per institutional guidelines.
Patients were closely monitored for HSRs during treatment and any adverse events were graded per CTCAE guidelines. Grade 1 is defined as cutaneous signs with transient flushing or rash and drug fever above 100.4oF. Grade 2 reactions include cutaneous effects, arterial hypotension (defined as 30% or greater decrease in blood pressure) with unexplained tachycardia. Grade 3 is symptomatic bronchospasm with or without urticarial rash, allergy-related edema, or angioedema hypotension. Grade 4 reaction is defined by cardiac or respiratory arrest.
If a subject developed a recurrent grade 1/2 HSR to oxaliplatin during the first scheduled oxaliplatin infusion while on the study, they were allowed to continue on the study and received subsequent oxaliplatin infusion at a regular rate given that their symptoms were adequately controlled with rescue medication or infusion rate adjustment.
Subjects who developed recurrent grade 2 HSR to oxaliplatin during the second or later oxaliplatin infusion were discontinued from the study and omalizumab was deemed to be not effective. Subjects who developed grade 3 or 4 HSR at any point during the trial were taken off the study, and no further oxaliplatin was administered.
Patients received imaging every 8 weeks. Patients had an end-of-treatment visit within 7 days of completing therapy and then had a 28-day posttreatment follow-up visit for toxicity assessment.
We estimated that a maximum of 30% of patients treated with premedication and slower infusion rate alone would not have a HSR during the next 2 oxaliplatin infusions (in other words, at least 70% would react again). We hypothesized that the use of omalizumab would reduce this rate by half—that the HSR rate in the subsequent 2 cycles would be less than 35%. The study was designed to enroll 12 patients. This sample size would have achieved 79% power to detect a decrease from a HSR rate of 70% (the null hypothesis) to 35% using a 1-sided binomial test. Based on this estimation, if fewer than 6 HSR events occurred over the next 2 cycles on omalizumab, the drug would be considered worthy of further study.
Nine patients enrolled on the study, 8 with colon cancer and 1 with gastric cancer. Demographic characteristics are summarized in Table 1. Patient age ranged from 39 to 76 years. One patient was enrolled in the study twice for repeat oxaliplatin rechallenge (enrolled as both patient 2 and 6). Prior to starting omalizumab, 5 patients had not been rechallenged after their initial HSR. One patient had received attenuated oxaliplatin dosing prior to enrollment on this study. Two patients had received premedications with H1 and H2 blockers and with steroids to prevent repeat HSR prior to study enrollment. One patient had received dilutional desensitization with repeat HSR prior to enrolling on the study.
Patients had received between 3 and 26 prior oxaliplatin-containing treatment cycles. Five subjects were able to receive 8 or more additional cycles of oxaliplatin on study (8, 8, 8, 9, and 12; Figure 1). Five patients came off treatment due to disease progression (after cycles 4, 8, 8, 9, and 12). One patient came off study secondary to patient choice (after 8 cycles). Two patients came off study secondary to oxaliplatin HSR (both after cycle 1 on study). One patient received 12 cycles and came off for progression of disease; they went back on the study approximately 7 months later but had an HSR to the first dose of oxaliplatin upon second study entry. The patient with gastric cancer received 5 chemotherapy cycles on study but had to stop treatment secondary to peripheral neuropathy. Omalizumab injections were well tolerated in all patients with no adverse events, including HSR or local skin reaction (Table 2).
Patient 7 did not have evaluable disease. The rest of the patients had stable disease (SD) by RECIST 1.1 criteria, including patient 3, who had a 28.12% decrease in tumor size.
Progression-free survival (PFS; range, 3.8-15.4 months) and overall survival (OS; range, 4.5-25.2 months) ranged significantly among patients (Figure 2).
Patients’ IgE levels were checked once, at baseline, and ranged from 20 IU/ml to 224 IU/ml. There was no clear correlation between IgE levels and ability to continue on treatment. However, formal conclusions cannot be drawn given the limited number of subjects in the study.
The treatment of metastatic GI cancers largely involves chemotherapy. Oxaliplatin is a mainstay of treatment and is typically given in combination with a fluoropyrimidine antimetabolite (5FU or capecitabine) with the further addition of oxaliplatin or irinotecan. Immune therapy has demonstrated effectiveness only in patients with DNA mismatch repair-deficient/microsatellite instability–high tumors, which account for approximately 4% of patients with metastatic colorectal cancer.25 Therefore, it remains important for each patient to be able to maximize the benefit from each approved chemotherapy regimen. Patients are often removed from treatment with oxaliplatin secondary to either peripheral neuropathy or HSR. Given that 10% to 19% of patients receiving oxaliplatin eventually develop HSR, an intervention that could allow for continued treatment with oxaliplatin despite HSR has the potential to improve survival for these patients.
Omalizumab has been shown to be beneficial for patient groups with IgE-mediated allergic reactions including peanut allergies, severe persistent allergic asthma, and chronic idiopathic urticaria. Oxaliplatin HSRs are believed to be IgE mediated, and therefore there was rationale to see if administering omalizumab prior to oxaliplatin could abrogate HSRs.
This pilot study evaluated the role of omalizumab for its potential to treat HSR. We were able to treat patients for up to 12 cycles successfully by giving omalizumab the week before oxaliplatin infusion. The study met the primary end point, in that 89% of patients (8/9) were able to successfully receive at least additional cycles without HSR. In addition, 6 patients were able to receive 8 or more additional cycles of treatment. Given the small number of patients in this study, we can only hypothesize that an effective treatment for oxaliplatin HSRs will improve OS for these patients; however, omalizumab clearly appeared to offer a modest clinical benefit to most patients, affording prolonged disease control, and just 1 patient showed progressive disease by RECIST 1.1 while on study. The PFS and OS outcomes for these patients were variable, which likely reflects the fact that patients had had 1 to 3 lines of prior therapy; therefore, they did not compose a uniform group for this
Limitations of this study include that it did not finish accrual due to slow enrollment and enrolled just 9 unique patients. However, by the time the ninth patient enrolled, the study had already met its primary end point by having only 2 discontinuations secondary to HSR. Also, IgE levels were drawn only at baseline, making it impossible to know for sure that IgE levels were actually decreased with administration of omalizumab.
Patients with a history of oxaliplatin hypersensitivity were able to receive additional cycles of oxaliplatin when they received omalizumab prior to treatment. Given that this study met its primary clinical end point despite a smaller than planned sample size, the results warrant a larger randomized study of the use of omalizumab in preventing recurrent oxaliplatin HSR in patients with GI malignancies; this is in development. In a larger study, we will be able to better evaluate the benefit of continuing oxaliplatin in the setting of prior allergic reaction; the tolerance of additional oxaliplatin among all subjects; and the correlation of baseline IgE levels with IgE levels influenced by omalizumab administration.
Disclosures: HSH has consulted for AstraZeneca, Bayer, Genentech, and Natera Inc; and has equity in Compass Therapeutics and Processa; SS has consulted for AstraZeneca, Genentech, Ipsen, Imvax Inc, and QED Therapeutics; NVU has consulted for AstraZeneca, BostonGene, Incyte, Helsinn Healthcare SA, QED Therapeutics, and Taiho Oncology, Inc.; has received research funding from EMD Serono, Ipsen, and Taiho Oncology, Inc.; and has long position holdings in Exact Sciences and Natera Inc.
Stacey Stein, MD1; Kirsten Dooley, BS, APRN2; Nataliya V. uboha, MD, PhD3; and Howard S. Hochster, MD4,5
1Yale School of Medicine, New Haven, CT
2Yale Cancer Center, New Haven, CT
3University of Wisconsin School of Medicine and Public Health, Madison, WI
4Rutgers Cancer Institute, New Brunswick, NJ
5RWJBarnabas Health, New Brunswick, NJ