ASCO Annual Meeting Spotlight
Key news updates from the ASCO Annual Meeting
Wednesday, August 13, 2014
BY MARK FUERST
CHICAGO -- Adding panobinostat to the standard-care combination of bortezomib and dexamethasone significantly improves progression-free survival (PFS) in patients with multiple myeloma, according to the results of a randomized, double-blind, placebo-controlled, Phase III trial reported here at the ASCO Annual Meeting (Abstract 8510)
“Panobinostat is a significant advance in the treatment of patients with relapsed or relapsed and refractory multiple myeloma,” said the study’s lead author, Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.
“These are the first Phase III results to show meaningful clinical benefit and provide scientific support for adding panobinostat to bortezomib-based treatment for patients with relapsed or relapsed and refractory multiple myeloma and provide a strong rationale for the use of histone deacetylase inhibitors as part of the therapeutic armamentarium in this setting.”
Asked for his opinion for this article, Sagar Lonial, MD, Professor and Vice Chair of Clinical Affairs and Director of Translational Research for the B-cell Malignancy Program at Emory University School of Medicine, called the results exciting and said they may “allow a new mechanism to treat relapsed multiple myeloma, and move treatment to an earlier setting to debulk the disease and get to better outcomes.”
Also commenting, Mikkael Sekeres, MD, Associate Professor of Medicine and Director of the Leukemia Program at Cleveland Clinic, said, “This is another combination that seems to do better than what we had before in multiple myeloma with a promising new agent, panobinostat. … “We have so many options for multiple myeloma and so many combination therapies. What is the best combination for relapsed/refractory multiple myeloma? Does this change that? What about sequencing?”
Almost all patients with multiple myeloma ultimately relapse and become resistant to treatment, so new therapies are critical for continuing to manage the disease and improve outcomes, said Richardson, who is also Professor of Medicine at Harvard Medical School.
Panobinostat is an oral pan-histone deacetylase (HDAC) inhibitor that has been shown to modulate the acetylation of proteins involved in multiple oncogenic pathways, ultimately inducing cell cycle arrest and apoptosis. Richardson noted that one of the targets is HDAC6, an enzyme that has been identified as an important target in multiple myeloma.
In preclinical studies, panobinostat was synergistic in combination with bortezomib and dexamethasone.
Panobinostat inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by bortezomib, he said. A three-drug combination of panobinostat, bortezomib, and dexamethasone has shown substantial clinical activity in patients with relapsed or refractory multiple myeloma, inducing durable responses even in patients with disease that is refractory to bortezomib.
The PANORAMA 1 (PANobinostat ORAl in Multiple MyelomA) trial, conducted at 215 centers in 34 countries, enrolled 768 patients, median age of 63, with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy and were not bortezomib-refractory. About two-thirds of patients had relapsed disease and one-third had relapsed and refractory disease.
About 48 percent of the patients had received at least two prior regimens. Previous treatments included bortezomib (43% of patients), thalidomide (51%), and lenalidomide (20%). One-quarter had received both bortezomib and immunomodulatory agents. Slightly more than half had autologous stem cell transplantation.
Patients were stratified based on the number of prior lines of therapy and prior bortezomib therapy. They were randomly assigned to receive either panobinostat (387 patients) or placebo (381 patients) in combination with intravenous bortezomib and dexamethasone. For cycles 1 to 8, patients received 20 mg of oral panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; 1.3 mg/m2 of intravenous bortezomib on days 1, 4, 8, and 11; and 20 mg oral dexamethasone on days 1-2, 4-5, 8-9, and 11-12 of every 21-day cycle.
Patients with clinical benefit after the first eight cycles proceeded to the second treatment phase. In this phase, which consisted of four 42-day cycles, the panobinostat regimen remained constant and bortezomib administration was reduced to days 1 and 8 and dexamethasone administration was reduced to days 1-2 and 8-9.
The primary endpoint of the trial was progression-free survival; secondary endpoints included overall survival (OS), overall response rate (ORR), complete response/near complete (CR/nCR) rate, duration of response (DOR), and safety. An independent review committee confirmed PFS and ORR.
After a median follow up of 28 months, the three-drug combination led to a significant improvement over the two-drug combination, with median PFS of 12.0 months versus 8.1 months, respectively, which represents a 37 percent improvement.
“The primary endpoint was met, with a clinically relevant increase in median PFS of 3.9 months in the panobinostat-bortezomib-dexamethasone arm,” Richardson said. The PFS benefit was maintained regardless of baseline characteristics and regardless of prior treatment history.
The final overall survival data are not yet mature, but an interim analysis shows no difference in median OS in the panobinostat arm (33.64 months) and the placebo arm (30.39 months), he reported.
The findings also showed that adding panobinostat to bortezomib and dexamethasone led to a significant increase in higher-quality responses compared with use of standard-of-care therapy alone, with a nearly two-fold increase in CR/nCR response rates (28% vs. 16%, respectively).
The overall response rate was also higher in the panobinostat arm versus the placebo arms -- 60.7 vs. 54.6 percent. The median duration of response, time to response, and time to progression also favored the panobinostat arm.
Side effects were consistent with those previously seen in previous panobinostat studies, he said. The most common Grade 3/4 adverse events in the panobinostat-combination arm were thrombocytopenia (67% vs. 31% with placebo), lymphopenia (53% vs. 40% with placebo), neutropenia (35% vs. 11% with placebo), diarrhea (26% vs. 8% with placebo), and asthenia/fatigue (23.9% vs. 11.9%). Adverse events were generally manageable through supportive care and dose reductions, he said.
In an analysis of platelet kinetics, “following an initial decrease in platelet median levels during the first two weeks of treatment, platelet levels rebounded to baseline by day 1 of each cycle. Thrombocytopenia is reversible and not cumulative.”
Toxicity resulted in treatment discontinuation in 36 and 20 percent of patients in the panobinostat and placebo arms, respectively. The all-cause death rates were similar (8% in the panobinostat arm and 5% in the placebo arm).
In conclusion, Richardson said, “these results confirm the efficacy of panobinostat, bortezomib, and dexamethasone previously observed in the PANORAMA 2 trial with patients who were heavily pretreated and bortezomib-refractory. It shows the superiority of a triple-drug combination versus a dual-drug combination. This is a new option with an HDAC inhibitor as a novel mechanism of action. The activity in high-risk populations is promising.”
He said that in the future, the use of subcutaneous bortezomib may improve tolerability. Other panobinostat-containing combinations are under evaluation in multiple myeloma, and additional HDAC inhibitors are also under study. Trials of panobinostat in myelodysplastic syndromes and myelofibrosis are also underway.
In May panobinostat was granted priority review by the Food and Drug Administration, and additional global regulatory submissions are underway.
“If approved, panobinostat will be first in its class of anticancer agents available to this population,” Lonial said. “It will be a new option with a novel mechanism of action in multiple myeloma.”
He noted that because overall survival for multiple myeloma patients has about doubled in the last decade, the prevalence of the disease is going up. Among those with relapsed/refractory multiple myeloma, the median OS is six to nine months. “Most patients relapse. It’s not uncommon to see patients who have had 10 to 12 lines of prior therapy before entering a relapsed/refractory trial. And there is decreasing durability of response with each additional line of therapy. New treatment options are needed in this patient population.”
As for the PANORAMA 1 study, he noted that although the difference in overall response rate between the panobinostat and placebo arms was only six percent, “CR and near CR were almost twice as high. Getting depth of response is important.”
Lonial pointed out that of course, the incidence of adverse events was higher with three drugs versus two drugs. “However, toxicity was early, and with appropriate management, mitigated or reduced.” Earlier multiple myeloma trials with another HDAC inhibitor, vorinostat, saw a lot of gastrointestinal toxicity, which was not seen with panobinostat. “Hematologic toxicity with panobinostat was more neutropenia, which should not impact the ability to give this combination therapy,” he said.
The debate among oncologists comes down to using three or two drugs in the early-relapse setting. “Would you rather use bortezomib as single agent or along with dexamethasone, or add in panobinostat and double the CR rate, which is an important endpoint in patients with early relapse?” Lonial asked.
The Discussant for the study, Robert Z. Orlowski, MD, PhD, of the University of Texas MD Anderson Cancer Center, noted that the “activity in high-risk patients seemed comparable, although this subgroup was small and not stratified.” He also pointed out that 43 percent of patients had received prior bortezomib. “But if they had to be sensitive, did this select patients more likely to respond?” Orlowski asked. “A better hazard ratio was seen in patients who had prior bortezomib.”
A lower dose intensity was given to the panobinostat-bortezomib-dexamethasone group of patients, which meant that “panobinostat had to work harder to overcome this. Perhaps a lower dose or schedule could have been better,” he said.
Wednesday, August 13, 2014
BY MARK FUERST
CHICAGO -- Combination immunotherapy with ipilimumab and nivolumab achieves long-term survival for advanced melanoma patients, according to updated data from an expanded Phase I study. Concurrent treatment with the two drugs led to an unprecedented median survival of 40 months for patients with advanced melanoma-- nearly double the median overall survival found in previous studies of either agent alone.
“Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20 to 25 percent survived for two years, so it’s truly remarkable that we’re seeing a median survival of over three years in this trial,” said the lead author, Mario Sznol, MD, Professor of Medical Oncology at the Yale School of Medicine, at the American Society of Clinical Oncology, in presenting the results here at the ASCO Annual Meeting (Abstract LBA9003).
“Even in the latest era of targeted and immunotherapy agents, the median survival is on average only about 16 to 18 months with any new treatment alone,”
Still, while encouraged by the use of these two drugs together, experts noted, of course, that the trial is small and early, and that randomized Phase III trials, now under way, will be important to validate the initial results.
At an ASCO news conference, the moderator, Steven O’Day, MD, Clinical Associate Professor of Medicine at the University of Southern California Keck School of Medicine, commented: “These results are similar to childhood leukemia survival curves, approaching an 80 percent plateau, which is palpably excitable for melanoma. The early results are very impressive. The proof of the pudding will be if the survival data holds up.”
Nivolumab and ipilimumab are antibody drugs that target and block two distinct checkpoints (PD-1 and CTLA-4, respectively) on T cells, disarming the tumor’s defense against the immune system and boosting the immune system’s ability to fight melanoma. “Both drugs produce significant clinical activity as monotherapy in advanced melanoma,” Sznol said at the briefing. Ipilimumab is FDA-approved for the treatment of metastatic melanoma, and lasting antitumor effects have been observed with nivolumab as a single-agent therapy.
Initial data on 53 patients presented at the 2013 ASCO Annual Meeting showed an objective response rate (ORR) of 40 percent with concurrent administration of the two drugs. This study showed “rapid and deep tumor regressions in about one-third of patients, with a preliminary overall survival of 80 percent at one year with limited follow-up,” Sznol said.
The report at this year’s meeting included updated safety, survival, and clinical efficacy data of study cohorts 1 through 3. Those patients received ipilimumab and nivolumab every three weeks for four cycles, followed by nivolumab alone every three weeks for four cycles. At week 24, patients who did not have disease progression or severe side effects could continue nivolumab plus ipilimumab every 12 weeks for eight cycles.
The follow-up data confirmed that complete responses have increased in cohorts 1 through 3. Sznol said that overall, 22 out of 53 patients (41%) responded to the treatment, and nine (17%) had complete responses. Tumor shrinkage was rapid and extensive ─ 42 percent of the patients had a greater than 80 percent tumor reduction by week 36. The responses were durable, with 18 of 22 responses (82 percent) ongoing at the time of the analysis.
“I actually believe that is an underestimate of complete responses,” he said. “Probably the number of patients who had truly complete responses is even higher than that because we had many patients with near complete responses.” Durable objective responses are ongoing, with the median duration of response not yet reached.
A new cohort (cohort 8) enrolled 41 patients, median age of 58, using a Phase II/III dosing regimen of nivolumab monotherapy at 3 mg/kg every two weeks, following the initial combination induction dose, until disease progression. These patients had a preliminary ORR of 43 percent and a complete response rate of 10 percent.
Sznol said that the response rate was 57 percent for patients who had ipilimumab blood levels above the median and only 14 percent for those with drug blood levels below the median.
“In our experience these responses were just as active in patients with BRAF-mutated and BRAF wild type disease,” Sznol said. Clinical responses were seen regardless of PD-L1 status, and across all dose levels. Other studies of anti-PD-1 monotherapy have shown reduced activity in patients with tumors with low or negative PD-L1 expression.
“It suggests that we are picking up activity in patients who might not have responded to anti-PD-1 alone. I’m confident that the activity of this combination regimen is real.”
All 94 patients had inoperable stage III or IV melanoma and had undergone up to three prior systemic therapies. About half of the patients had very advanced disease (stage M1c), and a little more than half of them had no prior systemic treatments.
“The most convincing data that the two drugs have a synergistic effect comes from survival data,” Sznol said. Across the doses, the one- and two-year median overall survival rates were 85 and 79 percent, respectively. The median survival duration was 39.7 months. At the nivolumab 1 mg/kg and ipilimumab 3 mg/kg dose being tested in an ongoing Phase II/III trial, one-year and two-year overall survival rates were 94 and 88 percent, respectively.
The rate of side effects related to induction of immune reactivity against normal tissues was higher than previously observed for either single agent, but there were no new safety signals with 22 months follow-up for the initial concurrent cohort, he said. Grade 3 or 4 adverse events occurred in about two-thirds of patients.
“This would raise a concern, but this is similar to that seen with ipilimumab,” he said. “The side effects were manageable and resolved with algorithms defined for ipilimumab. I’m confident any new safety signals can be managed,” he said.
About one-quarter of patients discontinued treatment due to treatment-related adverse events, and there was one drug-related death in cohort 8 from multi-organ failure as a result of colitis.
In conclusion at his presentation, Sznol said, “Concurrent therapy with nivolumab and ipilimumab results in unprecedented two-year overall survival rates. There was more than 80 percent reduction in tumor volume in most responding patients. We saw a similar response profile for additional patients in cohort 8. There was a high incidence of grade 3-4 events, but standard safety guidelines are available to manage or reverse adverse events.”
The team plans to continue to follow patients in all cohorts of this study.
Phase II and III trials are investigating the use of concurrent nivolumab plus ipilimumab versus nivolumab or ipilimumab in patients with advanced melanoma, and the concurrent combination versus ipilimumab. This combination is also being investigated in other tumor types, Sznol noted. “It shows a 45 percent ORR in renal cell carcinoma, which is also encouraging.”
During the news briefing, in response to a question about the safety of the combination, he said: “I believe this regimen is not hard to manage in the clinic. There is not a lot of toxicity during maintenance. Most toxicity is during induction.”
Jedd Wolchok: Strong Rationale to Combine the Drugs
Asked for his opinion for this article, Jedd Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center, said, “There is a strong rationale to combine these two drugs. They have non-redundant pathways to activate T cells. Once a drug blocks CTLA-4, the next thing T cells do is induce PD-1. To intervene at that level seems logical.”
Wolchok noted that there is little cross-resistance between the two drugs. What is not clear, though, he said, is whether combination or sequential use is the best approach in terms of toxicity and survival.
The 79 percent two-year survival rate across all dose levels of the concurrent combination is “precedent setting,” Wolchok said. “The doses in Phase II and III led to an 88 percent survival, which compares favorably to the literature. This is not a flash in the pan. With the 40 additional patients, the types of response and response rates are consistent with what we saw last year.”
The response rate for patients with PD-L1-negative tumors may be lower than those with PD-L1 positive tumors “but we are not going to withhold treatment based on tumor type. The tumor type doesn’t matter with the combination,” he said, adding that this combination is a reasonable option for patient regardless of BRAF status as well.
The better response with higher blood levels of ipilimumab supports the concurrent combination. “The amount of ipilimumab present seems to be important to outcome. Ipilimumab induces inflammation, which induces PD-L1 expression,” he said. It may also be possible to induce inflammation by priming the tumor upfront with an oncolytic virus, using radiation therapy to cause inflammation in the tumor site, or using cryotherapy to create inflammation.
In the future, if the combination therapy proves out, it will be offered to many advanced melanoma patients. “For patients with a PD-L1 negative tumor, we may be able to use just a PD-1 blocking agent and get a good outcome. But some patients will need this combination,” Wolchok said.
The Discussant for the study, Jeffrey Weber, MD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center, agreed that with a two-year overall survival rate of 79 percent, “it doesn’t get better than that in metastatic melanoma.
“I cannot help but be impressed,” he said. “Although there was a high rate of toxicity, much of it is biochemical due to asymptomatic liver enzymes.”
Some open questions related to PD-1 blockade remain: “How long should we treat -- one year, two years, or until progression? Is treatment every two or three weeks needed continuously? Can we prime briefly, then boost?” Weber asked.
In addition, he said he wondered whether the increase in toxicity, which may be synergistic, is justified by the benefit of the nivolumab and ipilimumab combination: “Can PD-1 antibody treatment be continued after grade 3-4 immune-related adverse events induced by ipilimumab or concurrent therapy?”
Tuesday, August 12, 2014
BY MARK FUERST
CHICAGO -- Substituting bortezomib for vincristine in standard frontline therapy for mantle cell lymphoma (MCL) significantly improved outcomes in newly diagnosed patients who were ineligible for bone marrow transplant (BMT), according to the results of an international, randomized Phase III trial. The bortezomib-based therapy (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone, or VR-CAP) resulted in a 59 percent relative improvement in progression-free survival (PFS) over standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).
“This bortezomib combination should be considered the new standard treatment for newly diagnosed MCL patients who require treatment,” lead author Franco Cavalli, MD, Scientific Director of the Oncology Institute of Southern Switzerland, said in an interview at the ASCO Annual Meeting in presenting the study (Abstract 8500). “This data will affect the practicing oncologist. This is the typical MCL population they see daily, and reflects the vast majority of newly diagnosed MCL patients.
"This is one of the largest studies ever conducted in newly diagnosed MCL. The substantial improvement seen in PFS and in secondary endpoints, including complete response, time to next therapy, and time to progression with the bortezomib-based regimen, expands our understanding of bortezomib’s contribution to patients with MCL."
He explained that MCL is a rare, incurable, aggressive subtype of non-Hodgkin lymphoma (NHL) with poor prognosis. It comprises about six percent of NHL, with 3,000 to 4,000 cases per year in the United States. R-CHOP is the standard frontline therapy for MCL patients not considered for intensive treatment and BMT, but the progression-free survival time is limited.
Bortezomib is approved for the treatment of patients with relapsed MCL, but “incorporating bortezomib into frontline therapy may improve outcomes for newly diagnosed MCL patients,” Cavalli said.
The study was a randomized, open-label, multicenter Phase III study in newly diagnosed MCL patients not considered for BMT to compare the efficacy and safety of R-CHOP versus VR-CAP. The study included 487 patients, median age of 66, with previously untreated stages II, III, or IV MCL who were not candidates for BMT. The patients were randomly assigned to receive six to eight 21-day cycles of R-CHOP (244 patients) or VR-CAP (243 patients).
The primary endpoint was PFS, and secondary endpoints included time to progression, time to subsequent anti-lymphoma treatment, overall survival, response rate, and safety.
The patient characteristics were well-balanced. Three-quarters of the patients were male, and three-quarters had stage IV disease. Patients received a median of six cycles of treatment. Only a few patients discontinued treatment--many for adverse events or death. The mean relative dose intensity was similar and well-balanced between the two arms.
After a median follow-up of 40 months, the median PFS in the VR-CAP arm was 24.7 months compared with 14.4 months in the R-CHOP arm as determined by an independent review committee. Median overall survival had not been reached at the time of follow-up, while a median overall survival of 56.3 months was observed in patients treated with R-CHOP, Cavalli said.
“By investigator assessment, the PFS was 30.7 months in the VR-CAP arm compared with 16.1 months in the R-CHOP arm--a 96 percent improvement. The investigators more closely resemble the practicing oncologist than the independent review committee.”
The median PFS was 44 months in the 16 percent of patients who were not over age 60 or did not have a reason for eligibility for transplant.
Asked for his opinion, Mikkael Sekeres, MD, Director of the Leukemia Program at the Cleveland Clinic, said, “This is a very large study, and many MCL patients are not available for BMT. My bias is to wait for overall survival data instead of PFS. But this may be as good as it gets in this hard-to-treat group.”
“The overall survival data are not mature, but the survival curves are diverging. We will eventually see a difference in overall survival,” Cavalli said. “We already show an impressive difference in PFS.”
The bortezomib combination demonstrated improvements in median time to progression (30.5 vs. 16.1 months), median time to subsequent treatment (44.5 vs. 24.8 months), and complete response (CR) rate (53 vs. 42 percent) compared with standard therapy.
In terms of safety, the majority of patients in both arms received all planned treatment cycles, and treatment exposure was similar between the arms. “VR-CAP was associated with additional but manageable toxicity compared to R-CHOP, which was consistent with known side effects of bortezomib and the R-CAP backbone,” he said.
Serious adverse events were reported in 38 percent of patients receiving VR-CAP compared with 30 percent of R-CHOP patients. Grade 3 or higher adverse events were reported in 93 percent of VR-CAP and 85 percent of R-CHOP patients.
The rates of peripheral neuropathy were similar between the two arms. “Events appeared to resolve more frequently and more quickly with VR-CAP,” he said. “There was a higher rate of thrombocytopenia with VR-CAP, but no difference in bleeding events.” There were higher rates of neutropenia and infection with VR-CAP.
Cavalli noted that the trial required more frequent checking of blood for patients in the VR-CAP arm, which may explain the higher rate of thrombocytopenia in that arm--“This may actually be less pronounced than it appears in the VR-CAP arm.”
The use of subcutaneous administration of bortezomib has shown to offer an improved systematic safety profile. “I’m personally convinced that with a switch to subcutaneous bortezomib the toxicity profile will become even more manageable,” he said. “There is no reason not to incorporate bortezomib into treatment. We do not need to save bortezomib in case of relapse.”
Cavalli said that the next step in the research is to add in rituximab maintenance: “Our data are almost equivalent to European data that includes rituximab maintenance after R-CHOP. We also need to compare this regimen to one that includes ibrutinib.
“The first goal is to get rid of high-dose chemotherapy, which is cumbersome and expensive. If we improve frontline therapy, MCL patients may not need any autologous BMT.”
How to Improve Therapy?
The Discussant for the study, Michael Williams, MD, the Byrd S. Leavell Professor of Medicine and Professor of Pathology and Chief of the Division of Hematology and Oncology at the University of Virginia, said: “We can safely add in an active single agent, bortezomib, as a substitute for vincristine and improve PFS in R-CHOP with apparent safety.”
He agreed that some side effects may be ameliorated if bortezomib is given in weekly or subcutaneous doses, and noted that the U.S. Intergroup E1411 trial is also testing the use of bortezomib in MCL, and is currently accruing patients.
Williams asked several questions about how to continue to improve therapy for MCL patients.
- Can we add in maintenance rituximab?
- Can that really control disease for an extended period for many patients?
- Should we add in lenalidomide or ibrutinib?
He suggested the possibility of bringing this type of therapy to the frontline to avoid cytotoxic therapy. A lenalidomide/rituximab combination can apparently lead to good disease control with an 81 percent response rate and a “quite high” 93 percent PFS at 12 months, he said. Another study of ibrutinib in relapsed/refractory MCL suggests a higher PFS for patients who have had previous bortezomib therapy.
“This disease is a great model system to test targeted therapies--both alone and in combination with traditional therapies and in combination with standard combinations,” Williams said.
“We have entered a new era in lymphoma therapy. We have improved clinical and molecular prognostic tools, leading to risk-adapted therapy.” This includes PET-based staging and assessment of treatment response, targeted therapeutic agents, next-generation immunotherapeutics, and novel integration of new agents into traditional regimens.
“In 2014, the standard of care for MCL has not been established. For the asymptomatic, indolent MCL subtype, it is okay to watch and wait. Younger, fit patients should receive rituximab plus a high-dose cytarabine-based regimen followed by autologous stem cell transplant [ASCT]. Perhaps new agents or minimal residual disease assessment will allow decreased need for ASCT.”
Older patients with comorbid illness or declining health require ASCT, he said. The role of R-CHOP followed by maintenance rituximab every two months or rituximab plus bendamustine with rituximab maintenance is still undefined.
Clinicians may be able to incorporate an active single agent, bortezomib, into frontline therapy, Williams said. “Phase I and Phase II studies show the safety and efficacy of bortezomib-plus-chemotherapy combinations. The Phase III trial results presented by Cavalli expand on that.”
Williams said that a handful of selected agents and their targets are now in clinical trials for MCL as single agents or as combination regimens, including lenalidomide (microenvironment); palbociclib (CDK4/CDK6); everolimus and temsirolimus (mTOR); idelalisib (PI3K); ibrutinib (BTK); ABT-99 (BCL2); vorinostat and romidepsin (HDAC); and antibody drug conjugates (CD79b and CD22).
There are potential strategies for this new era, he said. “We can optimize current regimens, risk-adapt therapies based on clinical and biomarker profiles and PET-based response, and rationally incorporate new agents into therapeutic algorithms, either concomitantly or sequentially.
“The high cost of therapeutics, including diagnostics, labs, imaging, and therapeutics, demands careful stewardship in lymphoma management.”
Tuesday, July 29, 2014
BY MARK FUERST
CHICAGO -- Adoptive T cell therapy may provide a new, personalized strategy for advanced cervical cancer, according to a small, federally funded Phase II study reported here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA3008).
In a study among three other abstracts highlighted at an ASCO news conference on progress in immunotherapy, researchers used a personalized immunotherapy approach to treat two patients with widespread metastases, both of whom had complete responses after a single treatment with human papillomavirus (HPV)-targeted T cells, and who at the time of the report had been cancer free for 15 and 22 months, respectively.
The study shows that “adoptive transfer of HPV-targeted T cells can cause complete remission of metastatic cervical cancer and that this remission can be long-lasting,” said the lead author, Christian Hinrichs, MD, Assistant Clinical Investigator at the National Cancer Institute.
One implication of the study is that cellular therapy might have application to a broader range of tumor types than previously recognized. This is the first time adoptive T cell therapy has been tested in cervical cancer. Previously, it has shown promise in melanoma, leukemia, and sarcoma.
Asked for his opinion for this article, Renier T. Brentjens, MD, PhD, Director of Therapeutics and Associate Member in the Leukemia Service at Memorial Sloan Kettering Cancer Center, said, “This proof-of-principle study demonstrates that T cells can root out and get rid of cervical cancer. It is yet another example of the treatment of solid tumor patients with metastatic disease -- some of whom, by definition, are incurable. Yet, these researchers were able to expand a viral protein expressed by cervical cancer and completely eradicate the disease.”
Hinrichs cautioned that the treatment is still experimental and is associated with significant side effects -- “We also need to explore why this therapy worked so well in certain women, and not in others,” he said.
Metastatic cervical cancer, which is caused by HPV, leads to approximately 4,000 deaths in the U.S. each year. “Chemotherapy is not curative and rarely provides durable palliation,” he said. The median survival with the two standard first-line therapies -- chemotherapy and a combination of chemotherapy and bevacizumab -- is 13 and 17 months, respectively; and there are no second-line treatments that extend survival.
Although the HPV E6 and E7 oncoproteins would appear to be attractive therapeutic targets for immunotherapy, clinical trial results have been disappointing, Hinrichs continued. “Adoptive T cell therapy is an emerging immunotherapy platform, but the study in epithelial cancers has been limited. This is the first example in an epithelial cancer.”
HPV-targeted adoptive T cell therapy essentially augments the natural immune response to HPV in the tumor. A customized treatment was created for each patient by culturing T cells harvested from the patient’s tumor, testing the cells for reactivity against the HPV E6 and E7 antigens, and preferentially extracting and then expanding the reactive cultures. The patient then receives a single infusion of tumor-infiltrating lymphocytes, followed with aldesleukin dosed to tolerance.
In the study, 9 patients, ranging in age from 30 to 59, received adoptive T cell therapy. Two patients had a complete response and one had a partial response, with a 39 percent reduction in tumor volume, that lasted months; the remaining six patients had progressive disease.
Hinrichs said that one of the complete responders is a 36-year-old woman with HPV16-positive metastatic squamous cell carcinoma of the uterine cervix who had multiple tumor sites and had undergone three different cytotoxic chemotherapy combinations. Her response has now lasted 22 months.
The patient with a complete response had what Hinrichs called a very aggressive primary tumor refractory to chemoradiation whose disease had spread to her pelvis and distant sites. This 36-year-old patient had HPV18-positive adenocarcinoma cervical cancer and had complete regression at all sites, a response that at the time of the report had lasted 15 months.
The treatment was associated with serious side effects, Hinrichs reported. The most common severe adverse events associated with the therapy are hematologic effects that result from the conditioning regimen, which consists of lymphocyte-depleting chemotherapy of cyclophosphamide and fludarabine. All patients had suppressed blood counts and bone marrow counts; and about half of the patients have febrile neutropenia.
“The cells themselves do not seem to cause any autoimmunity,” he noted, adding that all the toxicities are reversible. With only a single infusion, “it’s a little bit more tolerable to handle intense toxicities for just one treatment,” he said.
During the question-and-answer period of the news briefing, Hinrichs said this form of adoptive T cell therapy does not pose the danger of generating the “cytokine storm” seen in chimeric antigen receptor (CAR) T-cell therapy. In CAR T-cell therapy, T cells infused into the patient expand and release cytokines that cause fever, hypotension, nausea, and other symptoms that can be severe. The key difference, Hinrichs said, is that the tumor-infiltrating lymphocytes used in HPV adoptive T cell therapy are generated from naturally occurring T cells in the tumor, in contrast to those composed of the genetically engineered T cells used in CAR T-cell therapy.
Hinrichs said that with such promising results, the team now plans to recruit 35 patients for an expanded study. The same study is also exploring adoptive T cell therapy for treatment of other HPV-related cancers, such as throat cancer and anal cancer. An increasing number of medical centers working on cellular therapies now offer adoptive T cell therapy, he said.
At his ASCO presentation, Hinrichs concluded: “Durable, complete tumor regression can occur following a single infusion of HPV-targeted tumor-infiltrating T cells. An immunotherapy can induce regression of cervical cancer. Adoptive T cell therapy can mediate regression of an epithelial cancer. Continued study of HPV tumor-infiltrating T cells for patients with metastatic cervical cancer is warranted.”
At the news briefing, the designated ASCO expert, Don S. Dizon, MD, Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, commented: “Because of the association between cervical cancer and the HPV virus, adoptive immunotherapy is a promising approach. These preliminary data demonstrate not only the viability of this approach, but that gains in survival can be realized in a cancer where patients have little to no effective treatment options and where median survival is usually less than two years.”
Also very positive, the moderator of the news briefing, Steven O’Day, MD, Clinical Associate Professor of Medicine at the University of Southern California Keck School of Medicine, said, “Young women who have failed to respond to chemotherapy can activate T cells and produce a durable response. This approach, well-studied and established in select melanoma patients, can now be moved to the HPV virus to tease out T cells to the virus that provoke a response, expand the T cells, and give the tumor-infiltrating T cells back to the patient. The study has implication for other solid tumors, such as head and neck cancers, as well.”
Brentjens said that to achieve a higher overall response rate, the researchers will need to identify why some patients did not respond, and correct for that. The low response rate could be due to the quality of the T cells or how long they persist, he speculated. “We can work on fixing such problems by taking the successes and looking at the non-responders to see the differences. How cells are cultured or expanded can have a significant difference in response.
“The success in metastatic cervical cancer bodes well for adoptive immunotherapy moving forward in solid tumors. The goal is to produce a frontline therapy for cancer that one day replaces more toxic chemotherapy.”
To extrapolate this technology to cancers that are not virally induced, however, may be more difficult, he said. “In principle, it should be possible. Where we cannot generate and manipulate a patient’s own T cells, another way to overcome the problem may be to use CAR T cells.”
The Discussant for the presentation, John Timmerman, MD, Associate Professor in the Department of Medicine, Hematology/Oncology, at UCLA's Jonsson Comprehensive Cancer Center, discussed harnessing immunity to those patients who are challenged by deletion/tolerance of high-affinity T cells. The choice of the tumor antigen is very important, he noted.
“Targeting of a viral or tissue-specific antigen by T cells can lead to durable tumor remissions, with several impressive complete responses in Hinrichs’ study. It requires a lot of work to manufacture T cells with the specificity for these well-chosen antigens to achieve the optimal effects.”
Monday, July 07, 2014
BY MARK FUERST
CHICAGO -- After first-line therapy for follicular lymphoma, positron emission tomography (PET) status is strongly predictive of survival, and use of PET-computed tomography (CT) rather than contrast-enhanced CT scanning should be considered the new gold standard for response assessment in clinical practice. That was the conclusion of researchers presenting a pooled analysis of centrally reviewed scans in three multicenter studies, reported here at the American Society of Clinical Oncology Annual Meeting (Abstract 8502). Other experts, however, still question the overall value of imaging for such patients due to the limited benefits and potential risks.
Although follicular lymphoma mostly has an indolent natural history, there are still about 15 percent of patients who die within five years, said Judith Trotman, MD, Associate Professor of Medicine at the University of Sydney, who reported the new data. “High-risk FLIPI/FLIPI-2 scores alone fail to identify these patients. I share your frustration in the limits of CT research trying to crystal-ball predict overall survival. Despite the recommendations against routine use of PET-CT for follicular lymphoma in the 2007 International Harmonization Project criteria [JCO 2007;25:579-586], it is commonly used in response assessment.”
She noted that the predictive value of 18F-FDG PET-CT in response assessment after induction rituximab-chemotherapy for advanced-stage, symptomatic follicular lymphoma was recently reported in three trials. To provide more precise survival estimates from a larger patient cohort with longer follow-up, she and her colleagues conducted a pooled analysis of centrally reviewed scans of those three studies to identify the best cut-off points for survival when applying the increasingly adopted 5-Point Scale for response assessment of FDG-avid lymphoma.
Patient data and conventional CT-based response assessment were recorded for all patients undergoing central PET review in the prospective multicenter GELA (PRIMA and PET Folliculaire) and FOLL05 studies. PRIMA was a retrospective analysis of local PET interpretation within a prospective study with independent CT assessment of 122 patients. Results were confirmed by independent scan review of 61 patients.
FOLL05 was a retrospective analysis of local PET reports within a prospective study with local CT assessment of 202 patients; and PET Folliculaire was a prospective standardized PET acquisition/assessment in accordance to the 5-Point Scale with local CT assessment of 106 patients.
Scans were assessed independently by three reviewers applying the standardized 5-Point Scale. PET status with a score of 3 or 4 or more was compared with patient characteristics, CT-based assessment and survival endpoints of progression-free survival (PFS) and overall survival (OS). Only scans of sufficient quality for central review were accepted.
A total of 246 patients, median age of 56, were reviewed for post-induction PET-CT. Three-quarters of the patients received R-CHOP, and 15 percent had rituximab maintenance therapy. PET was performed a median of 30 days after the last chemotherapy.
Trotman reported that of the 246 scans performed at the end of the induction immunochemotherapy, about one-quarter were positive, with a cut-off of 3 or more (FDG uptake was more in the mediastinum), and about 17 percent with a cut-off of 4 or more (moderately greater in the liver). Patient and baseline disease characteristics did not differ significantly between PET-positive and PET-negative patients.
With a median follow-up of 55 months, the CT and bone marrow-based overall response rate was 96 percent, including about half that were complete responses (CR). “Both PET cut-offs were highly predictive of PFS and OS, with a cut-off of 4 or more points being most reproducible and discriminatory,” Trotman said. There was no difference in the individual baseline characteristics of PET-negative or PET-positive patients with either cut-off. A FLIPI (Follicular Lymphoma International Prognostic Index) score of 3 to 5 was associated with PET-positive status. “There was excellent concordance between post-induction CT and PET status,” she said.
Using these cut-offs, the hazard ratios for PFS and OS of PET-positive versus PET-negative patients were found to be 3.9 and 6.7, respectively. For PET-positive patients, the four-year PFS rate was 23.2 percent versus 63.4 percent in those who became PET-negative. The four-year OS rate was 87.2 percent versus 97.1 percent.
“Conventional CT-based response--CR/CRu versus PR--was weakly predictive of PFS, but not OS,” she said.
“In conclusion, this independent review of 246 scans and a median follow-up of 4.6 years after first-line rituximab-chemotherapy for follicular lymphoma confirms that post-induction PET-CT status is strongly predictive of PFS/OS. When performing PET-CT, conventional CT assessment provides limited additional value. PET-CT applying the 5-Point Scale should be considered the new gold standard for therapeutic response assessment in clinical practice.”
She stated that post-induction PET-CT is a platform to study response-adapted therapy: “Achieving PET-negative status can better assure patients, especially those otherwise in CRu or PR. The inferior survival of patients remaining PET-positive compels us to study PET-response-adapted approaches.”
Concerns from Discussant
The Discussant for the study, Christopher R. Flowers, MD, Associate Professor of Hematology and Medical Oncology at Emory University, said it is important to note that only scans of sufficient quality for central review were used in the study. “The response rate is quite high. Those who had a poor response had progressive disease. The response rate was high using PET as well. PET-positive scans with a score of 4 or more independently predicted PFS and OS in multivariate analysis.”
Similar results had also been seen in the U.S. National LymphoCare Study of 394 patients, with PET after rituximab induction therapy being predictive for PFS and OS, while CT could predict only PFS, Flowers continued.
He questioned whether this PET population was unique: “The behavioral characteristics are different from the broader population of follicular lymphoma patients. Those with stable disease fared poorly.”
He also wondered whether the results could be generalized to other regimens, including those that are commonly used, as well as rituximab and bendamustine plus other novel agents that will appear in years to come. “It is still unclear how PET clearance behaves in the broad population that receives maintenance therapy. How can PET be used to tailor therapy for follicular lymphoma?”
When Is Right Time?
Commenting on the study for this article, Mikkael Sekeres, MD, OT’s Clinical Advisory Editor for Hematology/Oncology, Director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Center, said: “When is the right time to get a PET scan in follicular lymphoma? This is a slow-growing cancer. It is interesting to correlate PET-positive and PET-negative scans following first-line therapy for OS. But is the test finding what it is supposed to find? There should be some demonstrable effect on management. How much are we spending on PET scans for cancer when there is no impact on outcome or alteration of surgical approaches?”
Sekeres added, “It is provocative to show that PET-positive scans can predict survival, but would you send a PET-positive patient for transplant? If not, then the patient should not get a PET scan at the end of first-line therapy. If we still follow the same paradigm, why do PET scans?”
In answer to a similar question from the audience after her presentation, Trotman responded: “Early follow-up of follicular lymphoma is important. R-CHOP patients have a median PFS of only 10 months. If I was treating a patient who was PET-positive, I would see that patient more frequently than a patient who is PET-negative.”
PET Scans and Transplantation
Another reason to do PET scans may be to avoid sending patients for autologous stem cell transplantation (ASCT), said René-Olivier Casasnovas, MD, of Hospital Le Bocage in Dijon, France, who presented a study at the meeting about using a PET-driven consolidation strategy in patients with high-risk diffuse large B-cell lymphoma (DLBCL) (Abstract 8503).
He noted that the GELA (Groupe d'Etude des Lymphomes de l'Adulte – i.e., Study Group of Adult Lymphoma) standard for young patients with high-risk DLBCL (an age-adjusted International Prognostic Index [aaIPI] score of 2-3) is rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) induction plus consolidative BEAM and ASCT.
“R-CHOP induction might be as efficient, and possibly less toxic, as R-ACVBP,” he said. “Also, patients who have a negative interim FDG-PET after two or four cycles of induction chemotherapy have a better prognosis. Early PET-negative patients with high-risk DLBCL may not need first-line ASCT.”
In untreated DLBCL, about half the patients who only receive rituximab chemotherapy will survive, versus about three-quarters of those who go on to have a transplant.
The study he reported was a Phase II randomized trial designed in 2007 to compare the dose-dense intensive regimen of R-CHOP14 with the standard dose-dense regimen of R-ACVBP14. Eligible patients were ages 18 to 59 who had previously untreated CD20+ DLBCL and an aaIPI score of 2-3.
Patients were randomly assigned to four cycles of either R-ACVBP14 or R-CHOP14 induction. Consolidation treatment was driven by centrally reviewed PET assessment after two (PET2) and four (PET4) induction cycles.
Patients classified as PET2-/PET4- received a sequential immunochemotherapy consolidation. Those who were PET2+/PET4- underwent ASCT. PET4+ patients were considered as not responding to induction treatment and were eligible for salvage therapy.
The primary endpoint was to evaluate the complete response rate after four induction cycles. The 222 patients (median age of 46) were randomized to receive either R-ACVBP (114 patients) or R-CHOP (108 patients). Virtually all had stage III/IV disease and elevated lactate dehydrogenase (LDH) levels, and one-quarter had an ECOG status of 2 or more.
After induction treatment, 47 percent of the R-ACVBP arm and 39 percent of the R-CHOP arm patients had a CR. PET2 and PET4 were negative in 30 and 53 percent of patients in the R-ACVBP arm, and 25 and 40 percent or patients in the R-CHOP arm, respectively. There were about one-quarter PET2-/PET4- patients in both arms.
Patients allocated to ASCT received the planned treatment in 83 percent of cases. Virtually all of those allocated to rituximab-chemotherapy received the planned treatment. Due to more frequent PET4+, patients in the R-CHOP arm more often received salvage therapy as post-induction treatment (39%) than did patients in the R-ACVBP arm (27%).
With a median follow-up of 45 months, event-free survival (EFS) was slightly higher in the R-ACVBP group (43%) than in the R-CHOP group (31%). Both four-year PFS and OS were similar for both groups of patients (75% and 83%, respectively).
In conclusion, Casasnovas said, “The primary objective was not reached due to missing bone marrow reassessment in the R-ACVBP arm. The better EFS in the R-ACVBP arm is related to a better metabolic response compared with R-CHOP. PFS and OS were similar in both arms, but after a higher frequency of salvage therapy in the R-CHOP arm. So, the PET-guided strategy may equalize the efficacy observed between the two arms. PET2 negativity allowed sparing ASCT in one-quarter of these high-risk patients with no risk of the disease control.”
The trial shows that a PET-driven treatment of high-risk DLBCL patients is feasible in a multicenter trial setting, he continued, and based on PET visual criteria at four cycles, the CR rate was higher in the R-ACVBP arm and salvage was more frequently used after R-CHOP, possibly explaining similar PFS and OS in the two induction arms.
Flowers, who was also the Discussant for this study, said: “PET-positive regions should be confirmed by biopsy. This is a cautionary tale. Surveillance imaging in NHL is commonly recommended by guidelines, but the use of imaging is being questioned due to limited benefits and potential risks. In general, studies show scan-only relapse rates in survival are relatively infrequently detected by PET only, with one to eight percent survival seen detected in isolated relapse.”
In addition, Flowers said, lifetime cancer mortality is increased for patients who undergo CT scans. “The five-year cumulative probability of lymphoma is important to consider even though the risk is quite low.”
There are alternatives to surveillance imaging, he stressed: “For example, use of absolute lymphocyte count [ALC] after completing therapy and in the follow-up period has predicted relapse. ALC/absolute monocyte count may also predict relapse,” and elevated LDH in DBLCL patients in remission has be shown to have a positive predictive value of only 14 percent.