ASCO Annual Meeting Spotlight
Key news updates and reports from the American Society of Clinical Oncology Annual Meeting.
Sunday, May 31, 2015
By Robert H. Carlson
Chicago--German researchers report from the results a randomized Phase III melanoma study that radical lymphadenectomy after positive lymph node biopsy does not prolong survival. As reported here at the American Society of Clinical Oncology Annual Meeting, with a median follow up of 34 months, 16.3 percent of patients under observation alone after excision of a sentinel lymph node with micrometastases died from melanoma, versus 15 percent in patients who had a radical lymphadenectomy (Abstract LBA9002).
“Based on our findings to date, complete lymphadenectomy cannot be recommended in melanoma patients with micrometastases in the sentinel nodes,” said first author Ulrike Leiter, MD, Consultant in Dermatologic Oncology at the University of Tübingen in Germany.
Speaking for the researchers in the German Dermatologic Oncology Group DeCOG-SLT trial, Leiter said the status of the sentinel lymph node is an important predictor of prognosis and recurrence and was included in the AJCC staging system in melanoma of one millimeter in tumor thickness or more.
In the DeCOG-SLT trial, 558 patients ages 18 to 75, with primary cutaneous melanoma tumors of at least 1 mm in thickness (excluding localization at the head and neck) were randomly assigned to observation (279 patients) or to radical lymphadenectomy (279 patients).
In the intent-to-treat groups of 233 patients under observation and 240 after radical lymphadenectomy, there were 38 (16.3%) deaths due to melanoma in the observation group and 36 (15%) in the lymphadenectomy group.
Total recurrences were 67 (28.7%) for observation versus 59 (24.5%) for radical lymphadenectomy; there were regional lymph node recurrences in 34 patients (14.6%) versus 20 (8.3%), respectively; and distant recurrences were 43 (18.6%) versus 42 (17.5%).
“We did not find any significant difference in distant metastasis-free survival--only 0.3 percent--80.4 percent for observation versus 80.1 percent for lymphadenectomy--between the two study groups at three years of follow-up,” the senior study author, Claus Garbe, MD, Professor in the Department of Dermatology at the University of Tübingen in Tübingen, Germany, said at an ASCO news conference.
“We cannot support the standard therapy, and we expect that the surgical praxis [practice] will change.”
Leiter said accrual was difficult, as only every third patients with a positive sentinel lymph node agreed to randomization, and the study took nine years to enroll the 483 patients.
Common Practice Challenged
In most of the world, including the U.S., a complete lymph node dissection is recommended for patients with melanoma who have a positive sentinel lymph node upon biopsy. Complete lymph node dissection increases the risk of infection, nerve damage, and lymphedema. According to the authors, lymphedema can occur in more than 20 percent of patients and persist long-term in five to 10 percent of patients.
“I think that our study is the beginning of the end of a general recommendation of complete lymph node dissection for patients with positive sentinel nodes,” Garbe said. “However, it is possible that this surgery may provide a smaller survival advantage than this study could detect. So, doctors may want to discuss this finding with their patients to help them decide whether this procedure is right for them.”
Following surgical dissection of the primary tumor, 483 patients with stage III melanoma and a positive lymph node biopsy were randomly assigned to observation only or to complete lymph node dissection. Patients in the observation group were monitored for disease recurrence with ultrasound every three months and CT/ MRI or PET scans every six months. Patients in the complete lymph node dissection group followed the same schedule of check-ups after that procedure.
Patients had a median follow-up of 35 months.
In the observation group, 14.6 percent of patients developed lymph node regional metastases compared with 8.3 percent in the complete lymph node dissection group. However, the differences in three- and five-year recurrence-free survival, distant metastases-free survival, and melanoma-specific survival were not statistically significant between the two groups, Garbe said, adding that based on the study design, a survival difference of 10 percent or greater between the two treatment groups was considered statistically significant.
Only patients with micrometastases in the sentinel lymph node were included in the study. Complete lymph node dissection should still be recommended for patients with clinically detectable macrometastases, the study authors said.
Garbe said another analysis of this study is planned in 2018, but he added that it is unlikely the overall findings of will change, because prior research has shown that approximately 80 percent of melanoma recurrences happen in the first three years after initial diagnosis.
Leiter said the much larger ongoing randomized Multicenter Selective Lymphadenectomy Trial (MSLT) II evaluating complete lymphadenectomy versus ultrasound observation is designed to detect a five percent difference in survival, versus the three percent difference in this DeCOG trial, but the final results from MSLT-II are not expected until 2022.
Discussant: Hard to Defend Not Discussing
Given these data, “I think it will be very hard to defend not discussing observation as an alternative to complete lymph node dissection,” said the Discussant for the study, Daniel G. Coit, MD, a surgical oncologist and Co-Leader of the Melanoma Disease Management Team at Memorial Sloan Kettering Cancer Center.
He said radical lymphadenectomy is currently standard practice for melanoma patients with a positive sentinel lymph node, despite a lack of robust clinical data supporting this approach and the significant morbidity of the procedure.
“At least 20 percent of patients with melanoma who undergo a radical lymphadenectomy experience grade 3 and 4 lymphedema that can take months to years to resolve,” he said. “Wound infection and nerve damage are also concerns, along with the additional cost of surgery.”
Although patients in the radical lymphadenectomy group had fewer recurrences in the lymph node basin--8.3 versus 14.6 percent--this did not translate into improved three-year relapse-free survival, he said. In fact, disease-free survival was virtually identical for both groups.
Coit said he would have like to see recurrence rates in the non-sentinel nodes. Proponents of this operation will cite fear of loss of control of the regional nodal basin, Coit said, which makes the data important.
He also asked:
· If nodal basin relapse was more common in the no-lymphadenectomy group and relapse-free survival was equivalent, what pattern of relapse was more frequent in the lymphadenectomy group?
· Should future trials of adjuvant therapy for patients with a positive sentinel lymph node require complete lymphadenectomy?
· How should the results of this trial impact the National Comprehensive Cancer Network guidelines for management of melanoma patients with a positive sentinel lymph node?
Conclude Long-standing Debate
The DeCOG-SLT study will likely change practice and conclude a long-standing debate about the role of complete lymph node dissection, experts said at the meeting.
“Up to now, what to do about a positive sentinel lymph node biopsy has always been a question: should we do a massive lymph node dissection in those patients?” said Gary Schwartz, MD, Chief of Columbia University Medical Center’s Division of Hematology & Oncology and Associate Director of the Herbert Irving Comprehensive Cancer Center.
“This study now suggests that that type of surgery, which is quite morbid and leaves people with massive arm or leg edema, is no longer necessary after the diagnosis of melanoma, that it will not improve the overall survival rate.”
The information from the lymph node is for staging, prognosis, and the risk of recurrence, he said. “If you go from node negative to node positive, survival is decreased dramatically. But if the sentinel lymph node biopsy is positive, do you need to take it to the next step and do a large groin dissection and face the associated problems with lymphedema that follow such a massive morbid operation?
“The data now show that despite the fact that the sentinel node is positive, taking out all the nodes does not improve survival. So why subject the patient to a massive node dissection?”
Schwartz said that much of what has been learned in breast cancer surgery is that less surgery is better, “and that’s what we’re seeing here.”
Of course, local recurrence may be impacted, he said, but if the disease occurs locally--in the groin, for example--the patient can undergo a second operation.
“But if there’s no difference whether or not you do a total lymph node dissection, and you’d only be left with cosmetic morbidity if you did, there’s no reason to do it at all.”
Long Assumed Optimal, Now Questioned
ASCO Expert Lynn Schuchter, MD, the moderator of the news conference, said this is the first study to offer solid evidence that many patients with melanoma don’t need extensive lymph node surgery.
“The findings should reduce the use of an approach that we have long assumed to be optimal,” she said. “This is great news for patients, who can forego extensive surgeries without compromising their survival chances.”
The new knowledge gained from this study will help spare thousands of patients with melanoma from unnecessary surgery and its significant side effects, she said.
Sunday, May 31, 2015
BY MARK FUERST
CHICAGO--Adding obinutuzumab to bendamustine more than doubles the duration of remission of patients with indolent non-Hodgkin lymphoma (NHL), according to an interim analysis of a Phase III, open-label trial presented at the American Society of Clinical Oncology Annual Meeting here (Abstract LBA8502).
“Obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, represents an effective treatment option for patients with relapsed/refractory, indolent NHL who are refractory to rituximab,” lead author Laurie H. Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency and Clinical Associate Professor at the University of British Columbia in Vancouver, said at an ASCO news conference.
Indolent NHLs are incurable with standard available therapies. The addition of the anti-CD20 antibody rituximab to chemotherapy, and maintenance therapy with rituximab, have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) in patients with indolent NHL. However, “patients with disease that is resistant to rituximab-based therapy have limited treatment options,” she said. “Bendamustine is effective in these patients, but remission duration is short--between seven and nine months.”
Obinutuzumab is a novel, glycoengineered anti-CD20 antibody that has shown activity in combination with bendamustine in preclinical studies. The drug is engineered to have higher efficacy and a higher direct cell death rate than rituximab, and has been shown to benefit rituximab-refractory patients as well as when added in with bendamustine, Sehn explained.
Previous research suggested that when monoclonal antibodies attach to the CD20 protein, some lymphoma cells die, and others appear to become more sensitive to chemotherapy. And while obinutuzumab has been tested in smaller clinical trials in various types of lymphoma, this is the first randomized Phase III trial to assess the potential benefit of obinutuzumab in patients with NHL.
The FDA recently approved obinutuzumab in combination with chemotherapy for patients with chronic lymphocytic leukemia (OT 2/10/15 issue).
For the study, called GADOLIN, patients were considered rituximab-refractory if they did not respond to either rituximab monotherapy or rituximab in combination with chemotherapy, or had disease relapse within six months of completing the last dose of a rituximab-based regimen (rituximab monotherapy or rituximab plus chemotherapy).
The study included 396 patients, median age of 63, with various types of NHL, the most common being follicular lymphoma. Bendamustine was administered in the standard dose of 120 mg/m2 on days 1 and 2 for up to six cycles in 202 patients. In the combination therapy arm, 194 patients received 90 mgm2 of bendamustine on days 1 and 2 plus standard obinutuzumab at a 1,000 mg flat dose on days 1, 8, and 15 of the first cycle and on day 1 for each successive cycle of chemotherapy.
Those patients who did not show progressive disease on the combination therapy then received obinutuzumab maintenance doses every two months for up to two years.
Clinical characteristics were comparable between the two groups, Sehn reported. “The patients had a high level of treatment resistance, with a median of two prior lines of therapies. More than 90 percent of patients in both groups were refractory to their last treatment, and the median time to the last treatment regimen was about four months in both groups.
Planned Interim Analysis
In a planned interim analysis, after an average follow-up of 21 months, patients in the combined group had significantly longer PFS compared with those who received bendamustine alone. The bendamustine group had a PFS of 14.9 months and the PFS was not yet reached in the combination group.
“We found a 45 percent reduction in the rate of progression with combined therapy,” Sehn said.
Progression-free survival as assessed by the researchers was 14 months in the bendamustine group and more than 29 months in the combination group--“a doubling of PFS with the combination,” she noted. The independent data review committee closed the trial early because it had met its primary endpoint of PFS.
Sehn noted that longer follow-up is needed to determine the potential overall survival benefit associated with obinutuzumab.
Safety Comparable Between the Two Groups
Importantly, safety was comparable between the two groups. Overall, the rates of adverse events, serious adverse events, grade 3 or higher adverse events, deaths, and withdrawals from therapy were similar in both arms of the study.
Low white blood cell counts and infusion-related reactions were slightly more frequent in the combination arm compared with the bendamustine arm. The rates of low platelet counts, anemia, and pneumonia were higher in the bendamustine-alone arm.
In the obinutuzumab-bendamustine and bendamustine-only arms, the most common hematologic adverse events were, respectively, neutropenia (35% vs. 29%) and thrombocytopenia (15% vs. 24%), and the most common non-hematologic adverse events were infusion-related reactions (69% vs. 63%), nausea (54% vs. 61%), fatigue (39% vs. 33%), and diarrhea (27% vs. 30%). No new safety signals were observed, she noted.
An adverse event that occurred during or within 24 hours after an infusion was considered to be related to any study drug.
In summary, Sehn said: “Obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, resulted in a statistically significant and clinically meaningful increase in PFS versus bendamustine alone. The safety profile of obinutuzumab plus bendamustine was as expected for the known safety profiles of the individual drugs, and no new safety signals were observed. The PFS improvement with obinutuzumab plus bendamustine is the first randomized evidence of benefit for a novel CD20 monoclonal antibody in rituximab-refractory indolent NHL.”
Sehn added: “Unfortunately, there is yet no cure for indolent lymphoma, so the overall goal of treatment is to increase the amount of time patients remain symptom-free and in remission. The fact that this new approach doubled average remission time marks a major step forward for our patients. Obinutuzumab may offer patients the chance to stay well for a significantly longer period of time, putting off the need for additional chemotherapy.”
In an interview, ASCO designated expert Merry-Jennifer Markham, MD, Assistant Professor of Medicine in the Division of Hematology & Oncology at the University of Florida in Gainesville, said: “Obinutuzumab is like a ‘super-rituximab.’ Most indolent NHL patients become refractory to rituximab. The response and PFS seen in this trial are robust, and the results are remarkable. This opens up the door for the possibility of more therapies to improve progression-free time substantially for these patients.”
Still, the obinutuzumab-plus-bendamustine combination should not yet be considered the standard of care, since the data are preliminary, she said. “It would be interesting to know about the results with longer maintenance, but obinutuzumab therapy has great potential.
“It is encouraging to see such impressive results for a novel anti-CD20 monoclonal antibody in a difficult-to-treat patient population such as those with rituximab-refractory indolent NHL. The fact that this approach stalled cancer progression by more than a year will be good news to patients, who urgently need additional treatment options.”
Sunday, May 31, 2015
BY ED SUSMAN
CHICAGO--More children are surviving childhood cancer now--and changes in treating their disease as children mean that their risk of a second cancer or heart disease in young adulthood is also diminished, researchers reported here at the plenary session of the American Society of Clinical Oncology Annual Meeting (Abstract LBA2).
In a remarkable study that included 34,033 children with a variety of childhood cancers such as leukemia, Hodgkin lymphoma, and Wilms tumor, researchers said that reductions in radiation therapy, x-rays, and chemotherapy have combined to reduce the risk of cancer, heart disease, and lung disease 15 years after the cancers have been cured.
Gregory T. Armstrong, MD, MSCE, the principal investigator of the Childhood Cancer Survivor Study and an associate member in the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, said: “We have shown, for the first time, that these survivors beyond the five-year time point are less likely to die of the long-term effects of cancer therapy and radiation therapy.
“This is a good-news story, which is not always the case with cancer survivorship stories,” he said in an interview.
“Our study follows kids who have hit the five-year time point. Clinically, as an oncologist, when we do that we will tell the patient: ‘Congratulations, you beat your cancer. You did a great job.’ And everyone assumes that beyond that, life is golden. The trouble is that beyond that, there are still real risks for survivors, and we have been showing that now for 20 years.
“We have learned how to use chemotherapy better and less,” he continued. “In Hodgkin lymphoma we are getting greater than 90 percent survival; in Wilms tumor we get greater than 90 percent survival; in acute lymphoblastic leukemia we are getting almost 90 percent long-term survival. In the last 20 years, a lot of fantastic clinical trialists have thought that maybe we can get away with less therapy. They did that, and they showed that five-year survival was fantastic.
“And now 20 years down the road, we can say, ‘Guess what? They are not dying of second brain tumors or second breast cancers or from heart disease from chemotherapy.
“From previous research we know that by the time someone is 25 years from their original cancer prognosis, 11 percent will have a second malignancy; 22 percent will have a second tumor--although not necessarily malignant. Similarly, for heart disease 11 percent have heart disease by age 40. These are soccer moms and business executives who are in the middle of their lives--and one in 10 is having heart disease. Those rates are too high,” he said.
News Conference Moderator
Jyoti D. Patel, MD, an ASCO spokesperson who moderated a news conference at which Armstrong discussed his study, said that despite tremendous advances, physicians still don’t always know when the benefits of aggressive therapy outweigh the possible side effects.
‘It’s clear that less aggressive therapy is paying major dividends for childhood cancer survivors,” said Patel, who is also Associate Professor of Medicine at Northwestern University Feinberg College of Medicine.
Stephen Hunger, MD, an ASCO designated expert and Professor of Pediatrics at Children’s Hospital of Philadelphia and the University of Pennsylvania, said: “This is really the first study to show definitively that the changes in treatment that we have made have led to decreased risk of late death.”
He noted in an interview that in some cases patients with childhood cancers get a second cancer later in life due to being dealt a bad genetic hand, but those patients are only a small minority of the cases. On the other hand, “clearly most of the cancers we seen in these survivors are related to chemotherapy or radiation therapy: For example, if you have received cranial radiation as a child, your risk of a brain cancer is higher than if you had not received cranial radiation as a child.
“We clearly knew we were increasing the cure rates in childhood cancer,” Hunger continued. “This study looked at patients treated in the early 1970s through the 1990s, focusing on patients who were alive five years after the initial diagnosis. The researchers looked at what happened over the ensuing decades, and found a decreased risk of late death and saw that for patients treated in the late 1990s there was a lower chance for late death than the patients treated earlier.
“They have the patient numbers to show that this was due to a decrease in death from other malignancies--presumably treatment-related malignancies, and reduced deaths from cardiac disease that might have been caused by cardiac toxicity and in cases of pulmonary toxicity.”
Big Drop in Late Mortality
Armstrong demonstrated that in the 1970s, late mortality at 15 years due to health-related causes among children treated for acute lymphoblastic leukemia was 2.8 percent. But by the 1980s, the late mortality in these patients had dipped to 2.3 percent, and to 1.9 percent by the end of the 1990s--a significant difference.
He said that a major difference in late mortality was the near elimination of cranial radiation in these leukemia patients. For example, in the 1970s, 86 percent of patients with acute lymphoblastic leukemia received cranial radiotherapy, compared with only 22 percent in the 1990s.
Similarly, Armstrong found that in Hodgkin lymphoma, children who had been cured of the disease had a 4.2 percent risk of late mortality if they had been treated in the 1970s. But by the end of the 1980s, that late mortality had decreased to 3.4 percent, and by the end of the 1990s, the mortality in these cancer survivors was 2.1 percent—i.e., half the rate 20 years earlier.
He said that one of the factors that has likely led to the decline in late death was the virtual elimination of chest radiation for these patients, along with the reduction of anthracycline-based chemotherapy.
And in Wilms tumor patients, the late mortality in the 1970s was 2.2 percent. By 1989 that rate had decreased to 0.6 percent, and at the end of the 20th century, the rate stood at 0.4 percent.
He said that reduction in the use of abdominal radiation and reduction in the use of chemotherapy were likely the reasons late mortality has declined in these survivors.
The study was an analysis of data from the Childhood Cancer Survivor Study. A total of 31 U.S. and Canadian hospitals currently participate. The cohort, initiated in 1994, is an NIH-funded resource. In the current analysis, the National Death Index was used to assess mortality among 34,043 five-year childhood cancer survivors. All were younger than age 21 at diagnosis.
On average, the five-year survivors were followed for 21 years after their diagnosis. The study found that 3,958 patients had died during that period, and 41 percent of those deaths were from other health-related causes that include death due to late effects of cancer therapy. Additionally, all-cause mortality was halved over these two decades--12.4 percent of patients diagnosed in the early 1970s died within 15 years of diagnosis, compared with six percent of those diagnosed in the early 1990s.
During the same time period, the cumulative incidence of deaths from other health-related causes decreased from 3.5 to 2.1 percent, Armstrong reported.
“While the modernization of cancer therapy has probably made the most significant difference, improvements in supportive care for survivors, and screening, detection, and treatment of late effects--like new cancers and heart and lung disease--have played an important role in extending their lifespan as well.”
Discussant: Lessons Are Applicable to All Cancers
The Discussant for the study, ASCO 2011-2012 President Michael Link, MD, the Lydia J. Lee Professor in Pediatric Cancer at Stanford School of Medicine, said that many of the lessons learned in the study are applicable to all cancers. “The ‘cost of cure’ borne by our patients is substantial. We owe it to our patients to remain focused on the consequences of our therapies. He concluded his talk with a quote and a photo of Giulio D’Angelo, MD—“one of the heroes of pediatric oncology,” he said: "Cure is not enough.”
Sunday, May 31, 2015
By Robert H. Carlson
CHICAGO--Fans who follow Twitter postings by John P. Leonard, MD (@JohnPLeonardMD), Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College, have come to enjoy his #LeonardList Top Abstracts tweets from important medical meetings.
He’s come through again with a “Top 5 Lymphoma Abstracts” list from this year’s American Society of Clinical Oncology Annual Meeting, tweeting one abstract a day in the five days leading up to the meeting.
In a telephone interview on Thursday, the evening before the start of the meeting, Leonard says he chose to highlight lymphoma research because it tends to be underrepresented at ASCO compared with the American Society of Hematology Annual Meeting--“But there are still some important abstracts at ASCO that patients and caregivers and those interested in the field should know about.”
The following is his list, along with some of his comments:
1. Abstract 8555: “Exercise patterns and quality of life among survivors of aggressive lymphoma,” by Raina Mahajan Ferzoco, Mayo Clinic Department of Health Sciences Research, et al.
“This focuses on patterns of aerobic exercise and quality of life in survivors of non-Hodgkin lymphoma-- it’s a correlation between exercise on their own and quality of life after treatment,” Leonard said. “We are learning more and more about the importance of exercise in cancer patients, and this study looked at more than 600 patients who had aggressive lymphoma and were survivors.
“The main take-home message is that significant exercise activity, as reflected by meeting recommendations from the standard guidelines, is associated with a better quality of life.
“It may be that there are a number of different benefits from counseling our patients on exercise. In the future it will be important to see if physicians intervene in this area and whether more patients will be exercising. Perhaps a prospective study will be done to see if interventions can actually cause improvements for patients in these outcomes.”
2. Abstract 8505:” Title: Brentuximab vedotin plus AVD for non-bulky limited stage Hodgkin lymphoma: A phase II trial,” by Jeremy S. Abramson, Massachusetts General Hospital Cancer Center, et al.
“This study tested brentuximab vedotin plus AVD (doxorubicin, vinblastine, dacarbazine), substituting brentuximab vedotin for bleomycin in the standard ABVD regimen.
“This small study is in a more favorable population with non-bulky disease, yet there was a substantial 24-percent rate of grade 3 and 4 peripheral neuropathy. Similarly, several patients had febrile neutropenia, which is not that common with ABVD. So perhaps there is more toxicity than has been recognized with the brentuximab-containing version of the regimen.
“Also, the authors noticed several false-positive PET scans--more than we generally see with ABVD. This will be important for clinicians to pay attention to when they are using brentuximab in this combination, because we don’t want treatment decisions made on the basis of a false-positive PET scan. We really should not act on PET scans before confirming with a biopsy.
“An ongoing randomized trial will answer this in a more definitive fashion, but it does bring a bit of pause to the idea of routinely plugging in brentuximab until we have randomized data.
3. Abstract 8507: “Allogeneic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: Results of the interim analysis of the AATT trial,” by Norbert Schmitz, Asklepios Hospital St. Georg, Hamburg, Germany, et al.
“This study focuses on fact that younger patients with peripheral T-cell lymphoma typically get an induction regimen--here it was CHOEP-14--and then in first remission usually get a stem cell transplant. There is some thought that allogeneic stem cell transplant might offer potential benefits over autologous transplant although with more toxicity than autologous transplant. These authors attempted to compare autologous transplant versus allogeneic transplant in first remission.
“The conclusion of this interim analysis is basically that this study is not going to be able to answer the question in a definitive way because a substantial number of patients relapsed before consolidation. So we still remain uncertain as to auto-versus-allo.
“One might interpret this as that allogeneic transplant is more toxic generally speaking so there is no reason to go on and use the more toxic regimen since autologous transplant, at least at this point, has not been effectively challenged by allogeneic.
“The other take-home message is that we need to work on getting more patients to transplant and having better induction regimens so these early relapses don’t occur.”
4. Abstract 8515: “Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant for relapsed and refractory aggressive B-cell non-Hodgkin lymphoma,” by Craig Steven Sauter, Memorial Sloan Kettering Cancer Center, et al; and Abstract 8516: “Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas,” by Stephen J. Schuster, Abramson Cancer Center, University of Pennsylvania, et al.
CAR-T cell therapy is getting a lot of attention and enthusiasm, and these studies look at two different approaches. The Memorial study took patients with poor-risk relapsed/refractory B-NHL and treated them with CAR-T cells following consolidative high-dose therapy and autologous stem cell transplant.
The Penn study similarly took relapsed B-cell lymphoma patients of various types, gave them similar therapy, and then gave them CAR-T cells.
“The net result is that some patients had fairly durable remissions, although the follow-up in these studies was generally in the range of one to two years at most--these are early days.
“This is promising data, but at the end of the day this is a relatively limited experience with aggressive lymphomas, in contrast to CLL and ALL. The challenge in interpreting these data is that the investigators are still working on optimal dosing and minimizing toxicity of cytokine-release syndrome. This is a heterogeneous group of patients, so it is difficult to interpret efficacy.
“And then there is patient selection. Patients getting on these studies often have to wait a couple of months so they have to have disease control in the meantime.
“So the jury is still out. I am encouraged that we are seeing progress in CAR-T therapy, but there is a lot of work to be done before we can say this is a standard of care or necessarily better than some of the other options we have.
“In other words: cautious optimism.”
5. Abstract 8504: “Evaluation of complete response rate at 30 months as a surrogate for progression-free survival in first-line follicular lymphoma studies: Results from the prospectively specified Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) analysis with individual patient data of 3,837 patients,” by Daniel J. Sargent, Mayo Clinic, et al.
“This is an analysis of more than 3,800 patients treated front-line for follicular lymphoma in different ways. The key question is whether there is an early endpoint that can predict progression-free survival, which is a standard endpoint commonly applied for follicular lymphoma studies.
“The challenge is that progression-free survival takes a long time to arrive at, and the authors wanted to know if there is a surrogate for progression-free survival that could then be used for drug approval or establishing superiority of one drug over another.
“They established that the percentage of patients who were in complete response at 30 months after therapy correlated with the ultimate progression free survival.
“I think this will lead to the complete response 30-month time point being an endpoint for various follicular lymphoma studies. The hope is that this will help speed up drug development.”
Top 10 Lymphoma Abstracts from #ASH14
Check out OT’s article about John Leonard’s Top 10 lymphoma abstracts from the most recent American Society of Hematology Annual Meeting in the 1/10/15 issue: http://bit.ly/1RAsGtd
Saturday, May 30, 2015
By Robert H. Carlson
Chicago--Nivolumab, a PD-1 inhibitor, was approved by the Food and Drug Administration in March for treatment of squamous cell non-small cell lung cancer (SC-NSCLC), which accounts for approximately 15 percent of all lung cancers. But does it work in non-squamous NSCLC in patients with advanced disease that progressed after platinum-based chemotherapy, and does it work better than the current second-line standard of care, docetaxel?
According to the Phase III CheckMate 057 trial, the answer is yes, data for which were presented here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA109).
The trial included 582 patients with advanced non-squamous non-small cell lung cancer randomly assigned to nivolumab or docetaxel.
Lead author Luis Paz-Ares, MD, PhD, Professor of Medicine and Chair of the Department of Oncology at Hospital Universitario Virgen Del Rocio in Spain, reported a 19.2 percent response rate for 292 patients receiving immunotherapy versus 12.4 percent for 290 patients receiving docetaxel, and a superior duration of response--17.1 months for immunotherapy versus 5.6 months for docetaxel.
Median overall survival was 12.2 months for nivolumab versus 9.4 months for docetaxel, and the one-year overall survival rate was 51 percent for nivolumab versus 39 percent for docetaxel.
Paz-Ares said 4.9 percent of patients stopped nivolumab due to toxic side effects versus 14.9 percent of patients on docetaxel.
“Nivolumab appears to be more potent against this most common lung cancer, but it is important to note that it is also far easier on patients compared with docetaxel,” Paz-Ares said. The number of patients having grade 3/4 adverse events was 10.5 percent for the immunotherapy versus 53.7 percent for docetaxel.
Nivolumab is a fully humanized IgG4 PD-1 immune checkpoint inhibitor antibody, and tumor levels of the ligand to PD-1, PD-L1, appear to influence response to the drug. A subgroup of patients with PD-L1 levels of one percent or higher in their tumors had a median survival with nivolumab greater than 17 months, versus nine months for docetaxel.
And while patients who received nivolumab had a reduction in risk of death of 27 percent compared with docetaxel patients, the subgroup of patients with high PD-L1 levels had a 41 to 60 percent reduction in risk of death, which was not observed in cases of low or undetectable PD-L1, he said.
Paz-Ares said nivolumab demonstrated efficacy and safety in an earlier Phase III trial, which compared nivolumab with docetaxel in patients with advanced squamous NSCLC.
The nivolumab dose in that trial and the trial reported here was 3 mg/kg every two weeks, and the docetaxel dose was 75 mgm2 every three weeks.
Grade 3/5 drug-related adverse events occurred in 10.5 percent (30 of 287) of nivolumab patients versus 53.7 percent (144 of 268) of docetaxel patients. There were no deaths in the nivolumab arm of the study, versus one in the docetaxel arm.
After discontinuation, 42.1 percent of nivolumab patients and 49.7 percent of docetaxel patients received subsequent systemic therapy.
Roy Herbst Asks: Is This Truly Checkmate?
The Discussant for the CheckMate 057 trial was Roy S. Herbst, MD, PhD, Professor of Medicine and Pharmacology and Chief of Medical Oncology and Director of the Thoracic Oncology Program at Yale School of Medicine.
“Is this truly ‘checkmate’ for NSCLC, or do we still have a lot of work to do on our endgame?” he asked provocatively in his first slide.
Cutting to the chase, his conclusion slides declared, “YES! Nivolumab is the new standard of care for previously treated non-squamous NSCLC. This is a positive, randomized Phase III trial that sets a new treatment standard,” he said.
There are still questions to be resolved, though of course: “Should this PD-L1 biomarker assay be used for patient selection? No, not yet,” he said. “It is an intriguing possibility, but for now it is only hypothesis generating. The biomarker was not prospectively stratified here, and data are incomplete, since 22 percent of patients had no measurement in the trial.”
Some issues with biomarkers in general, he noted, are the heterogeneity of multiple tumors and multiple passes within a tumor; the interval between biopsy and treatment; primary versus metastatic disease; antibody and staining conditions.
Herbst said that while higher PD-L1 levels were associated with improved response and survival, in this trial even the nivolumab patients with PD-L1 tumor levels less than one percent had activity at least equal to docetaxel, and with less toxicity.
“If a patient has a less than one percent tumor level of PD-L1, do we still give nivolumab?” he asked.
Herbst called for future studies with nivolumab to explore its potential benefit in a greater number of patients--in front-line therapy, in the adjuvant setting in earlier-stage disease, in small-cell lung cancer, and in ALK and EGFR mutants.
Considered Impossible Until Recently
“Even five years ago, an effective immunotherapy for lung cancer was considered impossible. Today we have such a treatment, and it surpasses the standard therapy both in terms of efficacy and patient quality of life,” said ASCO designated expert Gregory A. Masters, MD, Associate Professor of Medicine at Thomas Jefferson University, who was invited by ASCO to comment at a news conference on progress in cancer immunotherapy.