ASCO Annual Meeting Spotlight
Key news updates and reports from the American Society of Clinical Oncology Annual Meeting.
Thursday, July 30, 2015
BY ROBERT H. CARLSON
CHICAGO--Adding docetaxel-prednisone chemotherapy to standard androgen ablation and radiation therapy reduces the risk of death for men with high-risk, localized prostate cancer, according to data from the Phase III RTOG 0521 study. As reported here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA5002), the four-year overall survival rates after 5.5 years of follow-up were 89 percent in the standard-therapy group versus 93 percent in the group who received added docetaxel group. Similarly, five-year disease-free survival rates were 66 and 73 percent, respectively.
“This study is the first indication that chemotherapy has a role in the adjuvant treatment of localized prostate cancer, and we also expect to see an even bigger survival advantage over time,” said the study’s lead author, Howard Sandler, MD, Professor and Chair of Radiation Oncology and Cancer Therapeutics at Cedars-Sinai Medical Center in Los Angeles. “This finding could improve outcomes for thousands of men.”
He said he and his colleagues hypothesized that the addition of adjuvant docetaxel (at a dose of 75 mg/m2) and prednisone (10 mg) to 24 months of androgen suppression (LHRH agonist before radiotherapy, oral antiandrogens through the end of radiotherapy) and three-dimensional conformal radiotherapy/intensity-modulated radiation therapy (3DCRT/IMRT) would increase overall survival.
RTOG 0521 was designed to detect improvement in four-year overall survival in patients in any of three categories:
· Gleason score 7-8, any T-stage, and PSA greater than 20 ng/mL;
· Gleason score 8, stage T2 or higher, any PSA level; or
· Gleason score 9-10, any T-stage, and any PSA level.
All men enrolled had PSA levels of at least 150 mg/ml. In four years the trial enrolled 563 patients who were evaluable for response, at sites in the U.S., Canada, and Australia: 281 were randomly assigned to androgen suppression-radiotherapy and 282 to androgen suppression-radiotherapy-docetaxel. Median age was 66, median PSA was 15.1 ng/mL, 53 percent of the men had Gleason scores of 9 to 10, and 27 percent had clinical T3-4 tumors.
Sandler said the trial was designed with a short overall survival assessment period, and additional follow-up is warranted to determine the long-term benefit of chemotherapy added to the current standard of care of long-term androgen-suppression and radiotherapy.
The study was supported by grants from the National Cancer Institute and Sanofi, with additional support from AstraZeneca for patients participating in Australia.
Consistent with CHAARTED and STAMPEDE
“The potential role of docetaxel in hormone-sensitive prostate cancer is consistent with, and supported by our data and other studies, including CHAARTED (2014) and STAMPEDE (2015),” Sandler said.
Patient follow-up will continue to determine the long-term benefit of adjuvant chemotherapy in this setting, Sadler said, and an analysis of quality-of- life data will be performed at a later time.
Disagreement from Ian Tannock
The Discussant for the presentation, Ian Tannock, MD, PhD, Emeritus Professor of Medical Oncology at Princess Margaret Cancer Centre and the University of Toronto, Canada, though, disagreed with the implied recommendation of RTOG 0521, that docetaxel should routinely be added to standard androgen ablation-radiotherapy treatment.
“Given that RTOG 0521 reported a difference in overall survival of 93 percent versus 89 percent, using one-sided statistics, is this sufficient evidence to recommend docetaxel plus androgen-deprivation therapy after radiotherapy for men with M0 disease?” he asked rhetorically during his talk. It is expected that adding one active treatment – i.e., docetaxel in this case – to others, will lead to an improvement in disease-free survival.
“But disease-free survival improvement does not lead inevitably to improved overall survival.
“Men who don’t receive docetaxel might live longer after disease progression. And if you look at the breast cancer literature there are many examples where adjuvant trials lead to disease-free survival but you don’t get an improvement in overall survival. And in my view, for men with localized M0 disease if there is no effect on overall survival, then chemo delay is toxicity delay, and is the preferred strategy.
“Here is my recommendation: Men with localized M0 prostate cancer who receive local treatment with radiotherapy should not, in 2015, be routinely offered docetaxel in addition to androgen-deprivation therapy.”
Still, he said that this opinion might well change with longer follow-up on all three major trials: RTOG 0521, STAMPEDE, and GETUG-12.
Thursday, July 16, 2015
By Robert H. Carlson
Chicago – Anastrozole, letrozole, and fulvestrant, standard endocrine treatments for advanced breast cancer, were featured in three late-breaking abstracts presented in an oral abstract session here at the American Society of Clinical Oncology Annual Meeting.
The Phase III NSABP B-35 trial, comparing anastrozole with tamoxifen for prevention of breast cancer recurrence in women with ductal carcinoma in situ (DCIS) (Abstract LBA500), found anastrozole to be more effective in preventing DCIS and other breast cancer events.
In the multicenter, open label Phase III CALGB (Alliance) 40503 trial, bevacizumab was added to first-line letrozole in patients with hormone-receptor positive advanced breast cancer to test the hypothesis that anti-VEGF therapy could delay progression on endocrine therapy (Abstract LBA501). The study showed that the combination slightly increased progression-free survival but not overall survival, and also caused more toxicity.
And in the PALOMA-3 study, the CDK4/6 inhibitor palbociclib plus fulvestrant improved progression-free survival rates compared with use of fulvestrant alone in women with hormone receptor-positive HER2-negative advanced breast cancer whose disease had progressed on prior endocrine therapy (Abstract LBA502).
NSABP-B-35: Aromatase Inhibitor Superior
NSABP B-35, the first Phase III trial of anastrozole versus tamoxifen for DCIS, showed that anastrozole produced a significantly longer breast cancer-free interval, defined as the time from randomization to any breast cancer event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS.
“Anastrozole is quite a suitable drug for DCIS,” said the study’s lead author, Richard G. Margolese, MD, Professor and Director of Surgical Oncology at The Jewish General Hospital of McGill University in Montreal, Canada, who presented the data. “We now have another option for adjuvant therapy for DCIS.”
The 10-year breast cancer-free survival rate was 93.5 percent in the anastrozole group versus 89.2 percent in the tamoxifen group, he reported, noting that both drugs have an acceptable safety profile: Severe adverse reactions to either drug are uncommon, although such problems were slightly less with anastrozole.
“Anastrozole might turn out to be the preferable option for adjuvant treatment of DCIS, especially in women in whom there is concern about thromboembolism or uterine cancer because of various features in that person’s history,” Margolese said.
Patients in the study were postmenopausal, with ER and/or PR-positive disease, and had undergone wide local excision with negative margins and whole breast radiation. They were stratified in the trial by age--under 60 and 60 and over.
Patients were randomly assigned to receive tamoxifen at 20 mg/day and placebo for five years (1,538 patients) or anastrozole at 1 mg/day and placebo (1,539) for five years.
With a median follow-up of 8.6 years, 114 breast cancers were detected in the tamoxifen group compared with 84 in the anastrozole group. This included recurrences of DCIS as well as development of de novo DCIS or invasive breast cancer in either breast.
“In women younger than 60, the incidence was decreased conspicuously with anastrozole—about 95 percent at 10 years versus 88 percent for tamoxifen,” Margolese said. Women older than 60 had very similar results: 92 percent for anastrozole and 90 percent for tamoxifen.
He said there is no good explanation for this virtual equivalence of the two drugs among older women: “It requires more biologic probing.”
There were fewer ipsilateral recurrences in the anastrozole study arm--2.8 percent (0.9% invasive and 1.9% DCIS) versus 3.4 percent in the tamoxifen arm (1.4% and 2.0%, respectively). Contralateral breast cancer was also less in the anastrozole arm; 2.4 percent (1.3% and 1.1%) versus 3.5 percent for tamoxifen (2.3% and 1.2%).
Uterine cancers occurred far more frequently with tamoxifen, as expected: 1.7 versus 0.8 percent for anastrozole.
However, Margolese said that this was infrequent, representing only 1.6 percent of all patients.
Osteoporotic fractures were also infrequent, but more common among patients in the anastrozole arm--6.9 versus 5.0 percent for tamoxifen. “The number of osteoporotic fractures would be expected to be higher with anastrozole because it inhibits the production of estrogen,” Margolese said, adding, though, that the results here are not statistically significant.
"The good news is that tamoxifen and anastrozole are both very effective, but it seems that women have better chances of staying well with anastrozole," Margolese said at an ASCO news conference that highlighted the study. "Women should also consider the differences in side effects when discussing treatment options with their doctors."
‘Consider Full Range of Options’
Don S. Dizon, MD, Clinical Co-Director of Gynecologic Oncology and Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, was the designated ASCO expert at the news conference, and gave his perspective about the study: “Women with DCIS already have several great treatment options, and now they have one more. Aromatase inhibitors offer important advantages, but patients and their doctors should still consider the full range of options, including tamoxifen, or even foregoing adjuvant treatment, as every approach carries its own risks and benefits.”
Also commenting, in an interview before the meeting, ASCO 2014-2015 President Peter Paul Yu, MD, Director of Cancer Research at Palo Alto Medical Foundation, said: “We have seen in the metastatic setting that aromatase inhibitors are superior in response rates to tamoxifen, and we have seen in the adjuvant setting that aromatase inhibitors are better than tamoxifen. This is the next stage, chemopreventive treatment for DCIS.”
Yu said the improvement in incidence of adverse events in this trial is similar to what has been seen in other studies comparing aromatase inhibitors and tamoxifen.
And cost is not a great concern with either of these two treatments, Yu noted, since both drugs are generic.
CALGB/Alliance 40503: No Survival Advantage for Bevacizumab
High vascular endothelial growth factor (VEGF) levels in breast tumors have been associated with decreased response to endocrine therapy. Now, a multicenter, open-label Phase III trial that added bevacizumab to first-line letrozole in patients with hormone-receptor positive advanced breast cancer has tested the hypothesis that anti-VEGF therapy may delay progression on endocrine therapy.
In the efficacy analysis of CALGB/Alliance 40503 presented here by Maura N. Dickler, MD, Associate Member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, the trial began accruing patients in 2008, before bevacizumab lost its accelerated approval for breast cancer from the Food and Drug Administration in 2011 (because studies showed no effect on overall survival).
The 343 patients in the study had a median age of 58, with a range of 25 to 87. Treatment consisted of letrozole at 2.5 mg orally daily or letrozole plus bevacizumab at 15 mg/kg intravenously every three weeks. The primary endpoint was progression-free survival; secondary endpoints were response rate, clinical benefit rate, overall survival, and adverse events.
At 39 months of follow-up, median progression-free survival for patients receiving letrozole plus bevacizumab was 20 months, versus 16 months for those on letrozole alone. Dickler said there was no significant difference between the two study arms in overall survival--47 months for letrozole plus bevacizumab versus 41 months for letrozole alone. But, there was a significant difference in grade 3/4 toxicities: 23 percent of patients taking the combination had hypertension versus just two percent for those on letrozole alone; and proteinuria was also higher, in 11 versus zero percent, respectively.
PALOMA-3: Checkpoint Is Key Target
Resistance to endocrine treatment remains a major clinical problem for patients with hormone receptor positive breast cancer. Researchers in the PALOMA-3 study, funded by Pfizer, hypothesized that checkpoint inhibition might “unleash” the immune system to overcome this resistance.
The study added the CDK4/6 checkpoint inhibitor palbociclib to fulvestrant, and the combination was shown to improve progression-free survival compared with placebo and fulvestrant in women with HR-positive HER2-negative advanced breast cancer whose disease had progressed on prior endocrine therapy. The benefit from palbociclib was demonstrated across all pre-specified subgroups, including in both pre- and post-menopausal women, said the lead study author, Nicholas C. Turner, MD, a consultant medical oncologist at The Royal Marsden and a team leader at The Institute of Cancer Research in London.
Palbociclib is an orally selective drug that inhibits breast cancer cell proliferation and growth by preventing cell cycle progression from the G1 to S phase.
Turner explained that in a prior Phase II study, palbociclib in combination with letrozole significantly increased progression-free survival over letrozole alone in newly diagnosed advanced HR-positive breast cancer (Finn et al: Lancet Oncol 2015;16:25-35).
PALOMA-3, the first Phase III study of a CDK4/6 inhibitor in breast cancer, identified and confirmed that CDK4/6 is a key target in HR-positive breast cancer, he said, noting that the growth of HR-positive breast cancer is dependent on the cyclin dependent kinases CDK4/6 that promote the G1-S phase cell-cycle progression.
The trial included 521 patients in 17 countries in North American, Asia, and Europe, with both pre- and post-menopausal women. All had HR-positive, HER2-negative advanced breast cancer and had disease progression on prior endocrine therapy.
The trial was stopped early based on the efficacy seen in the interim analysis. At the time of that analysis, the median time to disease progression was 9.2 months in the palbociclib arm compared with 3.8 months in the placebo arm, he reported. Comparable benefits were seen in both the premenopausal and postmenopausal women.
“The curves separate early and then continue to separate with ongoing follow-up,” he said. “The palbociclib-fulvestrant combination was well tolerated, although there were frequent hematologic side effects: neutropenia was seen in 79 percent of patients on palbociclib and fulvestrant, and leukopenia in 46 percent.”
But the incidence of febrile neutropenia was very rare, he added--0.6 percent in both arms of the study.
Symptomatic adverse events with palbociclib were largely similar to placebo, with a small increase in fatigue, alopecia, and infections, but serious adverse events were the same in both arms. Discontinuation due to adverse events was also similar.
“This relatively easy-to-take new drug can substantially delay the point when women need to start chemotherapy, making this an exciting new approach for women,” Turner said.
The drug received Accelerated Approval from the FDA earlier this year (OT 3/10/15 issue), for use in combination with letrozole for women with metastatic ER-positive, HER2-negative breast cancer who have not yet received hormonal therapy for their metastatic disease. The approval was granted based on the results of the Phase II PALOMA-1 study.
In the interview before the ASCO meeting, Yu noted that palbociclib is already available and so could be prescribed off label: “So this is potentially a practice-changing abstract that we want to highlight so that doctors and patients are aware they have this choice.”
Perspective on All 3 Breast Cancer Studies from Joseph Sparano
CHICAGO--The three presentations each focus on therapeutically targeting three different hallmarks of cancer, including the tumor and the microenvironment, said the Discussant, Joseph A. Sparano, MD, Professor of Medicine and Obstetrics, Gynecology, and Women's Health at Albert Einstein College of Medicine and Associate Chairman for Clinical Research in the Department of Oncology at Montefiore Medical Center.
Beginning with microenvironment, Sparano said Maura Dickler’s presentation showed that the addition of the anti-EGFR agent bevacizumab significantly extended median progression-free survival when added to first-line endocrine therapy, reducing the hazard rate for progression by 26 percent. “This translated into about a four-month absolute improvement in median profession-free survival, but with no impact on overall survival.”
These results were similar to those seen in previous trials when bevacizumab was added to first-line endocrine therapy, he said, and show very consistent results, indicating a marginal benefit and added toxicity: “There is currently no role for bevacizumab [in breast cancer] in either the adjuvant or neoadjuvant setting outside the context of a clinical trial.”
Regarding the NSABP B35 study, he noted that anti-estrogen therapy is a cornerstone in the management of ER-positive disease, and that selective estrogen receptor modulators (SERMs) like tamoxifen or degraders like fulvestrant bind to the estrogen receptor, thus competitively inhibiting binding of estrogen to the estrogen receptor. In contrast, aromatase inhibitors block the conversion of androgens to estrogens, resulting in estrogen depletion in postmenopausal women for whom it is a major source of endogenous estrogen, more effectively reversing the genomic-mediated effects.
“In the NSABP B35 trial, these two strategies were directly compared for the first time in postmenopausal women with ER-positive and/or PR-positive DCIS who had undergone wide local excision with negative margins and whole breast radiation.” As expected, anastrozole was associated with fewer uterine cancers and thromboembolic events, and somewhat more osteoporotic fractures, and a higher rate of arthralgias.
“These findings provide additional evidence that estrogen deprivations are a more effective anti-estrogenic strategy than a SERM, including in younger women,” Sparano said.
He said it has been known for more than two decades that aromatase inhibitors are more effective than tamoxifen or megesterol in postmenopausal women with metastatic disease, and for more than a decade that aromatase inhibitors are more effective than tamoxifen as adjuvant therapy in postmenopausal women.
It has also been known that extended adjuvant therapy with an aromatase inhibitor following tamoxifen is most effective in women who were premenopausal at the time of diagnosis. And most recently it has been learned that ovarian suppression plus an aromatase inhibitor is more effective than tamoxifen as adjuvant therapy in premenopausal women at high risk for recurrence, including for women under the age of 35 who are node-positive, treated with chemotherapy.
Sparano's take-home message from the session:
· Anastrozole and probably other aromatase inhibitors are a good option for preventing ipsilateral recurrence, but more importantly, for preventing contralateral cancers and DCIS: “Anastrozole is perhaps best suited for younger postmenopausal women with an intact contralateral breast and/or uterus, or a prior history of thrombosis;”
· The role of bevacizumab in breast cancer remains uncertain: “A modest effect in prolonging progression-free survival, when added to aromatase inhibitors, has now been seen in two trials, but better alternatives are now available; the most effective combination in prolonging PFS was when bevacizumab was added to weekly paclitaxel;”
· There is no role for the use of bevacizumab in the adjuvant or neoadjuvant setting; and
· CDK4/6 inhibitors represent an important therapeutic advance in ER-positive metastatic breast cancer: “This represents an entirely new therapeutic modality, and we are just beginning to understand how to appropriately use these agents.”
He concluded by raising the issue of the high cost of cancer drugs overall as well as related to the drugs in these breast cancer studies. “The escalating costs pose a main challenge for patients, the community of health care providers, and the entire health care ecosystem,” he said.
“When considering the therapeutic index of new and existing drugs, we as a community need to have a deeper understanding of the cost of therapies that we prescribe, and the impact on the patients that we serve. The future is calling for us to consider value, not just the components of value, in caring for our patients. And the future is now.”
Monday, July 06, 2015
Ramaswamy Govindan, MD
Professor of Medicine
Co-Director, Section of Medical Oncology
Washington University School of Medicine
Alvin J Siteman Cancer Center
It has now been clearly demonstrated that the immune checkpoint inhibitors targeting PD1 and PDL-1 are effective in 20% of patients with metastatic non-small cell lung cancer (NSCLC). These drugs are generally well tolerated. Several important studies involving immune checkpoint inhibitors were presented at this year’s ASCO Annual Meeting.
The CheckMate 017 study is a randomized phase III study of nivolumab, a PD1 inhibitor in patients with metastatic squamous cell lung cancer who had developed progressive disease following platinum doublet therapy (Abstract 8009). In this study, 272 patients were randomized to receive nivolumab 3 mg/kg body weight intravenously every two weeks until disease progression on docetaxel of the standard dose of 75 mg/m² intravenously every three weeks. The primary end point of the study was overall survival.
The one-year survival rate was 42% with nivolumab and 24% with docetaxel, and the median overall survival was 9.2 months with nivolumab and 6.0 months with docetaxel. In general, the side effects are extremely well tolerated and the incidence of significant pneumonitis was very low.
One of the notable findings with nivolumab was the median duration of response--an impressive 17.2 months (range of 1.8 to 22.6+) compared with only 5.6 months with docetaxel (1.2+ to 15.2+ months). No biomarkers including PDL1 expression have been found to reliably identify patients who are likely to respond to nivolumab.
CheckMate 057 is a randomized study of nivolumab or docetaxel in metastatic non-squamous NSCLC following disease progression after initial therapy with a platinum doublet (Abstract LBA109). The results were similar to those in CheckMate 017. The median overall survival was 12.2 months for patients on nivolumab and 9.4 months for those on docetaxel, representing a 27% decrease in the risk of death for patients who were treated with nivolumab (p=0.0015).
The one-year survival rate for patients who received nivolumab was 51% for nivolumab and 39% for docetaxel. Treatment-related adverse events were higher with docetaxel than nivolumab (any grade: 88% vs. 69% and grade III and IV was 54% vs. 10% respectively).
These two studies clearly demonstrate the superiority of nivolumab in patients with advanced NSCLC over docetaxel in the second-line setting. Much work remains to be done to fully understand the mechanism of resistance (primary and acquired) to immune checkpoint inhibitors. Several novel immunotherapeutic agents are being tested in the clinic at the present time.
Two studies presented at this meeting showed encouraging response rates with immune checkpoint inhibitors in patients with small cell lung cancer (SCLC). The KEYNOTE-028 study is a single-arm phase II study of a PD1 inhibitor, pembrolizumab, administered at a dose of 10 mg/kg intravenously in patients with SCLC who had progressive disease following platinum-based therapy (Abstract 7502). The overall response rate was 35% (95% CI 15-59), and stable disease was reported in an additional 5% of patients.
In the CheckMate 032 study, 40 patients received nivolumab alone and 50 patients received nivolumab with ipilimumab, an anti-CTLA4 antibody (Abstract 7503). The overall response rate with nivolumab was 18%, and the combination produced a response of 17% with a median duration of response ranging from 4.1 to 11+ months with nivolumab and 1.1 to 11.1+ months with nivolumab and ipilimumab.
The median overall survival was 4.4 months with nivolumab and 8.2 months with nivolumab and ipilimumab. Ongoing and planned studies will further define the role of immune checkpoint inhibitors in patients with relapsed SCLC.
Several prospective clinical trials have clearly demonstrated that the EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib and afatinib produce significantly improved response rates and progression-free survival compared with platinum doublets in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Unfortunately, though, the majority of patients with metastatic EGFR-mutant NSCLC develop progressive disease following treatment with EGFR TKIs. The emergence of the EGFR T790M mutation accounts for acquired resistance in nearly 50% of patients in this setting.
Two papers published recently in the New England Journal of Medicine reported impressive response rates and promising progression-free survival with the use of third-generation irreversible EGFR TK inhibitors (AZD9291 and rociletinib) that target EGFR T790M mutation (Jänne et al: NEJM 2015;372:1689-1699 and Sequist et al: NEJM 2015;372:1700-1709). These two drugs are mutant-specific inhibitors and have very little normal tissue toxicities--i.e., severe rash, diarrhea, etc. The role of these two drugs in the initial therapy of patients with EGFR-mutant NSCLC has not been very well studied.
At this meeting, the preliminary results from a multi-center, multi-cohort study in which patients with EGFR-mutant metastatic NSCLC received AZD9291 either at 80 mg or 160 mg in the front-line setting were presented (Abstract 8000). The overall response rate for the entire group was 73% (95% CI: 60, 84) with an impressive disease control rate of 97% (95% CI: 89, 100). The response rate was numerically higher in the 160 mg cohort, with an 83% response rate (95% CI: 65, 94) compared with 63% in the 80 mg cohort (95% CI: 44, 80).
The progression-free survival at 12 months was 72% (95% CI of 55-84). It is not possible to estimate the median progression free survival at this point in view of the immature data.
Based on these preliminary observations, a large Phase III study (FLAURA) has been launched, which will enroll patients with metastatic EGFR-mutant NSCLC in the front-line setting. Patients will be randomized to AZD9291 or a first-generation EGFR TKI (gefitinib 250 mg orally once a day or erlotinib 150 mg orally once a day). The primary endpoint of the study is progression-free survival.
At this point, it is not very clear whether these agents are best utilized in the salvage setting after the development of resistance to first-generation EGFR TKIs or in the frontline setting. Third-generation EGFR TKIs have not yet been approved for use by the Food and Drug Administration in the United States as of July 2015.
It is important to consider biopsy of a growing and accessible lesion to determine the molecular mechanisms of resistance (T790M, Met amplification, etc.) to first-generation EGFR TKIs. Several ongoing studies are evaluating the third-generation EGFR TKIs alone or in combination with inhibitors of VEGF, MEK, C-MET, and immune checkpoints. Every effort should be made to enroll eligible patients in one of these trials.
Since invasive biopsies have certain risks, it is attractive to develop plasma-based assays to detect the emergence of EGFR T790M mutation (Abstract 8001). In the study presented by Dr. Lecia Sequist at this meeting, the response rate to rociletinib was identical whether the T790M was detected either through plasma-based assay or tissue-based assay. These results are rather encouraging.
It is heartening to see the continued progress in the treatment of patients with ALK-positive NSCLC. The results of a single-arm global phase II study of alectinib, a novel ALK inhibitor (Abstract 8008) were presented at this meeting. Alectinib produced a response rate of 50% in 122 crizotinib-resistant patients, with an encouraging duration of response (11.2 months). Most notably the disease control rate (83%) was outstanding. Grade III/IV adverse events occurred in fewer than 5% of patients.
It is likely that we will continue to see progress in the treatment of patients with targeted therapies with a better understanding of molecular pathogenesis of acquired resistance in certain groups of patients with oncogene- addicted tumors. Continued research efforts hopefully will improve the outcomes in patients with lung cancer who are treated with immune checkpoint inhibitors.
Tuesday, June 30, 2015
Axel Grothey, MD
Professor of Oncology
Division of Medical Oncology
Mayo Clinic Rochester, Minnesota
These are the highlights at this year’s ASCO Annual Meeting for gastrointestinal malignancies—specifically, colorectal cancer, gastro-esophageal cancer, pancreatic neuroendocrine tumors, carcinoid tumors, pancreatic cancer, and hepatocellular carcinoma.
The indisputable highlight in colorectal cancer (CRC) presented at ASCO 2015 was the demonstration that anti-PD-1 immune checkpoint inhibitors have significant activity in patients with hypermutated cancers. A high frequency of DNA mutations can be either induced by exogenous carcinogens like UV light (melanoma) and cigarette smoke (lung cancer) or linked to deficient DNA mismatch repair enzymes, the key genetic alteration in Lynch syndrome and in sporadic cancers due to methylation of the MLH1 mismatch repair gene promoter region. About 15 to 20 percent of stage II, eight to 10 percent of stage III, and four to five percent of stage IV colorectal cancers exhibit the deficient mismatch repair phenotype (synonymous with MSI-H) and thus accumulate hundreds to thousands of mutations which can lead to the expression of immunogenic neo-antigens. In a phase II study presented at ASCO 2015 (and simultaneously published in the New England Journal of Medicine), pembrolizumab, a PD-1 antibody, showed remarkable activity as salvage therapy in heavily pretreated patients with the deficient mismatch repair phenotype (MSI-H) with a response rate of more than 60 percent and a disease-control rate of more than 90 percent. Some of the responses showed a remarkable long duration. The same level of activity was found in non-CRC MSI-H tumors, whereas not a single patient with mismatch repair proficient (MSS) CRC showed a response.
These findings open the door for further studies investigating the MSI-H phenotype as a strong predictive biomarker for anti-PD-1/PD-L1 antibodies, which have already become standard of care in other malignancies. Given the remarkable activity observed in the presented trial it is conceivable that off-label use of the approved immune checkpoint inhibitors will be considered by oncologists and patients.
With MSI-H CRC now being identified as a subgroup for a specific therapeutic intervention, ASCO 2015 demonstrated that two additional subgroups, BRAF mutated and HER-2 overexpressing CRC, could benefit from specific targeted approaches.
It has long been recognized that activating BRAF mutations, which are found in about eight to 10 percent of CRCs, are associated with poor prognosis with standard treatment options. In contrast to BRAF-mutated melanoma, where the use of a BRAF inhibitor as a single agent exhibits a high response rate, albeit commonly of short duration, the same approach has only minimal activity in BRAF-mutated CRC. ASCO 2015 now showed several clinical trials with rationally designed combinations of a BRAF inhibitor, EGFR antibody, and a third agent that could either be a MEK inhibitor, a PI3K inhibitor, or conventional chemotherapy.
The most intriguing results were reported with a combination of vemurafenib (BRAFi), cetuximab (EGFR antibody), and irinotecan in pretreated patients with CRC. The combination appeared to be well tolerated and showed remarkable activity in a phase I/Ib study with a response rate of 35% and a PFS of 7.7 months, both results not previously seen in BRAF mutated CRC. This combination is currently being tested in a randomized intergroup trial, S1406, and could establish itself as a new standard of care in this patient population.
The other molecular subgroup of CRC which is emerging as a target for specific intervention is characterized by HER-2 overexpression. A pivotal trial presented at ASCO 2015 demonstrated a 35% response rate in patients with heavily pretreated, HER-2 positive CRC with a combination of lapatinib and trastuzumab. HER-2 overexpression can be found in about 4-5% of RAS wild-type CRC and has been correlated with a lack of response to EGFR antibodies. Some of the responses observed with the HER-2 targeted combination were found to be quite durable.
Taken together, the results of significant activity of specific targeted intervention in molecular subgroups of CRC could open the door for innovative therapies in the 15 to 20 percent of cancers characterized by MSI-H, BRAF mutation, or HER-2 overexpression. It is conceivable that routine clinical workup of a stage IV CRC will soon include testing for these molecular alterations in addition to standard RAS mutational analysis (KRAS/ NRAS exons 2,3,4).
In recent years, radioembolization of liver metastases has become one of the treatment options for CRC patients with liver-limited or liver-dominant metastases. The role of radioembolization (or SIRT: selective internal radiation therapy) as part of standard first-line therapy was investigated in the SIFLOX study, which compared mFOLFOX6 with mFOLFOX6 plus SIRT in 530 patients. The use of bevacizumab was optional in this trial. The primary endpoint, improvement in overall PFS, was not reached (10.2 vs 10.7 months for FOLFOX vs FOLFOX plus SIRT, p=0.43), but it is of note that 40 percent of patients had extrahepatic disease, which was naturally not influenced by the liver-directed approach. The secondary endpoint of PFS of liver metastases was reached with a hazard ratio of 0.69 (12.9 vs 20.5 months, p=0.002). In spite of an increased rate of responses in liver metastases (78.7% vs 68.8%) no increased rate of liver resection was seen, with SIRT. Overall survival data were not mature yet at presentation. The data indicate that SIRT could potentially be considered as a component of standard therapy in patients with liver-limited disease. Its definitive role in the management of patients with metastatic CRC will be further elucidated by two other randomized trials that will be presented within the next one to two years.
One potentially practice-changing trial in gastro-esophageal cancers was presented by David Cunningham: The OE05 trail randomized 886 patients with non-metastatic adenocarcinomas of the distal esophagus and gastro-esophageal junction to a neoadjuvant chemotherapy approach with either four cycles of ECX (epirubicin, cisplatin, capecitabine) or two cycles of cisplatin/ 5-FU (CF). As expected, ECX was significantly more toxic than CF--in particular with regard to hematologic side effects and diarrhea. In this large study no difference in resection rates and progression-free and overall survival was found, which questioned the importance of anthracyclines and a prolonged duration of neoadjuvant therapy in this setting. In fact, based on these data a neoadjuvant treatment approach along the lines of the MAGIC trial with a platinum/ fluoropyrimidine combination now appears to be an appropriate standard of care. In contrast, the role of anthracyclines in the management of esophago-gastric adenocarcinomas appears to be decreasing.
With regard to targeted therapy in gastro-esophageal cancers, ASCO 2015 showed interesting data for pembrolizumab and regorafenib.
The Cancer Genome Atlas project had identified four different subgroups of gastric cancer based on their gene expression profile, two of which--the Epstein-Barr related and the MSI-H cancers--are thought to be candidates for immunotherapy. The proof of principle for the activity of PD-1 antibodies was brought about by data from a phase II study with pembrolizumab in 39 patients with PD-L1 positive tumors based on immunohistochemistry.
Cancers were identified as positive for PD-L1 when stromal staining or staining in at least 1% of tumor cells was noted. Single-agent pembrolizumab induced sometimes durable responses in about 33% of patients based on investigator assessment. Intriguingly, median overall survival in this pretreated cohort of patients was remarkably long with 11.4 months. Additional studies are underway to define the role of PD-1 inhibitors in gastric cancers.
The efficacy of anti-VEGF therapy in advanced gastro-esophageal cancers has been demonstrated by two phase III trials in which ramucirumab, a monoclonal antibody against VEGF-R2, showed benefit in overall survival either as single agent or in combination with paclitaxel. Regorafenib is an oral multi-kinase inhibitor with significant anti-angiogenic properties, which is approved as single-agent salvage therapy in patients with metastatic CRC. In a randomized phase II trial with a 2:1 randomization of regorafenib vs placebo in 150 patients in second- or third-line metastatic gastro-esophageal cancer, regorafenib demonstrated a significant improvement in PFS with a hazard ration of 0.40 (median PFS 2.6 vs 0.9 months, p<0.0001). Overall survival showed a trend in favor of regorafenib.
The results confirm the activity of anti-angiogenic therapy in gastro-esophageal cancers. The role of regorafenib in this setting will need to be further defined in subsequent studies.
In Further Noteworthy GI Cancer News at the Meeting:
· A randomized phase II study of everolimus with or without bevacizumab in patients with advanced pancreatic neuroendocrine tumors (PNET), an increased overall response rate was noted in the bevacizumab arm (31% vs 12%, p=0.005), but no significant improvement in PFS or OS was seen;
· A single-arm phase II study of bevacizumab as single agent in PNET showed a 14% response rate;
· A phase III trial in 402 patients with metastatic carcinoid tumors compared octreotide with either interferon alpha or bevacizumab. Although the bevacizumab arm showed higher response rats (12% vs 4%, p=0.008), no difference in PFS was seen. The toxicity profile favored the bevacizumab arm;
· A randomized phase II study in pancreas cancer demonstrated the activity of PEGPH20, a hyaluronase which is able to degrade a hyaluronan (HA) layer around tumor cells, when added to a gemcitabine/nab-paclitaxel combination. The activity appeared to be limited to patients whose tumors were classified as “HA-high” by immunohistochemistry; and
· In a single arm phase II study in 47 pretreated patients with advanced hepatocellular carcinoma the PD-1 antibody nivolumab revealed a remarkable response rate of 19%, some of which were very durable. Immune-checkpoint inhibitors will be further investigated in future trials in this malignancy which clearly constitutes an unmet need.
Monday, June 29, 2015
Cynthia X. Ma, MD, PhD
Associate Professor of Medicine
St. Louis, Missouri
ASCO 2015 marked another exciting year in breast cancer research. I have summarized some of the key findings reported at this meeting, some of which may be practice changing, while others bring hope and optimism for novel biomarker and treatment strategies in development.
1. Success of cyclin dependent kinase (CDK)4/6 inhibition for women with hormone-receptor positive (HR+) HER2- advanced breast cancer progressed on prior endocrine therapy (Abstract LBA502)
There has been great enthusiasm for CDK4/6 inhibitors as a result of the PALOMA1 trial, which led to the accelerated FDA approval of palbociclib in combination with letrozole as first-line therapy for HR+ HER2- breast cancer in February 2015. At ASCO this year, Turner et al presented results from the PALOMA3, which was a double-blind, phase III study that randomized 521 patients (both pre- and postmenopausal women) with metastatic HR+ HER2- breast cancer progressed on prior endocrine therapy (relapsed or within 12 months of adjuvant endocrine therapy or progressed on endocrine therapy in the metastatic setting) at 2:1 ratio to receive either palbociclib (125 mg daily, 3 weeks on/1 week off) and fulvestrant or placebo plus fulvestrant. Pre- and Peri- menopausal women also received goserelin. The addition of palbociclib conferred a significant improvement in PFS (9.2 months vs 3.8 months, HR 0.422, 95% CI, 0.318 to 0.560; p<0.000001), with benefit observed across all pre-specified subgroups (age, race, menopausal status, sites of metastasis, sensitivity to prior hormonal therapy, number of prior lines of therapy). The overall survival data was not mature to report. Neutropenia was the most common adverse event (AE) in the combination arm, occurring in 79% of patients (grade 3 in 53%, grade 4 in 9%), but the incidence of febrile neutropenia was the same, 0.6%, in both arms. The overall incidence of severe adverse events (SAEs) was also similar. This trial provided further evidence for CDK4/6 inhibitors in the treatment of HR+HER2- breast cancer and the justification for palbociclib, in combination with fulvestrant, as a second-line or subsequent line therapy for this patient population.
2. Anastrozole adds to another adjuvant option for postmenopausal women with HR+ ductal carcinoma in situ (DCIS) (Abstract LBA500)
The NRG Oncology/NSABP B-35 trial randomized 3,104 postmenopausal women with HR+ DCIS to receive either anastrozole or tamoxifen for five years. At a median follow-up of nine years, the study demonstrated a statistically significant improvement in 10-year breast cancer free interval with anastrozole compared with tamoxifen (93.5% vs. 89.2%, HR 0.73, p-0.03). Interestingly the difference was limited to women younger than 60 (94.9% vs. 88.2%, HR 0.52, p=0.003). The incidence of contralateral invasive breast cancer was significantly reduced. No difference in overall survival was observed (92.5% vs. 92.1%, p=0.48). Tamoxifen was associated with more uterine cancer (1.7% vs. 0.8%) and thromboembolic events (grade 3/4 events: 2.4% vs. 0.7%), while anastrozole with more fractures (6.9% vs. 5%). The incidences of hot flushes, arthralgia, and myalgia were similar in both groups. This study provided support of anastrozole in HR+ DCIS. The choice of tamoxifen or anastrozole, however, should be individualized based on the AE profile and patient preferences.
3. Three different bisphosphonates associated with similar DFS in the adjuvant setting (Abstract 503)
While adjuvant use of bone anti-resorptive medications remains controversial due to variable individual trial results, the EBCTCG meta-analysis demonstrated a 34% reduction in risk of bone metastasis and 17% reduction in mortality with adjuvant bisphosphonate in postmenopausal women (Coleman, SABCS 2013, Abstract S4-07). At ASCO this year, S0307, a phase III trial that compared three different bisphosphonate for three years as adjuvant therapy for early-stage breast cancer--zoledronic acid (4 mg IV monthly x 6 then q3 months x 2.5 years); clodronate (1,600 mg PO daily), and ibandronate (50 mg PO daily)--was reported (n=6,097). At a median follow up of 5.4 years, no difference was observed in DFS among the three different bisphosphonates. Overall toxicity was low. The incidence of osteonecrosis of the jaw (ONJ) was the highest with zoledronic acid (1.27%) and the lowest with clodronate (0.31%). Therefore oral bisphosphonate may be reasonable if adjuvant bisphosphonate is considered. However, this trial does not have a no-bisphosphonate arm to address the question of whether bisphosphonate should be used in the adjuvant setting.
4. Denosumab prevents fracture in postmenopausal women in ABCSG 18 trial (Abstract 504)
Denosumab, a fully human monoclonal antibody against RANK-ligand, an essential mediator for osteoclast activity and bone resorption, is currently approved for fracture prevention in postmenopausal women with osteoporosis (60 mg Q6 months) and for patients with bone metastasis (120 mg Q4 weeks). ABCSG 18 was a randomized placebo-controlled double-blind multicenter phase 3 trial that investigated the effect of adjuvant denosumab (60 mg Q6 months) in postmenopausal breast cancer patients receiving aromatase inhibitor regarding bone health and breast cancer outcomes as well as safety. 3,425 patients were enrolled with the primary endpoint of first clinical fracture. There were no differences in the incidence of adverse events or severe adverse events, including arthralgia, vascular disorders, and muscular skeletal complaints; and no ONJ was observed. There was a significantly lower rate of fractures in the denosumab-treated patients (5.4% vs. 10.2% at 6 years, HR 0.5, p<0.001). Strikingly, patients with a normal baseline bone mineral density (T score > -1) showed a similar fracture risk and similar benefit from denosumab compared with those with lower bone mineral density (BMD). Denosumab improved BMD and reduced the incidence of new vertebral fractures. This data justifies the consideration of denosumab in postmenopausal patients on adjuvant AI therapy. It needs to be noted, though, that there is no data for denosumab in breast cancer outcomes in the adjuvant setting.
5. Neratinib shows promise as an extended therapy post trastuzumab in the adjuvant setting for HER2+ disease (Abstract 508)
The ExteNET trial is a phase III trial of neratinib, an irreversible tyrosine kinase inhibitor of HER1, 2, and 4, after adjuvant chemotherapy and trastuzumab for early-stage HER2+ breast cancer. The study randomized 2,840 patients to receive neratinib (240 mg daily) vs. placebo for one year, with the primary endpoint of invasive disease-free survival (iDFS). A significant improvement in iDFS was observed at two years (91.6% vs. 93.9%, HR 0.67, p=0.009). There was a lower rate of brain metastasis with extended use of neratinib. Patients with the HR+ group had a greater benefit (95.4% vs. 91.2%, HR 0.51, p=0.001). Diarrhea was the most common AE--40% grade 3 and above diarrhea, largely occurring during the first 30 days. Cardiac toxicity was infrequent in both arms. The study provides promising data for extended neratinib, and longer follow-up of this trial is eagerly awaited.
6. Androgen receptor (AR) targeting relevant for AR positive TNBC (Abstract 1003)
A phase II study of the AR antagonist enzalutamide in metastatic triple negative breast cancer (TNBC) positive was reported. Eligibilities include tumor AR+ (AR > 0% by immunohistochemistry), no limitation on prior therapy. The primary endpoint was clinical benefit rate (CBR) at 16 weeks in the evaluable patients (AR > 10%). In this single-arm study, 17% TNBC cases screened were AR+. Among the 118 patients with AR+ TNBC, 89 had AR > 10% of the tumor, with 75 evaluable. In the evaluable patients, the CBR at 16 week was 35%, and the CBR at 24 week was 29%. PFS was 14.7 weeks and 8.1 weeks for patients with AR > 10% and AR < 10%, respectively. A gene expression diagnostic test (PREDICT AR) was created that predicts enzalutamide benefit. The median PFS times were 16.1 weeks and 8.1 weeks for the PREDICT AR-positive and -negative population, respectively. Median PFS was 40 weeks if positive by PREDICT AR (0, 1 prior therapy). This study indicated that AR targeting is a valid approach for a subset of patients with TNBC.
7. Antibody drug conjugate (anti-Trop-2-SN-38) shows promise in treating metastatic TNBC (Abstract 1006)
In a phase I/II trial of IMMU-132 (sacituzumab govitecan) in patients with refractory advanced TNBC (median of four prior chemotherapy regimens), the antibody drug conjugate demonstrated an overall response rate of 28%--clearly an active drug. Nausea, neutropenia, and diarrhea were common toxicities. We look forward to seeing more data about this drug in the future.
8. Potentials of Smac (Second mitochondria-derived activator of caspases) mimetics in improving chemotherapy sensitivity in TNBC (Abstract 1014)
LCL 161, a Smac mimetic that inhibits the cellular inhibitor of apoptosis protein (cIAPs), was shown to improve the pCR rate in a phase II randomized trial of paclitaxel with or without LCL161 in a predefined gene signature positive group (37.2% vs. 16.4%), but not in the gene signature negative group. There was increased toxicity with neutropenia, fever, pneumonia, or pneumonitis. More studies are needed for a promising agent, and it is critical for the biomarker development for this agent.
In summary, continued progress is being made in the field of breast cancer management. We are eager to apply this new knowledge in our day-to-day practice and look forward to another productive year in breast cancer research.