ASCO Annual Meeting Spotlight
Key news updates from the ASCO Annual Meeting
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.
Sunday, July 06, 2014
BY MARK FUERST
CHICAGO -- Several novel agents may represent a paradigm shift as they appear to fill the unmet need for effective treatments of patients with chronic lymphocytic leukemia (CLL) positive for del(17p) and other adverse prognostic factors, according to new research reported here at the American Society of Clinical Oncology Annual Meeting.
The natural history of CLL is highly variable, with a median survival from diagnosis of more than 10 years in low-risk patients to two years in high-risk patients, noted Jeff Sharman, MD, Medical Director of the Hematology Research Program at US Oncology Research.
“New therapies are needed for high-risk, relapsed CLL patients, especially those who are unfit for chemo-immunotherapy,” he said in an interview: “CLL therapy is essentially changing completely because of the development of tyrosine kinase inhibitors [TKIs]. Cytotoxic therapy is going to be challenged for efficacy.”
Currently, about 30 percent of CLL patients in the United States receive single-agent rituximab, he noted. Frontline fludarabine, cyclophosphamide, and rituximab therapy in the del(17p) population shows a complete response of five percent and a median progression-free survival (PFS) of less than two years.
Idelalisib is a potent and selective inhibitor of PI3Kδ, which is critical for activation, proliferation, and survival of B cells and their homing and retention in lymphoid tissues. At the ASCO meeting, Sharman reported on the results from a Phase III, randomized, double-blind, placebo-controlled trial of idelalisib in combination with rituximab in 220 high-risk, relapsed CLL patients (Abstract 7011).
Samples for del(17p), del(11q), TP53 mutation, IGHV mutation, ZAP70 and CD38 expression, and β2-microglobulin were collected prospectively and tested using standard methods. Patients were stratified based on the presence of del(17p) and/or TP53 mutation, and on IGHV mutational status.
About one-quarter of the patients had del(17p), and slightly more than one-third had TP53 mutations. More than 80 percent were IGHV unmutated. The endpoints evaluated in the high-risk subpopulations in the preplanned first interim analysis include PFS and overall response rate (ORR).
The ORR was significantly higher in the idelalisib-plus-rituximab group (80.7%) compared with the placebo-plus- rituximab group (12.5%). Idelalisib plus rituximab retained robust efficacy across all high-risk subpopulations, he reported.
“Importantly, idelalisib plus rituximab achieved 76.5 percent ORR and PFS HR 0.13 in the highest-risk patients who were positive for both del(17p) and TP53 mutation, compared with 80.4 percent ORR and PFS HR 0.17 in those who had neither present.”
The main adverse events were diarrhea, pneumonitis, and abnormal liver function tests. “Across the database, half the patients who discontinued were, after dose reductions, able to restart treatment,” Sharman said. “The longest follow-up is four and a half years. We don’t know how patients will do if they stay on the drug for 15 years, or how long they will stay on it. Novel long-term toxicities certainly will evolve as we monitor patients longer.
“These results confirm the retained robust efficacy of idelalisib in high-risk CLL subpopulations and identify idelalisib as a potentially important novel treatment for all CLL patients, regardless of risk factors.”
The trial was terminated early because of an overall survival (OS) benefit in the idelalisib group. “The study was not powered for survival, but the results showed a benefit,” he said. “The effect of therapy, including survival benefit, accrues to patients with high-risk markers, including del(11q), del(17p), and IGVH, who appear to fare in a way similar to that of patients without high-risk markers.
“With the dramatic benefit in quality of life, PFS, and OS, doctors will have to prescribe idelalisib,” Sharman said. “The patient community is aware of the drug and will demand them to prescribe it.”
Similar data sets with similar TKIs will appear shortly, he predicted. “There will be cross-trial comparisons. Genomic markers will find the right subpopulations to treat. In certain populations, it may prove to be better than chemotherapy alone.”
Future studies will compare idelalisib against chemotherapy. “The next step is to test bendamustine plus rituximab with or without idelalisib, which is proceeding in clinical trials,” he said. “Looking into the future, two years from now when ibrutinib and idelalisib are approved for CLL, the majority of CLL patients requiring therapy will get some TKI either alone or in combination with other agents, such as rituximab or bendamustine.”
The Discussant for the study, Javier Pinilla-Ibarz, MD, of H. Lee Moffitt Cancer Center and Research Institute, said, “In the more heavily pretreated population, we see a dramatic benefit with the addition of idelalisib with rituximab. The IGHV-mutated patients show a dramatic effect.”
He added: “In the CLL world, we are happy to see so many drugs coming to the clinic. Second-generation monoclonal antibodies will also be of more importance. Immune therapy may have a role in combination with these drugs. We need to understand toxicity and how to sequence or combine these inhibitors.”
This includes adding in Bcl-2 inhibitors, such as ABT99. “Because of profound immune system suppression, lenalidomide and PD1 or PDL1 monoclonal antibodies may be important tools to incorporate into the treatment of these patients,” he said.
In another study reported at the meeting, single-agent ibrutinib continued to be effective three years after initiation of therapy in patients with CLL/small lymphocytic leukemia (SLL), including those with deletion 17p disease (Abstract 7014).
CLL/SLL is generally very responsive to chemo-immunotherapy, said Susan O'Brien, MD, Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, who reported the data. “However, relapses occur, and resistance develops. In particular, del(17p) is associated with poor outcomes using all currently available treatments. Effective targeted therapies are needed.”
The independent analyses she presented were based on all patients treated from first dose on the first study until data cut-off on the long-term follow-up study.
Patients in the study received 420 or 840 mg of ibrutinib daily. Included were 132 patients, median age of 68; 31 patients had not received previous treatment and 101 had relapsed/refractory disease. Slightly more than one-quarter of the patients had del(17p) and a similar amount had del(11q). The relapsed/refractory patients with del(17p) had a median of four prior therapies.
The updated best overall response rate by independent review was 78 percent for all-treated patients, including about 84 percent for previously untreated patients, 76 percent for of the relapsed/refractory patients, and 56 percent for relapsed/refractory patients with del(17p), she reported.
Additionally, five relapsed/refractory patients, two with del(17p), had a best response of partial response (PR) with lymphocytosis.
“Five of six patients who received prior idelalisib responded to ibrutinib,” O’Brien said. Two of the five responders continue treatment, with one additional patient moving on to stem cell transplant.
The median duration of response was not reached for all-treated patients, and was 25 months in patients with del(17p). The median time on study was 29.4 months for all-treated patients, and 27.3 months for relapsed/refractory patients with del(17p).
The median time to best response was 7.3 months, she said. More than 90 percent of patients who achieved a partial response with lymphocytosis converted to a better response. “The best response to ibrutinib improves over time.”
The 30-month PFS rate was 96.3 percent in the previously untreated group and 68.4 percent in the relapsed/refractory group. The 30-month overall survival rates were 96.6 and 79.9 percent, respectively. The median PFS and OS have not been reached, she said.
More patients receiving prior therapy experienced serious or grade 3 or higher adverse events, which decreased after one year on treatment, O’Brien noted. The most common adverse events were hypertension, pneumonia, and neutropenia. No new safety signals were observed in long-term follow-up. About two-thirds of patients remain on treatment with ibrutinib.
In conclusion, O’Brien said, “Single-agent ibrutinib leads to rapid and durable responses, and the median duration of response has not been reached. Ibrutinib therapy was well-tolerated, allowing for extended dosing. Continued treatment in the extension study shows that 64 percent of patients remain on single-agent ibrutinib.”
The Discussant for the study, Nicole Lamanna, MD, Associate Clinical Professor of Medicine in the Hematologic Malignancies Section of New York-Presbyterian Hospital, said, “The data is holding up well. Adverse events decline with time.
Most adverse events leading to study discontinuation are early—10 percent. Responses are rapid with a high ORR, which continues to improve the longer patients are on therapy. This data will change clinical practice.”
She noted that 42 percent of relapsed/refractory patients came off therapy. “There is a need for additional studies in this patient population and continued evaluation of mechanisms of resistance,” she said. “Can these patients be salvaged with other novel agents? We are eager to see long-term updates and determine whether any new or late-term toxicity issues may arise the longer patients are on oral therapy.”
Ibrutinib versus Ofatumumab
In another study, ibrutinib was compared with ofatumumab in CLL/SLL relapsed/refractory patients in a randomized, Phase III trial (Abstract LBA7008). Patients who had not responded to one or more prior therapies received 420 mg of oral ibrutinib daily (195 patients) until disease progression or intravenous ofatumumab at 300 or 2,000 mg for 12 doses (196 patients).
After a median follow-up of 9.4 months, “ibrutinib significantly lengthened PFS--median not reached--compared with use of ofatumumab (8.1 months), and significantly improved OS--median also not reached--compared with ofatumumab,” said John Byrd, MD, Professor of Medicine and Medicinal Chemistry at Ohio State University.
The ORR was significantly higher with ibrutinib (42.6%) than with ofatumumab (4.1%). Similar effects were seen in del(17p) and purine analog refractory subsets.
In conclusion, Byrd said: “Ibrutinib significantly improved survival and response as compared with ofatumumab. The impact of ibrutinib on PFS was observed irrespective of baseline clinical characteristics or molecular features.”
He noted that the overall survival benefit was observed despite crossover of 57 patients after confirmed progression.
He said toxicities were considered manageable and did not frequently result in dose reduction (needed by 4% of patients) or treatment discontinuation (also 4%), with 86 percent of patients continuing on ibrutinib.
“This study validates ibrutinib as an effective new single-agent therapy for CLL/SLL patients,” Byrd said.
In her Discussant remarks for this study, Lamanna said that the results overwhelmingly favor ibrutinib over ofatumumab. “Adverse events are similar between the two. It is important to keep in mind with ibrutinib and probably other oral agents that despite well-tolerability, patients report adverse events for a prolonged period of time given the continuous treatment versus the intravenous counterpart. This study represents a treatment paradigm shift for patients with relapsed CLL.”
Sunday, July 06, 2014
BY MARK FUERST
CHICAGO – A large, multicenter study confirms the significant single-agent activity of blinatumomab in difficult-to-treat patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).
Reporting the study here at the American Society of Clinical Oncology Annual Meeting (Abstract 7005), Max S. Topp, MD, of the University Hospital of Würzburg in Germany, said that outcomes are poor for adults with relapsed/refractory ALL, with median overall survival typically five to eight months, and that blinatumomab, an investigational bi-specific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19-expressing target cells, has shown anti-leukemia activity in this group of patients.
He noted that in a previous exploratory study of 36 adults with relapsed/refractory B-precursor ALL, more than two-thirds of patients had a complete remission (CR), and median relapse-free survival (RFS) was 7.6 months and median overall survival (OS) was 9.8 months. About 17 percent of patients had to have dose interruptions or discontinuations due to neurologic events.
At the ASCO meeting, Topp presented the results of a large, confirmatory Phase II study to evaluate blinatumomab’s efficacy and toxicity The study enrolled 189 patients, median age of 39, with Philadelphia chromosome-negative ALL who, less than 12 months before, had their first relapse and were refractory to post-hematopoietic stem cell transplantation (HSCT). More than one-third of the patients had at least two salvage therapies.
Blinatumomab was given continuously through intravenous infusion for four weeks on and two weeks off for up to five cycles. Cycle 1 included 9 μg per day of blinatumomab on days 1-7, and then 28 μg per day. Patients received blinatumomab for a median of two cycles. The primary endpoint was CR or CR with partial hematological recovery (CRh) within the first two cycles.
A total of 43 percent of patients achieved a CR or CRh. The majority of responses (80%) occurred within the first cycle. CRs/CRhs were seen in all subgroups, but were more prominent in patients with less than 50 percent bone marrow blasts, Topp reported.
Median RFS and OS were 5.9 and 6.2 months, respectively. In a landmark analysis, after two treatment cycles overall survival was 9.9 months among patients who achieved a CR/CRh.
Regardless of causality, the most frequent adverse events were pyrexia (occurring in 59% of patients), headache (35%), and febrile neutropenia (29%). The most frequent grade 3 or higher adverse events were febrile neutropenia (26%), anemia (15%), and neutropenia (15%); two percent had grade 3 or higher cytokine release syndrome (CRS).
The most common grade 3 or higher nervous system disorders were headache, encephalopathy, and ataxia. Only three patients had grade 5 adverse events considered treatment-related, including sepsis and candida infection.
Twenty eight patients died, but 27 of them did not have a CR/CRh while on the study, Topp noted. One patient died of a fatal adverse event after relapse following an initial CR/CRh.
In conclusion, he said, “the present study confirmed the anti-leukemia single-agent activity of blinatumomab in a difficult-to-treat population with relapsed/refractory ALL, with a CR/CRh rate of 43 percent. Responses were observed in all subgroups of patients. Adverse events were consistent with previous blinatumomab treatment experience in the setting of relapsed/refractory ALL.”
Fatal events were only seen in those with uncontrollable leukemia, he added.
Topp noted that a randomized, open-label Phase III trial of blinatumomab in this patient population is currently underway.
Asked for his opinion of the study, Mikkael Sekeres, MD, Director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee and OT’s Clinical Advisory Editor for Hematology/Oncology, said, “This BiTE antibody is an important treatment. This trial adds to data and confirms what has been seen previously. In adult, relapsed/refractory Philadelphia-negative B-cell ALL, we typically see response rates of 30 to 40 percent for CR or near CR.
“This report of a CR of 43 percent for single-agent therapy is a high response rate in patients who were previously treated -- particularly when a large percentage of them had prior salvage therapies.”
Discussant: Blinatumomab Has Been Around for a While
The Discussant for the study, Crystal Mackall, MD, Head of the Pediatric Oncology Branch of the National Cancer Institute, said, “Blinatumomab is not new to the community. We were impressed with first clinical trial in 2011 that demonstrated an incredible 80 percent rate of minimal residual disease [MRD]-negative CR in adults with B-cell ALL.
“These patients were molecularly refractory and largely had MRD. Many experienced prolonged survival, some following consolidation with HSCT. This is an agent that is able to eradicate chemo-resistant leukemia. This new trial is the first opportunity for us to see what blinatumomab can do in patients with high-burden ALL. It found a quite impressive 43 percent CR rate, and 82 percent had MRD negativity, which is a deep response.”
She noted that the responders with less than 50 percent bone marrow blasts had superior survival: “This agent is active in inducing remission, but has not shown ability to be curative as a single agent. The response rate varies greatly depending on the burden of leukemia. Those with greater than 50 percent leukemia had a lower response rate. If you’re thinking about using blinatumomab, probably you would want to use it in patients with a lower burden of disease.”
Toxicity was “quite acceptable,” Mackall continued, with most of the toxicity reported due to the underlying leukemia. She noted that cytokine release syndrome (CRS) is not uncommon with the use of blinatumomab, and said that because CRS tends to be worse with higher burden disease, it was surprising that there was actually not even more CRS in the patients in the study.
This diminished incidence may be related to alterations in dose, she speculated: During the first week, patients received a lower dose of blinatumomab than in the original study. “Does this offset efficacy? Would a higher dose be more efficacious or tolerable in patients with higher disease burden?” she asked.
Regarding neurotoxicity, Mackall said it was reassuring it was all reversible: “Neurotoxicity with blinatumomab may be related to CRS. Reversible neurologic toxicity is commonly associated with CRS from CAR T cell therapy. Essentially everyone -- 20 of 24 patients -- had their neurologic abnormalities resolved.”
She said she wondered what residual neurotoxicity there might be that did not resolve, but said it was likely reversible and would not pose a problem for this drug.
“Emerging data seem to clearly demonstrate that blinatumomab serves as an effective bridge to transplant in patients with chemo-resistant B-ALL,” Mackall said. “The data suggest that it is more effective in lower-burden disease. My guess is that the ongoing registration trial will be able to replicate these impressive response rates.
“The overlying question is whether blinatumomab can achieve a cure in a significant fraction of patients,” she continued. “Many of these patients will require consolidation for a cure.” HSCT may not be an option for some older and heavily pretreated patients, she noted.
Looking at future uses of the drug, Mackall asked, “Could blinatumomab be used to improve cure rates or preclude the need for a transplant if it was incorporated into the upfront regimen? Could the drug be used preemptively after allogeneic transplant to prevent relapse?”
Combination of ALL Chemotherapy with Ponatinib
In another report at the meeting, a combination of chemotherapy with the tyrosine kinase inhibitor (TKI) ponatinib showed high response rates and indications that it may be an effective treatment for patients with Philadelphia-positive (Ph+) ALL (Abstract 7064).
The third-generation TKI ponatinib is a potent BCR-ABL inhibitor, said Susan O’Brien, MD, Professor of Medicine and Chief of the Section of Acute Lymphocytic Leukemia at the University of Texas MD Anderson Cancer Center, who reported the data.
“Ponatinib suppresses T315I clones, commonly causing relapse in Ph+ ALL. It has high activity and acceptable single-agent toxicity.”
Complete cytogenetic response (CCyR) rates range from 40 to 50 percent in patients who do not respond to use of two or three TKIs and in those with the T315I mutation, she explained. Combinations of ALL chemotherapy and ponatinib are likely to be associated with better response rates, lower relapse rates, and a higher likelihood of eradication of minimal residual leukemia.
For the study, she and her colleagues enrolled 37 newly diagnosed Philadelphia-positive ALL patients, median age of 51, into a Phase II study of a combination of hyperCVAD with ponatinib in frontline therapy. The patients received eight cycles of hyperCVAD every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1, and then continuously for the subsequent cycles.
Patients who had a complete response received maintenance with ponatinib at 45 mg daily with vincristine/prednisone monthly for two years followed by ponatinib indefinitely. Patients received a median of six cycles, and 12 patients are currently receiving maintenance in complete remission. “All patients were in CR after cycle 1,” O’Brien said. “CCyR rates were 94 percent after one cycle and 100 percent after two cycles.”
Virtually all patients (95%) achieved a major molecular response and nearly 75 percent had a complete molecular response (CMR). Similarly, almost all patients (97%) were MRD negative. Eight patients had an autologous stem cell transplant (ASCT) after a median of four courses.
Grade 3 or higher toxicities included infections during induction, increased liver function tests, thrombotic events, myocardial infarction, skin rash, and pancreatitis.
The results showed that with a median follow-up of 13 months, 31 patients are alive and in complete remission. The one-year progression-free survival rate is an estimated 100 percent and one-year overall survival is 86 percent.
At the last follow-up, O’Brien reported, seven patients are alive post-ASCT, and 15 patients on ponatinib are alive. Of the other nine surviving patients, seven were switched to dasatinib, one to imatinib, and one patient is no longer receiving treatment. “Due to the vascular events observed, some patients were switched to alternative TKIs,” she said. In the remaining patients, the ponatinib dose was modified to 30 mg daily during consolidation, with subsequent reduction to 15 mg in patients in CMR.
In conclusion, O’Brien said, “HyperCVAD with ponatinib is highly effective in patients with Ph+ ALL, with high molecular response rates and durable responses.”
Also commenting on this study, Sekeres said, “This large study looked at the newest TKI approved for chronic myeloid leukemia. Now ponatinib is being applied to ALL. It shows a high response rate in patients who don’t typically have high responses -- in particular, an extremely high CCyR rate.
“Ponatinib may represent a new standard in treating these patients. ALL experts need to think more about combining new agents with established therapies.”
Friday, July 04, 2014
BY RAMASWAMY GOVINDAN, MD
Co-Director, Section of Medical Oncology;
Professor of Medicine, Division of Oncology
Washington University School of Medicine
Several interesting lung cancer papers were presented at American Society of Clinical Oncology Annual Meeting. Following are some key presentations that may be of interest to practicing clinicians.
It is now widely recognized that response to epidermal growth factor tyrosine kinase (EGFR TK) inhibitors varies depending on the type of EGFR mutations. There are differences in outcomes even between the two common sensitive EGFR TK mutations. Those with exon 19 deletions do relatively better compared with those with L858R mutation with EGFR TK inhibitor (EGFR TKI)s in terms of response rates and progression-free survival.
A number of randomized studies have shown improved response rates and better progression-free survival when patients with EGFR-mutated non-small cell lung cancer (NSCLC) were treated with EGFR TKIs upfront compared with use of cytotoxic chemotherapy. However, no study has yet shown improved overall survival in patients with EGFR-mutated NSCLC in this setting. Updated results from LUX-Lung 3 and LUX-Lung 6 studies (Abstract 8004) revealed significant differences in outcomes between the two common sensitive EGFR TK mutation groups (exon 19 deletion and L858R) when treated with afatinib.
Both LUX-Lung 3 and LUX-Lung 6 studies randomized patients with previously untreated EGFR-mutant NSCLC to either afatinib or cytotoxic chemotherapy (cisplatin and pemetrexed in LUX-Lung 3 and cisplatin and gemcitabine in LUX-Lung 6). Based on the results of these two studies (primary endpoint: progression-free survival), afatinib has been approved for use in the frontline therapy of EGFR-mutant NSCLC.
The updated data presented at this meeting showed significant improvement (more than one year) in overall survival in patients with exon 19 deletion when treated with afatinib compared with chemotherapy (LUX-Lung 3: 33 vs. 21 months, HR 0.54, p=0.0015; LUX-Lung 6: 31 vs. 18 months, HR 0.64, p=0.0229). There was no improvement in overall survival in the L858R subgroup in either of these two trials when patients were treated with afatinib upfront. Though the combined analysis of patients with common mutations showed a modest (and statistically significant) improvement in overall survival in patients treated with afatinib, most of the benefit seems to be driven by the exon 19-deletion subgroup. Unfortunately there are no data available comparing erlotinib or gefitinib with afatinib in this subgroup.
A Japanese randomized phase II study (Abstract 8005) presented at this meeting reported significant improvement in progression-free survival in 154 patients with previously untreated EGFR-mutant NSCLC with the combination of bevacizumab and erlotinib compared with erlotinib alone (16 vs. 9.7 months, HR 0.54, 95% CI: 0.36-0.79, p=0.0015) with better outcomes in patients with exon 19 deletion compared with L858R.
Not surprisingly, the combination therapy was associated with greater incidence of grade 3 and 4 toxicities (chiefly, hypertension events). Addition of bevacizumab did not impact qualify of life measurably, however. Overall survival data were not available at this time.
These data are somewhat reminiscent of the BeTa trial, where this combination therapy showed some evidence of activity in the EGFR-mutant NSCLC subgroup. An ongoing study in the United States is evaluating this combination in patients with EGFR-mutant NSCLC (NCT01532089).
Three papers presented at this meeting highlighted the promise of the third-generation EGFR TKIs. Despite producing dramatic regressions in EGFR-mutated NSCLC, first-generation EGFR TK inhibitors such as gefitinib and erlotinib eventually become ineffective. AZD 9291 is a third-generation EGFR TKI effective against both “sensitive” (exon 19 deletion, L858R) and T790M involving EGFR TK in pre-clinical models. In a phase I study with two different cohorts, a dose-escalation one and an expanded cohort, the overall response rate was 51% among 177 patients (Abstract 8009). The response rate among 107 patients with centrally confirmed EGFR T790M was an impressive 64 percent, with an overall disease-control rate in this “difficult-to treat” patient population with no standard therapy of 94 percent. Even more strikingly, no dose-limiting toxicities were observed.
Given the fact that this is a mutant-selective inhibitor, normal tissue toxicities (rash and diarrhea) seen typically with the first-generation inhibitors were virtually absent. The response rate with this agent in the T790M-negative group was a modest 23 percent. However, the activity seen in patients in the EGFR T790M group is certainly encouraging.
A similar study used a different compound, CO-1686, a potent oral inhibitor of key activating and T790M resistance mutations and designed to spare wild-type EGFR signaling (Abstract 8010). In a phase 1/2 study of 72 patients, an overall response rate of 58 percent was reported in 40 patients with centrally confirmed EGFR T790M. Median progression-free survival was not reached and is estimated to exceed one year.
The third study reported a response rate of 29 percent and disease-control rate of 75 percent in 48 patients with T790M with HM61713, another EGFR- mutant selective inhibitor (Abstract 8011). Several ongoing clinical trials are now available for patients with EGFR-mutant NSCLC prior to and after therapy with first-generation EGFR TKIs. It is important to biopsy progressing lesions following targeted therapy to identify mechanisms of resistance. It may be possible relatively soon to identify the circulating tumor DNA for these” resistance” mutations.
Updated results from the ASCEND-1 trial of ceritinib (Abstract 8003) in advanced anaplastic lymphoma kinase (ALK+) NSCLC continued to show impressive activity of this agent regardless of whether patients had received an ALK inhibitor previously. Overall response rates were 59 percent for the entire group, 55 percent in those who had received a prior ALK inhibitor (mainly crizotinib), and 66 percent in those who had not received any prior ALK inhibitor.
The progression-free survival rates at one year were 39, 28, and 61 percent, respectively. An important practical point is that 59 percent of patients treated with ceritinib required at least one dose reduction. In a small group of patients (n=14) with measurable brain metastases, the overall response rate was 50 percent. A number of new- generation ALK inhibitors are being studied now in the clinic.
Advanced NSCLC--Biomarker unselected
Results of two large phase III studies in molecularly unselected patients with advanced NSCLC may be of interest to the practicing clinicians. The SQUIRE study (Abstract 8008) randomized patients with previously untreated squamous type NSCLC to cisplatin and gemcitabine or the same chemotherapy with necitumumab (antibody-targeting EGFR). The median overall survival improved from 9.9 months with chemotherapy alone to 11.5 months with the addition of necitumumab (HR 0.84, p=0.012), results were very similar to those of the FLEX study of cisplatin and vinorelbine with or without cetuximab (11.3 vs. 10.1 months, respectively, HR 0.87, p=0.04).
The REVEL study (Abstract LBA8006) randomized patients with advanced NSCLC in the second-line setting to docetaxel with either placebo or ramucirumab. There was an improvement in overall survival with the addition of ramucirumab to docetaxel compared with use of docetaxel alone (10.5 vs. 9 1 months, HR 0.857, p=0.0235). This is perhaps the first time a combination therapy with docetaxel has been shown to be beneficial (albeit, modestly). Unfortunately, there are no clear biomarkers to select patients for either one of these two novel agents.
Surgically resected NSCLC
The addition of erlotinib postoperatively in the RADIANT study following standard of care of therapy (surgery with or without adjuvant therapy) did not improve disease-free survival (primary endpoint) or overall survival in patients with stage IB-IIIA NSCLC whose tumors were “positive” for EGFR by immunohistochemistry (Abstract 7501). The median disease free survival was 48.2 months with placebo and 50.5 months with erlotinib (HR 0.90, p=0.3235).
Of 973 patients, only a small number of patients (n=161) had EGFR mutation. Though the median progression-free survival was superior with erlotinib (46.4 months) compared with placebo (28.5 months), these results were not statistically significant by the design of the study. Unfortunately, this study was not powered or designed to test the hypothesis that patients with EGFR-mutant stage IB-IIII NSCLC would benefit from erlotinib following surgical resection and standard postoperative therapy. A large national study (ALCHEMIST trial) being planned to address the role of molecularly targeted therapy in surgically resected EGFR-mutant NSCLC (with erlotinib or placebo) and ALK-positive NSCLC (crizotinib or placebo), will likely open for enrollment in late summer or early fall of this year.
I am pleased to note the emergence of a number of salvage therapy options for patients with EGFR-mutant and ALK-positive NSCLC. It is highly unlikely that we will make substantial gains with empiric combination therapies without a clearly identified set of biomarkers. I would urge my colleagues to genotype patients with NSCLC on a regular basis at the time of initial diagnosis and when possible at the time of relapse in clearly defined molecular subsets (EGFR mutant, ALK positive) following targeted therapies so that patients can be enrolled in appropriate clinical trials. I do not see a role for targeted therapies in patients with completely resected NSCLC in routine clinical practice.