ORLANDO, FL—Monoclonal antibodies (MABs) have revolutionized cancer therapy with their novel way of targeting, either alone or in combination with other agents, to treat neoplasms. Now researchers are linking an MAB with a cytotoxic agent to allow chemotherapy to target the cancer cell directly. This focused delivery of the cytotoxic agent to tumor cells may maximize the antitumor effect while minimizing normal tissue exposure, potentially resulting in an improved therapeutic index. Targeted delivery is also expected to result in less toxicity than non-targeted systemic delivery of currently used cytotoxic chemotherapy combinations.
“MABs provide the opportunity to deliver potent drugs to the target working as a drug shuttle,” said Andre Goy, MD, MS, Chief of the Division of Lymphoma at the John Theurer Cancer Center at Hackensack (NJ) University Medical Center, speaking here at the American Society of Hematology Annual Meeting.
Dr. Goy reported on an evaluation of one such investigational combination, inotuzumab ozogamicin (CMC-544), in patients with indolent B-cell Non-Hodgkin's lymphoma (NHL) who have disease relapse or are refractory to rituximab and chemotherapy, or anti-CD20 radioimmunotherapy (Abstract 430).
Conjugated to Calicheamicin
Inotuzumab ozogamicin is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antitumor antibiotic that binds DNA. The CD22 antigen is expressed on about 90% of B-cell malignancies, including NHL.
Monotherapy with the agent has demonstrated efficacy and tolerability in heavily pretreated patients, and is being investigated in patients with indolent B-cell NHLs that are refractory to rituximab alone, rituximab in combination with chemotherapy, or radioimmunotherapy.
Inotuzumab is also being combined with rituximab followed by high-dose therapy and autologous stem cell transplant in relapsed/refractory NHL patients.
“Inotuzumab ozogamicin is one of the many antibody-drug conjugates that are in the pipeline with unlabeled antibodies or antibodies plus radiation,” noted Myron Czuczman, MD, Head of the Lymphoma/Myeloma Service at Roswell Park Cancer Institute, asked for his opinion for this article.
He predicted that this “encouraging” therapy will be available to private practitioners within two years. “Based on activity in relapsed/refractory disease, this will be a welcome addition to the armamentarium,” said Dr. Czuczman, who says some of his lymphoma patients who have failed to respond to other therapies have achieved durable remissions with inotuzumab ozogamicin.
The antibody-antigen complex is rapidly internalized upon binding with CD22, and calicheamicin is released inside the tumor cell, Dr. Goy said. Calicheamicin binds to DNA, and induces double-strand DNA breaks and apoptosis.
CD22 is expressed only on mature B-cells, which allows for targeted delivery of cytotoxic agents, and should not affect the ability to generate new B-cells, he said.
Dr. Goy was the lead author of a Phase II, multicenter, single-arm open-label study to evaluate the safety and efficacy of the agent. The 54 patients who were eligible for this trial had CD22-positive indolent B-cell NHL, primarily with follicular lymphoma not transformed (45 patients) that had progressed after two or more systemic therapies. They had exhibited no response or had progressed within six months from completion of the most recent rituximab or rituximab-containing therapy, or within 12 months of the completion of radioimmunotherapy.
The patients, median age of 62, received inotuzumab ozogamicin at 1.8 mg/m2 every 28 days for four to eight cycles, with the dose and/or frequency adjusted based on toxicities. The patients received a median of two doses.
Nearly half (43%) of the patients had four or more therapies, more than half (59%) had a high Follicular Lymphoma International Prognostic Index (FLIPI) score at entry, three-quarters were refractory to rituximab, and one-third were refractory to chemotherapy, Dr. Goy reported.
After a median follow-up of 6.2 months, the overall response rate (ORR) was 50%, with a complete response rate of 19%. The estimated progression-free survival was 11.1 months.
“The ORR was 58% among follicular lymphoma patients and 85% among patients who discontinued treatment due to an adverse event,” said Dr. Goy. “Of the 21 follicular lymphoma patients who responded, only four have relapsed or progressed.”
Patients with low- or intermediate-risk FLIPI scores responded best. In contrast, only one of seven patients with bulky disease responded.
Treatment was discontinued in 32 (59%) of 54 patients, mostly due to thrombocytopenia or disease progression, he said. Eleven serious adverse events were reported for six patients. For the 25 patients with Grade 3 or 4 thrombocytopenia, platelet counts recovered within one month. Platelet counts tend to drop quickly and somewhat linger, he said.
In conclusion, Dr. Goy said, “Inotuzumab ozogamicin led to encouraging responses in patients with refractory or heavily pretreated follicular lymphoma with an average of three prior therapies, with a manageable toxicity profile.
“There is no question this is a strong compound. We are moving toward targeted chemotherapy for lymphoma. The challenge is how to integrate the targeted chemotherapy. There will still be cytotoxicity. We have a learning curve to find the best schedule and combination.”
Crucial Issue: Hematologic Toxicity
John Leonard, MD, Professor of Medicine at Weill Cornell Medical College in New York City, commented: “Any agent that is active in rituximab refractory patients is of interest, and this treatment is encouraging. The crucial issue is hematologic toxicity. For patients with low blood counts and low hematologic reserve in the bone marrow this will be an important issue. How will patients tolerate the drug?
“We now have the next generation of MABs that are reengineered or engineered to carry a toxin or radioisotope with greater efficacy,” he continued, noting the promising results also reported at the ASH meeting of brentuximab vedotin (SGN35), an investigational antibody-drug conjugate that delivers the highly potent chemotherapy agent monomethyl auristatin E directly to Hodgkin lymphoma cells and induces cell death via an anti-CD-30 antibody.
In a study of 102 heavily pretreated, refractory patients, brentuximab led to a 75% response rate and 34% complete response rate, with primarily Grade 1 or 2 adverse events, including peripheral neuropathy, fatigue, and nausea.
“These types of combinations take MABs to the next level by targeting a toxin to improve efficacy, but this has to be balanced with potential toxicity,” said Dr. Leonard.
Dr. Czuczman added: “There are an increasing number of exciting novel agents that are going to improve the ability to target cancer cells with less nonspecific toxicity. We can deliver toxins in a much safer way than we did in the past. It's becoming a kinder, gentler world with the use of these agents.”
The CD19 antigen can also internalize drugs to target B-cell malignancies, he said, and drug conjugates of CD22 with doxorubicin and liposomal doxorubicin have already been put to the test.
In addition, inotuzumab ozogamicin in combination with rituximab has demonstrated efficacy and tolerability in relapsed/refractory NHL patients, including diffuse large B-cell lymphoma (DLBCL) patients who were ineligible for high-dose therapy and autologous stem cell transplant.
Dr. Goy is an investigator in an ongoing trial of 34 patients who have CD20+/CD22+ B-cell DLBCL, have received one or two therapies, and have at least two adverse prognostic factors. Rituximab was administered at 375 mg/m2 on Day 1, then inotuzumab ozogamicin at 1.8 mg/m2 on Day 2 every 21 days for up to six cycles.
Patients who responded to the inotuzumab ozogamicin plus rituximab combination who had sufficient peripheral blood stem cells could then proceed to transplantation.
To date, 19 patients who received a median of two cycles have been assessed, and four responded, for an overall response rate of 21% (2 complete response and 2 partial responses). Another five patients (26%) showed stable disease. Three patients have had both a response to the inotuzumab ozogamicin plus rituximab combination and sufficient stem cell collection to allow for transplantation.
The safety profile was similar to that of inotuzumab ozogamicin alone, with the most common adverse events being thrombocytopenia, neutropenia, lymphopenia, nausea, and fatigue, Dr. Goy said.
“This study shows we can combine inotuzumab ozogamicin with rituximab with little added toxicity,” said Dr. Czuczman. “The two have different mechanisms of tumor kill—rituximab uses the immune system and inotuzumab ozogamicin delivers a chemotherapeutic agent to the cancer cell in a unique way—which is very exciting.”
Most MAB combination agents have some myelosuppression, he noted, which is essentially reversible by delaying the next treatment.
Despite its early success, inotuzumab ozogamicin needs to show more durability, said Dr. Leonard. “When combined with rituximab, can we add standard chemotherapy? How will the drugs be sequenced or combined?”
The two treatments will probably be used in sequence to reduce the possibility of toxicity. “The hope is to improve on chemotherapy or to have the treatment be less toxic and substitute for chemotherapy.”
The treatment of lymphoma has changed with new developments in biotechnology and an increased knowledge base about the sensitivity of tumor cells, said Dr. Czuczman. “Soon it may be difficult to figure out which treatments to use first. The options are expanding every year. We will have to develop a personalized therapy based on risk factors derived from biomarkers. Once we identify the targets that are overexposed, we will then be able to choose the appropriate tool from the medical shelf.”