New Therapies Harness Power of the Immune System Against Cancer

Striking Results of Investigative Immunotherapies for Melanoma and Cervical Cancer Highlighted

FOR IMMEDIATE RELEASE:
June 2, 2014
Contact: 

Kate Blackburn
(312) 949-3232
kate.blackburn@asco.org

CHICAGO – New research on innovative immunotherapies for advanced or high-risk melanoma and cervical cancer were presented today at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO).  These treatments – used alone or in combination – fight cancer by activating and amplifying the body’s immune response to the disease. 

The new studies find high activity with investigative drugs for advanced melanoma, and show for the first time that ipilimumab, a treatment already approved for advanced melanoma, can substantially decrease the risk of melanoma recurrence in certain patients with earlier-stage disease.  In addition, another small trial reports that a one-time, personalized immunotherapy treatment induces complete and long-lasting remissions in a small number of women with advanced cervical cancer – a disease with little to no effective treatment options.

"The field of immunotherapy has exploded in the last decade, and more and more patients are benefiting,” said press briefing moderator Steven O'Day, MD, ASCO expert and clinical associate professor of medicine at the University of Southern California, Keck School of Medicine. “Having a potential new way to keep melanoma at bay is a major advance for patients who live under the constant fear of recurrence after surgery. It’s also incredibly exciting that we’re extending the benefits of immunotherapy beyond melanoma, to diseases like cervical cancer where patients urgently need better options.”

Featured studies include:

  •  Adjuvant ipilimumab improves recurrence-free survival in patients with high-risk stage III melanoma: Study marks the first time adjuvant (post-surgery) ipilimumab is shown to be effective in earlier-stage melanoma, though side effects are considerable. 
  • PD-1 targeting immunotherapy MK-3475 has high and long-lasting activity against metastatic melanoma: Large phase I trial finds high survival rates in patients with advanced melanoma, including those previously treated with ipilimumab; one-year survival rate is 69 percent across all patient subgroups.
  • Combination immunotherapy with ipilimumab and nivolumab achieves long-term survival for patients with advanced melanoma: Updated follow-up data from an expanded phase I study show concurrent treatment with ipilimumab and the anti-PD-1 nivolumab yields strong, long-lasting responses and high survival rates.
  • HPV-targeted adoptive T cell therapy may provide a new personalized strategy for advanced cervical cancer: Early study of HPV-targeted immunotherapy shows promising activity in metastatic cervical cancer, a hard-to-treat disease with few effective treatment options.

Media Resources:

  • Online Annual Meeting Media Resource Center: Visit www.asco.org/AMMRC for press releases, press briefing recordings, the press briefing schedule at-a-glance, embargo policies, high-resolution photos, print-friendly downloads, and the Virtual Press Room, an online repository of corporate and institutional press releases from third-party organizations. 
  • CancerProgress.Net: The home of ASCO's 50th Anniversary and a timeline detailing the progress made against 18 of the most common cancers. 
  • Cancer.Net: ASCO's cancer information website, providing doctor-approved information on more than 120 cancer types.

The Annual Meeting Media Resource Center will be updated frequently leading up to and throughout the Annual Meeting.

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING IS REQUESTED IN ALL NEWS COVERAGE.

Click here to view the disclosures for the 2014 ASCO Annual Meeting News Planning Team.

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About ASCO
Founded in 1964, the American Society of Clinical Oncology (ASCO) is the world’s leading professional organization representing physicians who care for people with cancer. With nearly 35,000 members, ASCO is committed to improving cancer care through scientific meetings, educational programs and peer-reviewed journals. ASCO is supported by its affiliate organization, the Conquer Cancer Foundation, which funds ground-breaking research and programs that make a tangible difference in the lives of people with cancer.  For ASCO information and resources, visit www.asco.org. Patient-oriented cancer information is available at www.cancer.net.

Adjuvant Ipilimumab Improves Recurrence-Free Survival in Patients With High-Risk Stage III Melanoma

Summary contains updated data not included in the abstract

The final analysis on the impact of ipilimumab on relapse-free survival from a randomized phase III study, EORTC 18071, indicates that adjuvant (post-surgery) therapy with ipilimumab for patients with high-risk stage III melanoma decreases the relative risk of cancer recurrence by roughly 25 percent compared to placebo. This is the third effective adjuvant treatment for lymph node-positive (stage III) patients who are at a very high risk of recurrence after surgery (interferon alfa-2a and peginterferon alfa-2b), though side effects were substantial. Longer follow-up on this study is needed to assess the overall survival benefit of this treatment approach.

“This is a promising treatment ─ we saw substantially fewer recurrences among patients who are at high risk of relapse,” said lead study author Professor Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France. “We’ve seen many impressive new treatments for advanced melanoma in recent years. This trial with ipilimumab is the first to show we may be able to give these new drugs earlier in the course of disease, where they can do more good and potentially cure more patients.”

The immunotherapy drug ipilimumab is FDA-approved for the treatment of inoperable stage IV (metastatic) melanoma, albeit at a lower dose than in the current study. This is the first study to show that ipilimumab is also effective in an adjuvant setting for earlier-stage disease. 

The impact on relapse-free survival was observed both in patients with microscopic metastases, and in patients with macroscopic metastases in lymph nodes, who are at the highest risk of relapse. (Microscopic metastases are tiny areas of cancer cells found during a lymph node biopsy or surgical removal of lymph nodes. Macroscopic metastases are larger areas of cancer in the lymph nodes.)

High-dose interferon alpha2b and pegylated interferon-alpha2b are approved by the FDA as a post-surgery treatment for patients with stage III melanoma who are at a high risk of relapse. The EORTC 18991 trial that resulted in the approval of pegylated interferon-alpha2b did not show an appreciable effect in patients with macroscopic metastases in lymph nodes.

In the present study, 951 patients with surgically treated stage III cutaneous melanoma were randomly assigned to receive ipilimumab or placebo. A sizeable proportion of patients had a high likelihood of recurrence because the cancer had spread to the lymph nodes. Ipilimumab (10 mg/kg) was given every three weeks for four doses, and the treatment continued at three-month intervals for up to three years.

At a median follow-up period of 2.7 years, ipilimumab substantially reduced the risk of melanoma recurrence. There were 294 recurrences in the placebo group compared to 234 in the ipilimumab group.  The three-year recurrence-free survival rates were 34.8 and 46.5 percent in the placebo and ipilimumab groups, respectively.

Overall, ipilimumab reduced the relative risk of recurrence by 25 percent compared to placebo. Subgroup analysis showed a 33 percent risk reduction among patients with microscopic disease in lymph nodes and a 17 percent reduction among patients with macroscopic disease.

Side effects were considerable, however. There have been five treatment-related deaths on the study, and 52 percent of patients discontinued treatment due to side effects, most within the first 12-16 weeks. The side effects were consistent with those observed in treatment of stage IV melanoma ─ inflammation of the colon (colitis), thyroid, and pituitary gland, and skin rash. 

Researchers will continue following patients on this study to evaluate overall survival. Dr. Eggermont remarked that adjuvant therapy with ipilimumab clearly emerges as a new option for patients with high-risk stage III disease and that more research is needed to fully assess the balance of benefits and risks associated with this treatment. A separate, ongoing phase III study (ECOG1609) is comparing two different doses (3 mg/kg and 10 mg/kg) of adjuvant ipilimumab with high-dose interferon.

This research was supported by Bristol-Myers Squibb Company.

ASCO Perspective:
“The results of this study are promising. Ipilimumab is an effective treatment in stage IV melanoma. This is the first study to demonstrate its clinical benefit in stage III melanoma,” said Steven O’Day, MD, ASCO Expert. “The magnitude of the clinical benefit, the side effects, and the dosing schedule warrant further follow up and additional comparative studies with interferon, which are ongoing.”

Relevant links from Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:

 Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:

To view the full abstract, click here.

PD-1 Targeting Immunotherapy MK-3475 Has High and Long-Lasting Activity Against Metastatic Melanoma

Summary contains updated data not included in the abstract

New findings from a large phase I study of 411 patients with advanced melanoma show that the PD-1 targeting antibody MK-3475 yields long-term responses in a high percentage of patients. In the study, the one-year overall survival was 69 percent across all patient subgroups, and responses were ongoing in 88 percent of patients at analysis, after a median follow-up of 12 months. Responses occurred across all dose regimens and in various subgroups of patients, including patients whose disease progressed following ipilimumab therapy, for whom there are currently no effective treatment options.

“This is probably the biggest phase I trial ever conducted in oncology. We were excited to see that MK-3475 was effective in previously untreated patients as well as in those who had multiple prior therapies, including ipilimumab,” said lead study author Antoni Ribas, MD, PhD, a professor of medicine at the David Geffen School of Medicine at the University of California in Los Angeles, CA. “These are early data, but they tell us we are on to something really important.”

The study enrolled 221 patients with prior ipilimumab treatment and 190 patients who had not previously received ipilimumab. All patients had advanced melanoma that had spread to the skin, lungs, or other major organs. Three different MK-3475 dose schedules as a single agent were tested.  

Overall, 34 percent of patients experienced tumor response, as assessed by Independent Review, including 40 percent of patients not previously treated with ipilimumab and 28 percent of patients whose disease progressed on prior ipilimumab. Responses were durable with 88 percent ongoing at the time of analysis. Activity was observed across all dose levels and patient subgroups, irrespective of prior ipilimumab therapy, performance status, LDH levels, BRAF mutation status, tumor stage, and number and type of prior therapies. The estimated one-year survival rate was 69 percent, and median overall survival duration was not reached. The estimated one-year survival rate was 74 percent in patients not previously treated with ipilimumab and 65 percent in patients who received prior ipilimumab therapy. Overall, eight percent of patients experienced serious treatment-related side effects, but only four percent discontinued treatment due to a drug-related side effect.

The FDA had previously granted a breakthrough therapy designation to MK-3475 for unresectable, or metastatic, melanoma. In May 2014, the FDA granted MK-3475 a priority review designation under its Accelerated Approval program. Ongoing randomized controlled studies are assessing the efficacy and safety of MK-3475 in advanced melanoma patients not previously treated with ipilimumab and those who progressed on or after ipilimumab. Studies in an adjuvant setting are planned.

An expanded access program for MK-3475 is now available for eligible patients with advanced melanoma who have been previously treated with ipilimumab and, if indicated, a BRAF inhibitor.

This research was supported by Merck.

*Dr. Ribas is the recipient of a 2000 Conquer Cancer Foundation of ASCO Career Development Award.

ASCO Perspective:
“This large phase I clinical trial demonstrates continued excitement for anti PD-1 therapy. We’re seeing that MK-3475 results in long-lasting clinical responses in the majority of patients, and impressive overall survival with low toxicity,” said Steven O’Day, MD, ASCO Expert. “Importantly, it’s effective regardless of prior ipilimumab treatment. Anti PD-1 as a single agent is a major breakthrough and improves on the initial success of ipilimumab in metastatic melanoma.”

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:


To view the full abstract, click here.

Combination Immunotherapy With Ipilimumab and Nivolumab Achieves Long-Term Survival for Patients With Advanced Melanoma

Summary contains updated data not included in the abstract

Long-term follow-up results from an expanded phase I study show that concurrent treatment with ipilimumab and nivolumab produces an unprecedented median survival of roughly three and a half years (40 months) for patients with advanced melanoma. In the study, the combination treatment nearly doubled the median overall survival found in previous studies of either agent alone.

“Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20-25 percent survived two years, so it’s truly remarkable that we’re seeing a median survival over three years in this trial. Even in the latest era of targeted and immunotherapy agents, the median survival is on average only about 16-18 months with any new treatment alone,” said lead study author Mario Sznol, MD, a professor of medical oncology at Yale School of Medicine in New Haven, CT. “While we’re encouraged by what we’re seeing with the use of these two drugs together, this trial was small, so a randomized phase III trial will be important to validate our initial results.”

Nivolumab and ipilimumab are antibody drugs that target and block two different “gatekeepers” or checkpoints (PD-1 and CTLA-4, respectively) on T cells, disarming the tumor’s defense against the immune system and boosting the immune system’s ability to fight melanoma. Ipilimumab is FDA-approved for the treatment of metastatic melanoma. Lasting antitumor effects have been observed with nivolumab as a single-agent therapy.

In the study, 94 patients with inoperable stage III or IV melanoma who had undergone up to three prior systemic therapies received concurrent treatment with ipilimumab and nivolumab. Approximately 53 percent of patients had very advanced disease (stage M1c), and 55 percent had no prior systemic treatments.

Long-term follow-up data on the 53 patients enrolled in the initial four concurrent dosing cohorts are being reported. Those patients received ipilimumab and nivolumab every three weeks for four cycles, followed by nivolumab alone every three weeks for four cycles. At week 24, patients who did not have disease progression or severe side effects could continue nivolumab plus ipilimumab every 12 weeks for eight cycles. 

Overall, 22 out of 53 patients (41 percent) responded to the treatment, and nine (17 percent) had complete remissions. Tumor shrinkage was rapid and extensive ─ 42 percent of the patients had a greater than 80 percent tumor reduction by week 36 ─ and the responses were durable, with 18 of 22 responses (82 percent) ongoing at time of analysis. Across doses, the one-year and two-year median overall survival rates were 85 percent and 79 percent, respectively, and the median survival duration was 39.7 months. (At the nivolumab 1 mg/kg and ipilimumab 3 mg/kg dose being tested in an ongoing phase II/III trial, one- and two-year overall survival rates were 94 and 88 percent, respectively). The rate of side effects related to induction of immune reactivity against normal tissues was higher than previously observed for either single agent, but side effects were manageable and reversible in almost all patients.

Clinical responses were seen regardless of tumor BRAF mutation status or PD-L1 status, and across all dose levels. According to the authors, the activity of the combination in the PD-L1 negative subgroup was higher than observed in prior trials of nivolumab alone, and therefore supports the observation that the combination is more effective than nivolumab by itself. In addition, the authors stated, if the activity is validated in the phase III trial, patients with melanomas that test positive for a BRAF mutation would have an even more effective immunotherapy option in addition to targeted therapy for treatment of their disease.

Researchers will continue following patients in all cohorts of this study, including a separate cohort of 41 patients who received the combination treatment every three weeks for four cycles, followed by nivolumab alone every two weeks for up to two years. A separate, ongoing phase III study comparing nivolumab plus ipilimumab versus nivolumab or ipilimumab alone, and a phase II randomized study comparing  nivolumab plus ipilimumab to ipilimumab alone, completed accrual; findings have not yet been reported.

This research was supported by Bristol-Myers Squibb and Ono Pharmaceutical.

ASCO Perspective:
“Anti CTLA-4 and anti PD1 single-agent therapies for metastatic melanoma have made significant contributions in recent years. This study combines the two checkpoint inhibitors concurrently in efforts to improve clinical outcomes further,” said Steven O’Day, MD, ASCO Expert. “This update on the initial group of 53 patients treated with ipilimumab and nivolumab confirm continued excitement, with remarkable clinical benefit and longer survival than we’ve typically seen.  Phase III trials will be necessary to determine the benefit of combination checkpoint therapy versus sequential single-agent therapy and delineate the price of additional toxicities.”

 

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:


Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:

To view the full abstract, click here.

HPV-Targeted Adoptive T Cell Therapy May Provide a New Personalized Strategy for Advanced Cervical Cancer

A small, federally funded phase II study shows striking results in several women with advanced cervical cancer, using a new type of personalized  immunotherapy, known as adoptive T cell therapy. In the study, two patients with widespread metastases had complete remissions after a single treatment with the HPV-targeted T cells, and have been cancer free for nearly a year or longer.

“This proof-of-principal study shows that adoptive transfer of HPV-targeted T cells can cause complete remission of metastatic cervical cancer and that this remission can be long-lasting,” said lead study author Christian Hinrichs, MD, an assistant clinical investigator at the National Cancer Institute in Bethesda, MD. “One implication of the study is that cellular therapy might have application to a broader range of tumor types than previously recognized. This treatment is still considered experimental and is associated with significant side effects. We also need to explore why this therapy worked so well in certain women, and not in others.”

Women with metastatic cervical cancer – caused by the human papillomavirus (HPV) – have limited treatment options. The median survival with the two standard first-line therapies, chemotherapy and a combination of chemotherapy and bevacizumab, is 13 and 17 months, respectively. No second-line treatments that improve survival are available. 

HPV-targeted adoptive T cell therapy essentially augments the natural immune response to HPV in the tumor. To develop the therapy, HPV-targeted T cells (immune cells that specifically attack tumor cells harboring HPV proteins) are grown from a patient’s tumor in the laboratory. Those cells are subsequently infused back into the patient to fight the cancer. This is the first time adoptive T cell therapy has been tested in cervical cancer; it has previously shown promise in melanoma, leukemia, and sarcoma.

In the study, nine patients received adoptive T cell therapy, and three responded to the treatment. One patient had a partial response, with a 39-percent reduction in tumor volume, and two patients had complete remissions. Those two patients had widespread metastases, and the disease had progressed despite prior therapy. At the time of analysis, those patients remained in remission for 11 and 18 months after treatment. The treatment was associated with serious side effects, the most common being low blood counts, infections, and metabolic disorders.

Researchers are planning to expand this study to enroll additional patients. The same study is also exploring adoptive T cell therapy for treatment of other HPV-related cancers, such as throat cancer and anal cancer.

Adoptive T cell therapy is being offered at an increasing number of major medical centers in the United States and other countries. More than 4,000 women die of cervical cancer each year in the United States. The disease disproportionately affects underserved populations – who are less likely to undergo cervical cancer screenings – and most patients are younger. Along with screening and preventative vaccines, better treatments are needed to reduce cervical cancer deaths in the future.

This research was supported by the National Cancer Institute, National Institutes of Health.

ASCO Perspective:
“Novel treatments are needed for women with recurrent or metastatic cervical cancer. Because of the association between cervical cancer and the HPV virus, adoptive immunotherapy is a promising approach for these patients,” said Don S. Dizon, MD, FACP, ASCO Expert. “These preliminary data demonstrate, not only the viability of this approach, but that gains in survival can be realized in a cancer where patients have little to no effective treatment options and where median survival is usually less than two years.”

Relevant Links From Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:


Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:

 

To view the full abstract, click here.