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BY GUEST BLOGGER | JUNE 20, 2011
CURE invited Wendy K. D. Selig, CEO of the Melanoma Research Alliance, to share her thoughts on the strides melanoma research has had this year, particularly from the news coming out of ASCO earlier this month.
"This clearly is the year of melanoma." These were the words of George Sledge, Jr., MD, president of the American Society of Clinical Oncology (ASCO), in a BusinessWeek interview, following news that made headlines regarding the latest exciting research results presented at ASCO's recent annual meeting.
We at the Melanoma Research Alliance (MRA) are obviously delighted with the reports, especially because the progress has energized the entire medical community to accelerate finding solutions to defeat this deadly disease.
While much more remains to be accomplished, the word out of the ASCO conference regarding metastatic melanoma is that patients and all those at risk for this deadly disease are now witnessing the launch of an era of unprecedented therapeutic opportunities. Until recently, patients with inoperable metastatic melanoma had very few treatment options. In fact, patients with disseminated stage 4 melanoma have a median life expectancy of less than one year.
Earlier this year, the immunotherapeutic ipilimumab (now known as Yervoy), based on the first demonstration of improved survival in a randomized melanoma trial, received FDA approval. The advances continued with a report that vemurafenib, a so-called BRAF inhibitor that works by a completely different mechanism than ipilumumab, also confers improved overall survival in patients with advanced metastatic melanoma compared to standard chemotherapy.
Vemurafenib and ipilimumab represent two major kinds of drugs with activity against melanoma (signaling pathway inhibitors that target the tumor directly and immune-modulating drugs that work indirectly, respectively) for which there is now a growing, rich pipeline of clinical development.
These are significant milestones, providing platforms for further progress. Ongoing research is building upon these results by identifying mechanisms of drug resistance and biomarkers of treatment response, as well as investigating the value of combinatorial therapies. As the largest private funder of melanoma research, MRA is dedicated to remaining at the forefront of these, and other, critical avenues of research. We need to pursue new avenues because, despite the exciting advances that are benefiting patients today, not everyone responds to the new treatments, and too many people are seeing their cancers eventually return.
Combination treatment strategies supported by strong preclinical data are next in line and will benefit from recently updated FDA regulatory guidance in this area that will facilitate their development. Combination therapies will be critical for providing significant benefit to patients. This is one reason MRA applauds Genentech/Roche, makers of vemurafenib, and Bristol-Myers Squibb, makers of ipilimumab, for entering into an agreement to test these compounds in combination.
It is also noteworthy that these advances in melanoma, which have emanated from decades of scientific groundwork, have also revealed treatment paradigms applicable not only to melanoma but to many other forms of cancer as well.
Included in the $25 million to date the MRA is investing in cutting-edge translational science are projects investigating combination therapies such as BRAF inhibitors and immunotherapies as well as research to better understand the biological mechanisms of BRAF inhibitor resistance.
The recent findings and enthusiasm among researchers in the field motivate all of us at MRA and throughout the melanoma research community to redouble our efforts, so that, collaborating with all stakeholders, one day no one will have to suffer or die from melanoma.
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BY GUEST BLOGGER | JUNE 12, 2011
CURE invited Diane Gambill, PhD, a CURE advisory board member, to share her thoughts on some of the myeloma studies highlighted at the 2011 annual meeting of the American Society of Clinical Oncology.
The FDA approval of the first proteasome inhibitor, Velcade (bortezomib), in 2003 ushered in a new era in the treatment of multiple myeloma. Unfortunately, one consequence of introducing a new drug is the inevitable emergence of resistance. Cancer cells have a dismaying ability to quickly "learn" how to defend themselves against new anticancer agents almost as quickly as they can be introduced into the clinic.
Help for emerging resistance might be on the way. As is often the case, a successful therapeutic agent generates interest in developing the next generation of similar drugs, each developed with a goal of improving on the first generation. Toward that end, the next generation of proteasome inhibitors is currently in clinical development.
Carfilzomib inhibits the activity of the proteasome in a slightly different way than Velcade; thus, it is postulated that carfilzomib might work in patients whose myeloma has become resistant to Velcade. At this year's meeting of the American Society for Clinical Oncology, several phase 2 trials testing this notion were presented.
In one study (PX-171-003-A1), carfilzomib was given as a single agent in 266 patients with myeloma that had received Velcade and Revlimid (lenalidomide) as previous treatments either separate lines of treatment or in combination. Results were promising with a 24% overall response rate including 1 complete response and 13 very good partial responses. The most frequent grade 3/4 toxicities (considered moderate to severe) were anemia (63%), thrombocytopenia (77%), neutropenia (29%) and fatigue (20%). The incidence of grade 3/4 peripheral neuropathy, which is often associated with myeloma and can be a dose-limiting side effect of intravenous Velcade (see note below about new data with subcutaneous administration of Velcade), was low at 1.1% (3 patients). The most notable result, however, was that responses jmappear to be durable. This might be due in part to fewer patients discontinuing therapy due to toxicity, the so-called dose-response effect. Although the data are not yet mature, median overall survival was 15.6 months in all patients and 20.7 months in patients with a response.
Currently available options for patients with relapsed and/or refractory myeloma include Revlimid with low-dose Decadron (dexamethasone) or Velcade with Decadron. A second phase 2 trial presented at this year's meeting addressed the question of whether adding carfilzomib to Revlimid and low-dose Decadron was safe and effective. In this study (PX-181-006), 52 patients were treated with the combination of three drugs. This trial enrolled patients who were less heavily pretreated than the 003-A1 study (at least two prior therapies) and prior Velcade or Revlimid were not required but 75% of the patients had received prior Velcade and 62% had received prior Revlimid. This trial resulted in an overall response rate of 78%, which included 12 complete responses and 9 very good partial responses. The most frequent grade 3/4 toxicities were anemia (13%), thrombocytopenia (12%), neutropenia (17%), fatigue (12%) and diarrhea (6%).
Keeping in mind that phase 2 trial results need confirmation in randomized clinical trials, we await the results of phase 3 trials in relapsed/refractory myeloma. The FOCUS trial is currently under way to determine how carfilzomib compares wtih best supportive care, and the ASPIRE study has already enrolled 144 patients to assess the relative efficacy of Revlimid plus low-dose Decadron with or without carfilzomib. Completion dates for these trials are scheduled for spring of 2012.
The current choices for treatment of myeloma include several effective agents developed over the past decade. Will carfilzomib be next? Several other agents are in late-stage clinical trials for relapsed and/or refractory myeloma including the monoclonal antibody elotuzumab, a third proteasome inhibitor (NPI-0052), and a host of other early-phase compounds. In terms of proteasome inhibitors, it is also worth nothing that a recent publication in the medical journal Lancet Oncology showed, in a randomized clinical trial, that subcutaneous administration in patients with relapsed myeloma was generally safer than intravenous administration with significantly less grade 3 or 4 peripheral neuropathy.
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BY GUEST BLOGGER | JUNE 7, 2011
CURE asked Anas Younes, MD, professor in the department of lymphoma/myeloma, division of cancer medicine at MD Anderson Cancer Center in Houston, and a CURE advisory board member, for his thoughts on the lymphoma advancements announced at this year's American Society of Clinical Oncology.
For the 80,000 or so patients with Hodgkin and non-Hodgkin lymphoma who are diagnosed annually in the U.S., the largest oncology congress in the world, ASCO (American Society of Clinical Oncology), brought some good news and hope for the future. But as expected, several well-designed clinical studies also failed to demonstrate substantial benefits. Going through the large number of presentations, I will highlight the most important ones here.
More is not better for newly diagnosed patients with advances stage diffuse large B cell lymphoma (DLBCL)
DLBCL is a curable lymphoma. However, with current standard R-CHOP chemotherapy, the average cure rate of patients with advanced stage is approximately 50%. When patients relapse, they are treated with a second-line regimen, such as RICE or DHAP, and responding patients get autologous stem cell transplant (ASCT). This strategy can cure up to 50% of responding patients in the relapsed setting. So wouldn't it make sense to offer ASCT (or other forms of more intensive therapy) upfront rather than wait for relapsed disease? But four independent groups, using different strategies, reported that the answer is "No." Thus, RCHOP-21 remains the standard of care.
In the first study from the United Kingdom, Cunningham et al compared dose-dense RCHOP given every 14 days (RCHOP14) with standard RCHOP-21 in 1080 patients. With a median follow up of 39 months, there was no difference in the overall response rate (88% for RCHOP-21 vs 90% for RCHOP-14), complete remission rate, progression free survival (PFS) or overall survival (OS) in the two treatment groups.
Stiff et al compared CHOP-21 (or RCHOP-21) x 8 with CHOP/RCHOP x 6 followed by autologous stem cell transplant (ASCT) in 397 patients with high-intermediate or high-risk (HI/H) age-adjusted international prognostic index (IPI). Although there was a trend for improved PFS for the ASCT arm, there was no difference in OS (74% for chemo + ASCT vs 71% for chemo alone). This means that it did not matter whether a patient had ASCT upfront or at the time of relapsed disease. However, from a practical point of view, keeping ASCT for the time of relapse seems more appropriate.
Schmitz et al also compared intensive front-line therapy with stem cell rescue using 3 sequential courses of R-Mega-CHOEP with R-CHOEP-14 in 306 young high-risk patients with aggressive B cell lymphoma and found no significant difference between the two treatment arms.
Finally, Milpied and colleagues compared 8 cycles of RCHOP14 to a different regimen that incorporated ASCT and reported no difference between the two treatment approaches, and RCHOP14 was as good as the ASCT-containing regimen. Because RCHOP14 is as good as RCHOP21, as discussed above, the standard of care remains RCHOP21.
Increasing impact of targeted therapy and small molecules
So if more is not better, how do we improve on RCHOP21? Incorporating novel targeted therapy with RCHOP is the way to go. But for these trials to be successful, we need to incorporate biomarker analysis to preselect patients who are likely to benefit from these novel approaches. Some of these clinical trials have already started. Examples, RCHOP + lenalidomide, RCHOP + bortezomib, and RCHOP + everolimus. Patients are encouraged to participate in these clinical trials so we can hopefully improve the standard of care and move beyond RCHOP.
The best example of successful targeted therapy in preselected patients based on biomarkers is the antibody drug conjugates (ADCs). In this strategy, a naked antibody is conjugated to a drug, or a toxic chemical, that binds to a specific receptor, internalize, and kill the tumor cell by releasing the toxic drug. At least one ADC, brentuximab vedotin (or SGN-35) is expected to gain FDA approval before the end of the year for the treatment of patients with relapsed Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL).
In a study of 102 patients with relapsed HL after failing stem cell transplant, the overall response rate was 75% and the CR rate was 34%. With a median follow up of 9 months, more than half of the patients who achieved CRs remain in remission. Brentuximab vedotin is currently being combined with ABVD in newly diagnosed patients with HL, and other combination studies will be conducted soon. The second study of brentuximab vedotin was in systemic ALCL. The response rate was 86% in 58 treated patients, with 53% achieving CRs. Tomorrow information on the duration of response will be presented demonstrating durable remissions for responding patients, especially those with CRs. A combination study of brentuximab vedotin with CHOP chemotherapy in newly diagnosed ALCL is currently enrolling patients.
But sometimes less specific drugs may give better outcome, as long as toxicity is not increased. An example is lenalidomide, which works by several mechanisms, including antiangiogenesis, immune-stimulatory property, and direct anti-tumor effect. Lenalidomide alone has a good single-agent activity in patients with relapsed diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (28% and 27% response rates, respectively). Because lenalidomide can enhance the immune response, it has been shown to be particularly active when combined with monoclonal antibodies, such as rituximab.
With this background, two groups combined lenalidomide with rituximab (RR) alone or with RCHOP for the treatment of newly diagnosed indolent/follicular lymphoma and DLBCL. In the first trial, Samaniego et al from MD Anderson Cancer Center reported the RR regimen produced an overall response rate of 90% in 70 evaluable patients, with 60% achieving complete remissions (CRs). The overall response rate in 41 FL patients was 87% with the vast majority achieving CRs. These results compare favorably with chemotherapy-based frontline regimens, including RCHOP and R-bendamustine. A randomized study comparing RR with R-Chemo is under development. A second trail combined lenalidomide with standard RCHOP in a phase 1/2 study in patients with newly diagnosed DLBCL. Nowakowski et al from Mayo Clinic treated 30 patients with DLBCL or follicular lymphoma grade 3. Lenalidomide was given on days 1-10 of each cycle, and all patients required prophylaxis with pegfilgrastim. The investigators reported a response rate of 100% with CR rate of 83%. For comparison, the expected response rate with RCHOP alone is 84%-88% with CR rate of 63%-75%. So once again, there seems to be a benefit of combining lenalidomide with standard RCHOP, perhaps due to the enhancement of rituximab activity. Of course, more patients need to be enrolled on the phase 2 part, and if the data continue to hold, a randomized study will be required. As I discussed in my earlier post, as intensified front-line therapy failed to improve treatment outcome compared with standard RCHOP, progress will be made by incorporating targeted and biologic agents in smarter trials. The lenalidomide + RCHOP study is a good example.
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