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New therapies, new combinations, same goal
Novel treatments in the early stages of testing may provide alternatives for patients with hematologic malignancies.
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Medical science, by its very nature, is always striving to find new treatments, new techniques and better ways to extend life and improve wellness.
That process — again, by its very nature — moves in fits and starts. Some compounds that appear promising in phase 2 trials fail in phase 3, whereas other new combinations are tried, rejected and tried again in a different setting in hopes they ultimately will be accepted, giving physicians a new tool in their armamentarium.
HemOnc Today spoke with experts in diseases such as myeloma, leukemia and lymphoma to find out what new and emerging treatments for hematological malignancies are creating a buzz among physicians and researchers.
In many cases, these experimental treatments will not realize their early potential, but they all represent the hope that science eventually can overcome disease.
Excitement at ASH
Two potential new drugs stood out during the 2011 American Society of Hematology Annual Meeting and Exposition in December — the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 for chronic lymphocytic leukemia and the PI3K inhibitor GS-1101, also known as CAL-101.
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Photo courtesy of The Ohio State University Medical Center |
Susan O’Brien, MD, a professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and John C. Byrd, MD, director of the hematologic malignancies program at the Ohio State University Comprehensive Cancer Center, led the team that conducted a phase 1b/2 study of PCI-32765.
“Based on the results of this study, one can only come to the conclusion that this is going to be a great drug, even as monotherapy in relapsed patients,” Byrd said. “As follow-up continues, patients are going to progress, and we’re going to dissect out who is going to benefit from monotherapy and who will need combination therapy. One would expect from these results that this drug will play a major role in the treatment of CLL moving forward.”
PCI-32765 is an orally administered irreversible inhibitor of BTK, a central mediator of B-cell receptor signaling that is essential for normal B-cell development. The drug induces apoptosis and inhibits cellular migration and adhesion in malignant B cells.
In the results presented at ASH, patients aged 65 years or older with relapsed or refractory CLL were assigned to 420 mg daily PCI-32765 (n=27) or 840 mg daily PCI-32765 (n=34) in 28-day cycles until progression. Patients in the 420-mg cohort had a median number of three prior treatment regimens, and patients in the 840-mg cohort had a median of five prior treatments. About three-quarters of patients had at least one poor-risk molecular feature. Median follow-up time was 10.2 months for the 420-mg cohort and 6.5 months for the 840-mg cohort.
Objective response rate (ORR) in the 420-mg group was 70% at 10 months, up from 48% in initial results, and 44% in the 840-mg cohort. ORR appears to be independent of molecular risk features, Byrd said.
Six-month PFS was 92% in the 420-mg cohort and 90% in the 840-mg cohort.
Two patients discontinued treatment due to adverse events, and six patients required dose reductions. Researchers observed serious adverse events in 38% of patients; 10% of patients experienced serious adverse events potentially related to PCI-32765.
Byrd said he and O’Brien plan to present updated results at this year’s ASCO Annual Meeting. Eventually, they aim to get PCI-32765 approved as first-line therapy.
“If the follow-up continues to look as promising, this drug has the potential to supplant what we have now,” he said. “This is going to be a paradigm-changing drug.”
Brian Bolwell, MD, chairman of Taussig Cancer Institute at Cleveland Clinic, told HemOnc Today at ASH that the data is early but the concepts are scientifically sound.
“Fewer than 10% of the people who received the drug relapsed, but the follow-up is short — less than 1 year,” Bolwell said. “It would be nice to see some biological correlates to see if the drug is actually doing what we think it’s doing, but it’s good data. I’m optimistic about it. We have a lot of drugs to treat CLL but, at the end of the day, most patients will still have major problems with their disease at some point. A new class of drugs that looks to be very promising is terrific.”
Andre Goy, MD, MS, chairman and director of the John Theurer Cancer Center in Hackensack, N.J., and chief of the division of lymphoma, said Byrd has reason to be excited about PCI-32765 because an ORR of 70% is nearly unheard of.
“The results seen with these compounds clearly validate the BCR pathway as a very promising target,” Goy said. “The activity in CLL was even in patients with poor risk features, such as deletion 11q or 17p. In mantle cell lymphoma, the ORR was 70% in relapsed refractory MCL even after failing bortezomib and a 20% CR rate. The activity has been seen across the board in other types of non-Hodgkin’s lymphoma, including diffuse large cell lymphoma, where it seems to have a higher activity in the non-GC subtype. In addition the toxicity profile is very favorable — especially regarding hematological toxicity, which will help combining with other regimens.”
Goy and John Sweetenham, MD, professor of medicine and director of clinical research at the Cleveland Clinic Taussig Cancer Institute, said there is great potential for GS-1101, which also is used to treat CLL. The delta-isoform specific PI3K inhibitor kills stroma-exposed CLL cells and sensitizes them to treatment with other agents by releasing the cells from stroma and/or increasing their level of mitochondrial apoptotic priming.
“This looks like it’s going to be an active drug in several types of B-cell lymphoma,” Sweetenham said. “It’s another orally available drug, so it has advantages for that reason alone. It’s a specific molecular target, and the early phase 1 data are interesting.”
In results presented at ASH 2011, GS-1101 overcame the strong resistance observed in stroma-exposed CLL cells to the purine analogue fludarabine and the BH3-mimetic ABT-263, and the combination of GS-1101 and fludarabine led to a marked increase in sensitivity of stroma-exposed CLL cells.
CLL cells cultured without stroma were significantly more primed for apoptosis than CLL cells co-cultured with either a cell line cultured with StromaNKTert or primary human nurse-like cells. Adding GS-1101, with or without fludarabine, to CLL cells in culture with stroma was associated with increased apoptotic priming compared with CLL cells in culture that were untreated or treated with fludarabine alone. Researchers observed similar alterations in apoptotic priming when CLL cells were co-cultured with GS-1101 with or without ABT-263.
GS-1101 also has shown activity in Hodgkin’s lymphoma. In a preclinical study published online in the journal Blood, researchers screened five Hodgkin’s lymphoma cell lines and primary samples from patients with the disease for delta-isoform specific PI3K expression and constitutive PI3K pathway activation.
Meadows and colleagues determined that GS-1101 inhibited delta-isoform specific PI3K expression, resulting in the inhibition of Akt phosphorylation. Additionally, GS-1101 blocked induction of Akt activation in Hodgkin’s lymphoma cells cultured with stroma cells.
The combination of GS-1101 with the mTOR inhibitor everolimus (Afinitor, Novartis) also was shown to reduce cell viability and increase apoptosis. Conversely, GS-1101 reduced production of the stroma-stimulating chemokine CCL5 in Hodgkin’s lymphoma cells.
The future of treatment in CLL belongs to these novel agents, Byrd said.
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“As we understand more about these pathways, there will be additional drugs developed. Right now, we’re sort of where we were in the late 1990s with imatinib (Gleevec, Novartis),” he said. “If we look forward a decade, we’re going to be using a first- or second-generation kinase inhibitor, maybe with a monoclonal antibody, as our initial therapy for CLL. We won’t be using chemotherapy.”
Carfilzomib as treatment for multiple myeloma
Ravi Vij, MD, associate professor of medicine in the bone marrow transplantation and leukemia section at Washington University School of Medicine in St. Louis, is part of the team studying carfilzomib (Onyx Pharmaceuticals), a late-stage, selective next-generation proteasome inhibitor. The drug works by blocking proteasome activity and disrupting processes related to the growth and survival of cancer cells.
Vij presented final results at ASH from a phase 2 study that evaluated single-agent carfilzomib in bortezomib-naive (Velcade, Millennium Pharmaceuticals) patients with relapsed and/or refractory multiple myeloma.
“The response rates, especially in the bortezomib-naive group, have been encouraging,” he said in an interview. “Patients have been treated on traditional trials, then in patients with renal insufficiency, and it seems the drug is well-tolerated. The drug has also been studied in both refractory disease and the upfront setting combined with lenalidomide (Revlimid, Celgene) and dexamethasone with impressive response rates.
“Another study has looked at the drug being escalated to even higher doses than have been studied to date, and it appears there may be a dose-response relationship that may mean higher doses produce even better response than what has been seen in the PX-171-003 and PX-171-004 trials,” Vij said.
In the data presented at ASH, patients in cohort 1 (n=59) were assigned to 20 mg/m2 carfilzomib for all treatment cycles. Cohort 2 (n=67) was assigned to a dose-escalating regimen of 20 mg/m2 for the first cycle and 27 mg/m2 for all further treatment cycles, up to a maximum of 12 cycles. Prior therapies included thalidomide (59%; Thalomid, Celgene), lenalidomide (59%), alkylating agents (81%) and stem cell transplant (73%).
Best ORR was 42% in cohort 1, with a median time-to-progression of 8.3 months and median duration of response of 13.1 months. Best ORR was 52% in cohort 2. Median time-to-progression and duration of response have not been reached. Higher response rates in cohort 2 do not appear to be associated with higher adverse effects, Vij said.
Median PFS was 8.2 months (95% CI, 6-12.3) in cohort 1. Median PFS had not been reached in cohort 2. Median OS had not been reached in either group.
Carfilzomib earned orphan drug status in 2008.
The FDA granted fast-track status for carfilzomib in January 2011 based on results from a phase 2b study of single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. In December, the FDA granted a standard review to Onyx’s application to market the drug for patients with relapsed and refractory multiple myeloma rather than the accelerated assessment for which the company hoped.
The FDA sent a letter to Onyx noting the Oncology Drug Advisory Committee has shown a preference for phase 3 trials when granting accelerated reviews. The agency also questioned whether carfilzomib’s risk and benefit are appropriately balanced, noting the application was based on a single-arm study.
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Carfilzomib is being evaluated in two phase 3 trials.
The ASPIRE trial is analyzing the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three prior therapies. The FOCUS trial is looking at single-agent carfilzomib in relapsed and refractory patients. It is designed to support a regulatory filing in Europe.
Additionally, researchers are studying the drug’s efficacy in a phase 1b/2 study in patients with advanced solid tumors.
The most common side effects observed in multiple clinical trials of carfilzomib are thrombocytopenia, anemia, lymphopenia, pneumonia and fatigue.
Immunotherapy
Pomalidomide (Celgene) is an immunomodulatory agent that inhibits angiogenesis in multiple myeloma cells and alters the levels of inflammatory and regulatory cytokines while stimulating immune system cells to attack and destroy tumor cells. The drug is a chemical analogue of thalidomide, which received FDA approval in 1998 for treatment of patients with multiple myeloma.
Pomalidomide was the subject of four presentations at ASH.
Vij — who said the drug has shown “impressive responses,” even in patients who are refractory to bortezomib and lenalidomide — took special note of a presentation by Antonio Palumbo, MD, of the University of Torino in Italy, and Paul G. Richardson, MD, of the Dana-Farber Cancer Center.
Palumbo presented results from a phase 1/2 study of the combination pomalidomide/cyclophosphamide/prednisone in patients with multiple myeloma who relapsed or were refractory to lenalidomide. The first 24 patients entered phase 1 to determine the maximum tolerated dose of the combination. Seventeen patients were added to the second phase to determine safety and efficacy.
Twenty-three patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The maximum tolerated dose was determined to be 2.5 mg daily pomalidomide, 50 mg cyclophosphamide every other day and 50 mg prednisone every other day. Thirty-two patients were evaluable for safety and efficacy.
Two relapsed/refractory patients had complete response and 19 (59%) had partial response. In patients who were refractory to lenalidomide, 73% demonstrated at least partial response and one demonstrated complete response.
Researchers observed grade-4 neutropenia in 9% of patients, and 9% had grade-4 thrombocytopenia. Grade-3/grade-4 nonhematologic toxicities included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities.
Richardson presented results from a multicenter phase 1/2 investigation of the safety and efficacy of pomalidomide alone or combined with low-dose dexamethasone for patients with relapsed or refractory multiple myeloma resistant to lenalidomide and bortezomib.
Researchers identified 4 mg daily pomalidomide as the recommended dose in phase 1. In phase 2, 108 patients were randomly assigned to 4 mg daily pomalidomide alone and 113 were assigned to 4 mg daily pomalidomide for 21 days of a 28-day cycle along with 40 mg weekly dexamethasone. More than half (56%) of patients in the single-agent arm went on to receive the combination due to progressive disease.
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Two hundred nineteen patients underwent at least one cycle of treatment and 191 patients were evaluable for response. Patients in both arms underwent a median of five treatment cycles, and median duration of treatment was 5 months.
ORR was 34% in the combination arm vs. 13% in the single-agent arm. Complete response rate was 1% in both arms. Median duration of response was 7.7 months for the combination and 8.3 months for pomalidomide alone. The combination arm was superior for PFS (4.7 months vs. 2.7 months) and OS (16.9 months vs. 14 months.)
In patients who were refractory to lenalidomide and bortezomib, outcomes favored the combination for median PFS (3.9 months vs. 2 months) and median OS (13.7 months vs. 12.7 months).
A little more than half of the patients in the combination arm discontinued treatment due to progressive disease compared with 44% in the single-agent arm. Most common grade-3/grade-4 adverse events in the combination arm included neutropenia (38%), thrombocytopenia (19%) and anemia (21%). Nineteen percent of patients in the combination arm experienced grade-3/grade-4 thrombocytopenia, 47% experienced neutropenia and 17% developed anemia.
Celgene announced Jan. 26 that it intends to submit an application to the FDA for approval of pomalidomide for relapsed and refractory multiple myeloma in the first quarter of this year.
Changing modalities
Between kinase inhibitors, molecular antibodies and immunotherapy, the treatment of hematologic malignancies is branching out into a dozen different treatment modalities.
Byrd said chemotherapy will become obsolete, at least for CLL, but other experts are not so bullish. And unlike in decades past when chemotherapy was the best — and often the only — available treatment, Sweetenham said he does not foresee one modality dominating the others.
“The dominant paradigm is probably going to be combining two or three drugs. We’ve learned over the past 10 or 15 years that combining chemotherapy with monoclonal antibodies improves outcomes compared with administering either of those types of medications alone,” Sweetenham said. “The small molecule kinase inhibitor-type approach is exciting and will undoubtedly uncover a whole new paradigm in terms of how we treat patients. We’re going to take our established chemotherapy/monoclonal antibody therapy combinations and add these drugs into the mix, rather than using these drugs in isolation. Cancer is too smart to be beaten by just attacking one target.”
The ultimate goal, according to the experts, is to create a treatment plan unique to each patient. Physicians and researchers are making headway, even if final success is not imminent.
“We already see it in lung cancer, where a number of mutations are being looked at to make decisions in practice,” Goy said. “It’s beyond the buzzword now, as there is no question that individualized therapy will be an important aspect of the future, both to define the patients who should remain on conventional chemotherapy and to identify patients for whom we should explore other options. The activity seen with the kinase inhibitors targeting the BCR pathway will allow building non-chemotherapy options in some situations. There is no question that we have to continue in that direction.” – by Jason Harris
Disclosure: Drs. Byrd and Goy report no relevant financial disclosures. Dr. Sweetenham reports receiving research funding from Aegera Therapeutics, Avila Therapeutics, Celegene, Millennium Pharmaceuticals, Novartis and Seattle Genetics. Dr. Vij reports receiving research funding from Celgene and Onyx Pharmaceuticals, serving as an adviser for Celgene, Millennium Pharmaceuticals and Onyx, and serving on speakers’ bureaus for Bristol-Myers Squibb, Celegene, Cephelon, Facet Biotech Corp., Millennium Pharmaceuticals and Novartis.
For more information:
- Gandhi V. Blood. 2010;116:1999-2000.
- Kahl BS. Clin Adv Hematol Oncol. 2010;8:1-16.
- Lacy MQ. J Clin Oncol. 2009;27:5008-5014.
- Meadows SA. Blood. 2011;doi:10.1182/blood-2011-10-386763.
- Siegel DS. Abstract #985. Presented at: 52nd Annual Meeting of the American Society of Hematology; Dec. 4-7, 2010; Orlando, Fla.
- Tefferi A. J Clin Oncol. 2009;27:4563-4569.
- The following were presented at the 53rd Annual Meeting of the American Society of Hematology; Dec. 10-13, 2011; San Diego.
- Palumbo A. Abstract #632.
- Richardson PG. Abstract #634.
- Vij R. Abstract #813.
Going forward, is there a role for chemotherapy in the treatment of chronic lymphocytic leukemia?
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There may be a time in the future when we may be positioned to treat CLL patients without chemotherapy, but more likely we shall still keep chemotherapy as a quill in our armamentarium for the therapy of the disease.
The advent, for instance, of novel agents such as the immunomodulatory drugs PCI-32765 and CAL-101 may allow us to treat or at least maintain patients without chemotherapy. These novel agents and targeted therapies, including the many monoclonal antibodies coming down the pike, hold great promise.
In the near term, though, I foresee combining these novel, directed and/or targeted therapies with chemotherapy for enhanced or synergistic killing of the neoplastic cell.
There is no such thing as a free lunch. Even these novel agents have toxicity associated with them. Rather than saying we want to do away with chemotherapy, it’s more appropriate to say we want to have treatment that is the least toxic and the most effective that we can find. If these novel agents are less toxic, and they seem to be thus far, hopefully one day we will be able to avoid chemotherapy. Our ultimate goal is not to use chemotherapy. We’re not there yet, but we’re almost there.
Morton Coleman, MD, PhD, is the director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital-Weill Cornell Medical Center. He also is HemOnc Today’s section editor for hematologic malignancies. Disclosure: Dr. Coleman reports no relevant financial disclosures.
We’re certainly not at the point of eliminating chemotherapy in CLL, and I don’t think that time will come for at least the next decade.
One would hope that we will have a greater understanding of the molecular pathology of CLL and other cancers so we can pick targeted therapies that will be effective and, over the long term, control the disease without chemotherapy. I’m not as sanguine that day is on the immediate horizon. We currently have treatments that clearly and unequivocally prolong survival. We have had increasingly better response rates, overall response rates, PFS and, in fact, OS.
This new era of drugs — be it CAL-101 or PCI-32765 — are very exciting agents, but it’s still very early in their development. We do not have comparative data against chemotherapy. We’re not seeing the sort of molecular complete remissions with these agents that we see with the chemotherapy combinations.
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At some point we might have the right combination of drugs, but it is a little naive to say we’re right on the verge of making chemotherapy obsolete and that it will happen in the next few years. I think it’s going to take some time to work out how to use these novel drugs, and many times, we will end up combining them with chemotherapy.
It’s important to remember that these are drugs with potential toxicities, and even if they’re not the more nonspecific chemotherapy agents, like cyclophosphamide or fludarabine, these are still potent drugs with potent side effects. Lenalidomide is not a trivial drug. It’s very marrow-suppressive, particularly in CLL patients, even though it is very active. Changing treatments is not the equivalent of taking a multivitamin.
Right now, I don’t see any novel modality that doesn’t require long-term treatment. I think a lot of patients would rather take six cycles of chemotherapy for 6 months and avoid treatment for 5 years rather than taking a pill with side effects every day for the rest of their lives.
Andrew D. Zelenetz, MD, is chief of the Lymphoma Service at Memorial-Sloan Kettering Cancer Center. Disclosure: Dr. Zelenetz has served as an adviser and investigator with Genentech/Roche, and as an adviser for Celgene, GlaxoSmithKline and Seattle Genetics.