By Lynne Lederman, PhD
On this final day of the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting we look at two late breaking presentations. LBA 4008, presented late yesterday, showed proton pump inhibitors with low dose aspirin for at least 7 years offers modest benefits for people with Barrett’s esophagus, a risk factor for the development of adenocarcinoma of the esophagus. And, LBA 3505, presented today showed no benefit for using hyperthermic intraperitoneal chemotherapy (HIPEC) during surgery to treat most patients with colorectal cancer with colorectal peritoneal carcinomatosis, suggesting that those patients with CRC that has spread only to the peritoneum can avoid HIPEC treatment.
Chemoprevention of esophageal cancer with esomeprazole and aspirin therapy: efficacy and safety in the phase 3 randomized factorial ASPECT trial (LBA4008)
Janusz Jankowski, MD, Royal College of Surgeons, Ireland, presented an updated analysis of the ASPECT trial. The analysis showed that the risk of developing precancerous, high grade dysplasia or esophageal cancer could be reduced, and that the risk of death from any cause was delayed in individuals with Barrett’s esophagus (BE) with the use of the proton pump inhibitor (PPI) and low dose aspirin. This 7-year study is important because esophageal cancer, which is associated with BE is difficult to screen and treat, and the drugs used in the study, esomeprazole (a PPI) and aspirin, are dosed orally and available over the counter. Dr. Jankowski cautioned that people with heartburn should discuss their risk of BE with their health care provider and should not self-medicate with the study drugs.
Esophageal adenocarcinoma has a 5-year survival rate of less than 10%, and is increasing in incidence, probably due to an increase in gastro-esophageal reflux and BE, which are both associated with inflammation. PPIs reduce acid reflux, and aspirin reduces inflammation, so both agents can be preventative.
This study enrolled 2,563 patients with ≥1 cm BE and no high grade dysplasia or esophageal adenocarcinoma at baseline. Patients were randomly assigned 1:1:1:1 in a 2 x 2 factorial design to high or low dose esomeprazole alone or in combination with low dose aspirin. The primary composite endpoint was time to all-cause mortality, esophageal adenocarcinoma, or high grade dysplasia.
Median follow-up was 8.9 years. High dose esomeprazole had a statistically significant benefit on the combined endpoint compared with standard dose esomeprazole (P=.0459). Aspirin had no benefit in the no-aspirin arm in the primary analysis. Dr. Jankowski said it was stunning that the serious adverse event rate was low, about 1%.
In discussing this trial, Zev Wainberg, MD, David Geffen School of Medicine, UCLA, pointed out that despite the absolute benefits of high dose PPI and use of aspirin, there are many unanswered questions. Until there are more data, the question of whether all patients with BE should receive treatment with high dose PPI plus low dose aspirin can’t be answered.
A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7 (LBA3505)
This randomized, phase 3 trial (NCT00769405) showed that individuals with advanced colorectal cancer (CRC) may not require treatment with hyperthermic (heated) intraperitoneal chemotherapy (HIPEC) during surgery. HIPEC does not offer a survival advantage compared with surgery alone. The study results were presented by François Quenet, MD, Institut Régional du Cancer de Montpellier, Montpellier, France.
Patients with peritoneal CRC metastases are known to have a significantly worse prognosis than those with no peritoneal metastases.
At a median follow-up of 64 months, the median overall survival (OS) was not statistically significantly different between groups at 41.2 months in the non-HIPEC group and 41.7 months in the HIPEC group. Median recurrence-free survival was also similar between the two groups at 11.1 months in the non-HIPEC group and 13.1 months in the HIPEC group. In a subgroup analysis, as expected, patients with lower PCI scores had longer OS. For patients with a PCI score of 11 to 15, there was a significant survival advantage for patients who received HIPEC versus none. However, there were only 18 (13.5%) such patients in the HIPEC group and 28 (21.2%) in the non-HIPEC group.
The overall mortality rate at 30 days after surgery was 1.5% in both groups, and adverse events were comparable between groups at this time point. At 60 days, the total mortality rate was 2.6%. At 60 days, the rate of adverse events in the HIPEC group was significantly higher than that in the non-HIPEC group (24.1% versus 13.6%; P=.03). Hospital stays for the HIPEC group were also significantly longer.
Dr. Jankowski concluded that more research is needed to determine if there are patients with CRC metastases confined to the peritoneum who would still benefit from receiving HIPEC with surgery. Patients with a low PCI are not likely to benefit from HIPEC. The curative management of peritoneal carcinomatosis by cytoreductive surgery in this study yielded unexpectedly good OS results.
People with CRC metastases confined to the peritoneum with a low peritoneal cancer index can likely forgo HIPEC, whereas those with a high index may not benefit from either surgery or HIPEC. Meanwhile, other types of chemotherapy may be more effective than oxaliplatin, the type of chemotherapy used in HIPEC for this study.
In discussing this study, Larissa Temple MD Rochester Medical Center, said that it is too early to tell if this study will be practice changing, in part because of the relatively low median PCI score. A very high resection rate in this study likely contributed to a 30 and 60 day mortality lower than in retrospective data. Other ongoing randomized, controlled trials should provide more information as role of HIPEC treatment for CRC metastases confined to the peritoneum evolves.
Several late-breaking abstracts were presented today at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. These studies include LBA1509, identifying new tumor types with high microsatellite instability are associated Lynch syndrome; LBA2553, a retrospective study showing the effect of a precision medicine approach on survival across tumor types; LBA4001, describing a chemotherapy regimen that prolongs survival in pancreatic cancer, and LBA4002, demonstrating that preoperative chemotherapy with radiation also increases survival in pancreatic cancer.
Pan-Cancer Microsatellite Instability Predicts for the Presence of Lynch Syndrome (LBA1509)
Results of a prospective genomic study of 15,045 tumor samples from over 50 types of cancer reported by Zsofia K. Stadler, MD, Memorial Sloan Kettering Cancer Center, (MSKCC) showed that patients whose tumors have high microsatellite instability (MSI-H), a marker of a large number of genetic mutations resulting from an inability of cells to repair damaged DNA are also more likely to have Lynch syndrome, an inherited that increases the risk of multiple types of cancer.
Tumors from patients treated at MSKCC were analyzed with a genomic test, MSK-IMPACT, which uses next-generation sequencing (NGS) to detect mutations in cancer-related genes as well as MSI. Blood samples were also tested for germline mutations (deficiency) in DNA mismatch repair genes (MMR-D).
Genomic analysis were used to classify tumors into 3 groups: MSI-stable (MSS, no MSI; 93.2% of tumors), MSI-intermediate (MSI-I, moderate levels of MSI; 4.6%)), and MSI-H (2.2%). Inherited mutations in Lynch-syndrome associated genes occurred in 16% of those with MSI-H versus 1.9% of those with MSI-I and 0.3% of those with MSS tumors. Nearly half of patients had cancer types not or rarely associated with Lynch syndrome, including mesothelioma, sarcoma, and adrenocortical cancer, and 45% did not meet Lynch syndrome genetic testing criteria. MMR-D was found in 98.3% of the 57 MSI-I/MSI-H tumor samples tested.
Dr. Stadler said that findings suggest that all patients with MSI -H or MMR-D tumors should be tested for Lynch syndrome whatever the cancer type or personal or family history of cancer.
Matched therapy was an independent factor predicting longer survival in a multivariate analysis. PI3K/AKT/mTOR pathway abnormalities were associated with poorer outcomes compared with other genetic alterations. Ongoing clinical trials to further precision medicine approaches to treatment include the IMPACT2 and ASCO’s TAPUR trials.
Unicancer GI PRODIGE 24/CCG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas (LBA4001)
Thierry Conroy, MD, Institut de Cancerologie de Lorraine, Nancy, said the PRODIGE 24/CCG PA.6 trial showed that adjuvant mFOLFIRINOX therapy is superior to gemcitabine, the standard of care for the past 10 years.
Patients with non-metastatic pancreatic ductal adenocarcinoma who had all visible tumor surgically removed were randomly assigned to gemcitabine (n=246) or mFOLFIRINOX (n=247) for 6 months. At a median follow-up of 33.6 months the disease-free survival (DFS), the primary endpoint, was 21.6 months in the mFOLFIRINOX groups versus 12.8 months in the gemcitabine group (HR 0.58; 95% CI 0.46, 0.73; P<.0001). The median OS was 54.4 months for mFOLFIRINOX versus 35.0 months for gemcitabine (HR 0.64; 95% CI 0.48, 0.86; P=.003).
Although there were more severe adverse events (AEs), primarily hematologic, with mFORFIRINOX (76% versus 53%), they were manageable. It is recommended that patients be screened for underlying heart disease before treatment as a history of ischemic heart disease is a risk with either treatment, especially mFOLFIRINOX.
Dr. Conroy suggested mFOLFIRINOX should be considered a new standard of care for pancreatic cancer after surgical resection. Ongoing trials are examining optimal timing of chemotherapy in this setting, including pre-surgery as neoadjuvant therapy and dosing of half the cycles before and half after surgery as perioperative chemotherapy.
Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial (LBA4002).
In other encouraging news for patients with pancreatic cancer, the result s of the PREOPANC-1 trial showed that patients (n=119) randomly assigned to chemoradiotherapy for 10 weeks prior to surgery for pancreatic cancer as well as post-surgical chemotherapy had a better DFS than patients (n=127) who were randomly assigned to the same amount of chemotherapy after immediate surgery (9.9 months versus 7.9 months; P=.023). The 2-year survival for the preoperative chemotherapy group was 42% versus 30% in the post-surgery chemotherapy group. There was no significant difference between groups in median OS; however, in the subgroups of patients with complete resections, median OS was 42.1 months for preoperative chemotherapy versus 16.8 months for immediate surgery. Distant metastases-free interval was longer for the presurgical treatment group (HR 0.71; P=.013), as was locoregional recurrence-free interval (HR 0.55; P=.002).
Although these results are preliminary, Geertjan Van Tienhoven, MD, PhD, said the study investigators believe that this trial may be practice-changing. After the final analysis, efforts will be made to test for more effective preoperative treatments, eg, FOLFIRINOX alone or combined with stereotactic radiation therapy.
Median OS was 15.9 months for the pembrolizumab plus chemotherapy arm and 11.3 months in the placebo plus chemotherapy arm. The median progression-free survival (PFS) was 6.4 months for pembrolizumab plus chemotherapy arm compared with 4.8 months for the placebo plus chemotherapy alone arm.
These data suggest that pembrolizumab plus chemotherapy should become a new standard of care for the first-line treatment of metastatic squamous NSCLC across all the different levels of PDL1 expression, said study investigator, Luis Paz-Ares, MD, PhD, professor of medicine at the Hospital Universitario 12 de Octubre.
“Not only was there a PFS benefit, but there was a significant overall survival benefit with a hazard ratio of .6. There is no doubt in my mind that this benefits patients and that we need to adopt this starting today, if available,” said Dr. Aggarwal.
About the safety profile, Dr. Aggarwal said, “Overall, the toxicity profile seemed very manageable, and now we are very adept at managing immune-related toxicities since we’re been using these agents in the clinic.”
Interim results from the phase II KEYNOTE-427 trial showed a 38% response rate for advanced cleared cell renal cell carcinoma (RCC) patients receiving pembrolizumab monotherapy in the front-line setting. Three patients achieved a complete response, and 39 a partial response. The median progression-free survival was 8.7 months, and median overall survival has not been reached.
KEYNOTE-427, a single-arm, open-label design, enrolled participants with advanced clear cell or nonclear cell RCC. Eligible patients had measurable disease per RECIST criteria 1.1, no prior systemic therapy, and a Karnofsky performance status of greater than or equal to 70%. Participants received pembrolizumab at a dose of 200 mg IV every three weeks. Only data from Cohort A, which had 110 participants, were presented.
“The frequency of adverse events of special interest is consistent with what has been seen with pembrolizumab monotherapy in other tumor types,” said lead investigator David F. McDermott, MD, director of Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center.
“Treatment-related adverse events of any grade occurred in 80% of patients. Treatment-related grade 3 and 4 adverse events occurred in 30% of patients. Discontinuation due to treatment-related adverse events was reported in 11% of patients,” he said. “One patient died from treatment-related pneumonitis.”
Naomi Haas, MD, Associate Professor of Medicine at the Hospital of the University of Pennsylvania, described KEYNOTE-427 as a “really important” study.
Ipilimumab and nivolumab combination was FDA approved recently for first-line treatment in kidney cancer. “There’s a high response rate in that combination, but there’s also a lot of toxicity, and single agent pembrolizumab had an impressive response rate and less toxicity.”
She continued, “The complete response rate was not as high with the single agent pembrolizumab as it was in the ipilimumab and nivolumab combination, but it’s not clear to me that you can’t rescue some of those people later by adding a second agent and perhaps sparing people the toxicity, so I think it’s a really important first step to answering that, and I’d like to see something in the future that would include a single agent immune checkpoint inhibitor as a comparator arm in some of these combination immune checkpoint inhibitor trials.”
Erdafitinib, New Hope for Advanced Urothelial Cancer (Abstract 4503)
In the phase II study BLC2001, participants with metastatic or unresectable urothelial carcinoma who were treated with erdafitinib, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, had a 40% response rate. Three percent of patients had a complete response and 37% a partial response. These results come just a few months after the FDA granted Breakthrough Therapy Designation to erdafitinib for patients with metastatic urothelial cancer.
“This is really a very exciting trial,” commented Dr. Haas. “As in some of the other solid tumors, I think there’s a growing awareness that there are different subsets of urothelial cancer that might benefit from immune checkpoint inhibitors, and others that might benefit from other alternative treatment pathways.”
The trial enrolled advanced urothelial carcinoma patients with FGFR alterations, and 99 were treated with a median of 5 cycles of erdafitinib. Participants with prior treatment with immune check point inhibitors were eligible.
“This [trial] had a very impressive response rate in people that were pretty heavily pre-treated, and it was interesting that some of the patients who responded to this drug were resistant to immune checkpoint inhibitors,” said Dr. Haas.
Another CAR-T Drives Forward (Abstract 7505)
The investigational CAR-T product lisocabtagene maraleucel for relapse/refractory non-Hodgkin lymphoma (NHL) showed durable responses, according to results from the phase I TRANSCEND NHL 001 trial. Lisocabtagene maraleucel is an anti-CD19 CAR T-cell.
The overall response rate for patients in the CORE data set (which were patients who met all study inclusion criteria) was 49% and 46% complete response at 6 months. In the trial, lisocabtagene maraleucel was evaluated at two dosing schedules (single dose vs two-dose), and across both dosing levels 93% of patients who achieved the 6-month timepoint remained in remission at last follow-up.
“This anti-CD19 CAR T-cell has remarkable efficacy in a group of highly refractory aggressive B-cell non-Hodgkin lymphoma patients,” said Caron Jacobson, MD, who discussed the study. Dr. Jacobson is Medical Director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute.
“The median overall survival has not been reached in this population,” noted Jeremy Abramson, MD, Clinical Director, Center for Lymphoma at Massachusetts General Hospital. Nearly 90% of patients who achieved a complete response remain alive at 1 year. “These [outcomes] are far superior of what we would have anticipated with conventional therapies in largely chemo-refractory DLBCL population.”
About toxicity, Dr. Abramson said, “I think strikingly, lisocabtagene maraleucel has shown a low and manageable toxicity profile, with very low rates of severe CRS [cytokine release syndrome] and neurotoxicity, at 1 percent and 13 percent respectively. We continue to therefore evaluate this product for an outpatient administration.”
The press conference this morning featured several studies from the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting that attendees won’t see until Sunday or Monday. Two in particular were the SANDPIPER trial for advanced breast cancer and IMpower131 trial for advanced lung cancer. Also, Silicon Valley startup GRAIL, Inc., showcased its cancer detection prototype by presenting data from their lung cancer substudy.
Cancer Detection Test, No Longer a “Pipedream” (Abstract LBA8501)
GRAIL, Inc., the biotech startup backed by billionaires Jeff Bezos and Bill Gates, is on a mission to develop a diagnostic blood test that can detect cancer early on, and according to preliminary results, the startup is on the right path.
“Two years ago, it was a pipedream,” said Geoffrey R. Oxnard, MD, Associate Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, who presented the results from the lung cancer substudy. “It was completely just a brainstorm and had no data supporting it, and I didn’t believe this could be done. Today, we actually have data that show that this is really feasible.”
The data come from the large prospective trial Circulating Cell-free Genome Atlas (CCGA) Study (NCT02889978). The CCGA study aims to enroll 15,000 participants, 70% of which with a cancer diagnosis and 30% without, in the United States and Canada. To date, about 12,000 participants have been enrolled across 142 sites in the United States and Canada.
From the CCGA study, several substudies have been conducted, including a breast cancer substudy featured in the poster session this morning (Abstract 536) and the lung cancer substudy presented during the press conference. Two additional studies are slated for Monday (Abstract 12021; Abstract 12003).
The findings reported for the lung cancer substudy were based on 2,800 samples in a prespecified case-control study, which were divided into a training set and a test set. A total of 118 lung cancer cases and 561 non-cancer cases were evaluable in the training set. An independent test set was used for validation.
“This is not cancer genotyping where you’re looking in the blood for a key mutation and targeting that mutation,” said Dr. Oxnard. “This is cancer detection, and it requires a different approach.”
To detect cancer, the cell-free DNA was evaluated, and three assays were used: targeted sequencing, whole-genome sequencing (WGS), and whole-genome bisulfite sequencing (WGBS).
He explained that the white blood cells are also sequenced. “The white blood cells are rich with mutations, which can pollute the data and make you think that there’s cancer present in the cell-free DNA.”
“The opportunity, perhaps, with a test like this is it’s very specific for finding cancer,” said Dr. Oxnard. He stressed, “This is not a blood test. This is a sequencing method that shows promise and needs to be turned into a diagnostic.”
“The next step will be to optimize those assays and machine learning algorithms and validate in larger data sets,” Charlotte Arnold, spokeswoman for GRAIL, Inc., told OBR. “We also have an ongoing study called STRIVE, which is enrolling 120,000 women at the time of mammogram screening.”
The STRIVE study (NCT03085888) is more representative of how GRAIL’s cancer detection prototype would work in a general population because, unlike the CCGA study, the participants do not know if they have cancer.
“We are hoping to complete enrollment by the end of the year, and then we need at least a year’s follow-up before we start to report results,” said Arnold.
SANDPIPER, a “Modest Step Forward” (Abstract 1006)
The phase III SANDPIPER trial in women with advanced breast cancer showed that the investigational agent taselisib slowed tumor growth and extended progression-free survival (PFS) by 2 months when combined with standard hormone therapy fulvestrant. Overall survival data have not been reported yet.
This is the first placebo-controlled, randomized trial to evaluate the efficacy and the safety of taselisib when added to fulvestrant in patients with advanced disease, asserted leady study author José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center.
Taselisib, a PI3K inhibitor, targets the PIK3CA mutation. Only two drugs are currently FDA approved in this class, and both are for hematological malignancies.
“This is a very appealing target,” said ASCO Expert Harold Burstein, MD, PhD. “It’s a mutation that is probably the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”
A total of 516 postmenopausal women with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer were enrolled in the study. Participants were randomized to receive taselisib plus fulvestrant or fulvestrant plus placebo.
The trial met its primary endpoint: The median PFS was 2 months longer for the investigational agent arm (7.4 months) vs the placebo arm (5.4 months) (HR=0.70; P=.0037). The overall response rate was higher for the investigational agent arm (28%) than the placebo arm (11.9%) (P=.0002). Participants in North America and Europe who received taselisib had an even longer median PFS, 7.9 months compared to 4.5 months in the placebo arm.
For participants in the investigational agent arm, the most common severe side effects were diarrhea, colitis, and high blood sugar. Participants in the investigational arm were also more likely to discontinue treatment as a result of side effects. Seventeen percent of participants who received taselisib stopped treatment compared to only 2% in the placebo arm.
“It’s a modest step forward, but it’s an important step forward because it does suggest that we can effectively target the pathway and hopefully this gives us something we can build on so that we can use a targeted and precision approach in this very common type of breast cancer subtype,” said Dr. Burstein.
IMpower131 Met Co-Primary Endpoint, Technically (Abstract LBA9000)
Initial findings from the IMpower131 trial show the addition of PD-L1 inhibitor atezolizumab to chemotherapy extended median PFS by about three weeks for participants with advanced squamous non–small-cell lung cancer (NSCLC).
“Squamous non–small-cell lung cancer remains a very difficult to treat disease and there have been very limited new treatment options presented to us over the last few decades,” said lead study author Robert Jotte, MD, PhD, Medical Director and Co-Chair, USON Thoracic Committee, Rocky Mountain Cancer Centers. “Approximately 25 to 30 percent of patients with non–small cell lung cancer have tumors that indeed can be classified as squamous cell carcinomas.”
For this patient population, he noted, “First-line standard of care remains primarily platinum-based chemotherapy.”
The IMpower131 study had an all-comer design and enrolled 1,021 chemotherapy-naïve patients with stage IV squamous NSCLC. Any level of PD-L1 expression was accepted.
Patients were randomized to one of three arms. Arm A participants received atezolizumab plus carboplatin and paclitaxel. Arm B participants received atezolizumab plus carboplatin and nab-paclitaxel. Arm C served as the control and participants received carboplatin and nab-paclitaxel alone.
Only results for Arm B and Arm C were presented.
Median PFS was 6.3 months in Arm B (atezolizumab plus chemotherapy) and 5.6 months in Arm C (chemotherapy alone) (HR 0.71; P=0.0001).
For the interim analysis, the difference in overall survival was not statistically significant (14 months for Arm B vs 13.5 months for Arm C).
“The overall survival results are immature,” commented ASCO Expert David Graham, MD. “We hope that the results from progression-free survival translate to improved overall survival. If and when that’s shown, I think we’ll clearly have a new standard of care for the frontline treatment of squamous cell non-small cell lung cancers.”
Tomorrow morning we’ll learn the preliminary results for a trial very similar to IMpower131, KEYNOTE-407. The difference is KEYNOTE-407 is evaluating pembrolizumab plus chemotherapy.