Immunotherapy for Frail Adults With Common Malignancies: #ASCO18

Although immunotherapy drugs may now provide a treatment option for older patients with cancer who are ineligible for, or whose disease fails, chemotherapy, there are many unanswered questions about the efficacy and adverse effects of immunotherapy in this patient population. Highlighting these knowledge gaps, as well as discussing ways to reconcile those gaps in clinical practice, will be the focus of an Education Session on June 4 titled “Treating Frail Adults With Common Malignancies: Best Evidence to Personalize Therapy.”*

“People should come to the session to get a deep dive into the current existing evidence base for older or more vulnerable adults who are receiving immunotherapy,” said session Chair Ronald J. Maggiore, MD, of the University of Rochester Medical Center. Older adults are often not candidates for standard chemotherapeutic treatments because of comorbidities and poor performance status, Dr. Maggiore said.

The session will focus on non–small cell lung cancer (NSCLC), which Dr. Maggiore will discuss, as well as bladder cancer and lymphoma. The session will also cover immunotherapy recently approved by the U.S. Food and Drug Administration (FDA) for these cancer types, including pembrolizumab for patients with bladder cancer, Hodgkin lymphoma, and NSCLC.¹

However, the clinical trials that led to many of the immunotherapy drug approvals included younger patients than oncologists typically see, Dr. Maggiore said. Most of the patients enrolled in the seminal studies of immunotherapy for NSCLC were in their early to mid-60s, yet 50% of patients diagnosed with lung cancer in the United States are older than 70.² These trials also excluded patients with poor performance status from participation a priori,^3,4 although post-marketing and FDA safety analyses have been somewhat encouraging for single-agent checkpoint inhibitors in older adults or those with poorer performance status, Dr. Maggiore added.

It can be challenging to apply data from these trials to clinical decision-making for older patients, particularly if they have other comorbidities, Dr. Maggiore said. One of the issues is that, as patients age and develop comorbidities, immune function may decline and there may be changes in the tumor microenvironment, all of which could affect the efficacy of immunotherapy drugs.

The session will feature a clinical vignette to illustrate some of the key challenges in deciding how to treat older patients with immunotherapy, Dr. Maggiore said.

Older Patients in Advanced Bladder Cancer Trials

Dr. Ravindran Kanesvaran

During his presentation, Ravindran Kanesvaran, MD, of the National Cancer Centre Singapore, will discuss the characteristics of older patients with advanced bladder cancer who could benefit from immunotherapy drugs.

Patients who are frail or who have poor renal function are ineligible for cisplatin-based chemotherapy, which is the standard of care for advanced bladder cancer. “Thanks to immunotherapy, patients who may not have received the current standard of care can potentially get some treatment that can prolong their life and give them good quality of life,” Dr. Kanesvaran said.

The recent approvals of pembrolizumab and atezolizumab in the first-line treatment of patients with advanced bladder cancer who were cisplatin-ineligible were based on single-arm phase II clinical trials that reported good tolerability and antitumor activity. ^5,6 Moreover, because trial participants were ineligible for cisplatin treatment because of poor performance status or comorbidities such as kidney dysfunction, neuropathy, or hearing loss, they tended to be elderly (median age: 74 and 73 years for the pembrolizumab and atezolizumab studies, respectively).

“Now we know these data specifically apply to older patients with advanced bladder cancer. In general, clinical trial enrollments are biased toward younger populations, and it is a challenge to decide how to extrapolate those data to the older patient,” Dr. Kanesvaran said.

Immunotherapy for Older Patients With Lymphoma in the First-Line and Relapsed Settings

Dr. Raul Cordoba

As is the case with most cancer types, clinical trials of immunotherapy drugs for Hodgkin and non-Hodgkin lymphoma have included few patients older than 65. Raul Cordoba, MD, PhD, MS, of the Fundacion Jimenez Diaz University Hospital, in Madrid, Spain, will review data on PD-1 inhibitors and CAR T-cell therapy for patients with aggressive relapsed lymphoma.

“So far, clinical data on efficacy and safety of immunotherapy in older patients with lymphoma seem to be similar to younger patients, but we need longer follow-up,” Dr. Cordoba said. Research should be conducted to understand the relationship between baseline immune function, as evaluated through a comprehensive immune assessment, and outcomes of immunotherapy in older patients, he said.

Dr. Cordoba will also discuss early clinical studies testing combination nivolumab and brentuximab vedotin as first-line treatment of patients with advanced Hodgkin lymphoma. “This strategy seems to be attractive in older patients with Hodgkin lymphoma who are not candidates for conventional chemotherapy because of frailty or comorbidities,” Dr. Cordoba said.

–Carina Storrs, PhD

*Program information updated as of February 22. For session time and location information, please refer to the ASCO iPlanner on the Attendee Resource Center (am.asco.org/arc).

References:

1. National Cancer Institute. FDA Expands Approval of Pembrolizumab for First-Line Treatment of Non-Small Cell Lung Cancer. cancer.gov/news-events/cancer-currents-blog/2017/fda-pembrolizumab-lung-expanded. Published June 6, 2017. Accessed February 21, 2018.
2. Ferrara R, et al. Cancer Treat Rev. 2017;60:60-8.
3. Reck M, et al. N Engl J Med. 2016;375:1823-33.
4. Brahmer J, et al, N Engl J Med. 2015;373:123-35.
5. Balar AV, et al. Lancet Oncol. 2017;18:1483-92.
6. Balar AV, et al. Lancet. 2017;389:67-76.

https://bit.ly/2LfRjxv

ASCO Aims to Reduce Obesity Risk for Cancer #ASCO18

Obesity is a major public health issue in the United States, and the rates have risen dramatically since 1990.¹ In many states, 36.5% of adults and 17.0% of children and adolescents are obese.²  Obesity contributes to major noncommunicable diseases including cardiovascular disease, diabetes, and cancer, both in terms of risk and mortality. As many as 84,000 cancer diagnoses each year are attributed to obesity, and overweight and obesity are implicated in 15% to 20% of total cancer-related mortality.³

Obesity is also associated with a worse prognosis after a cancer diagnosis and may negatively affect the delivery of systemic therapy, contribute to the morbidity of cancer treatment, and raise the risk of second malignancies and comorbidities.³

ASCO has been raising awareness of the connections between obesity and cancer risk and outcomes since 2013 when the Energy Balance Work Group was developed to evaluate the evidence and generate recommendations for the role ASCO should take in these areas. Despite the strong connections between obesity and both cancer risk and cancer outcomes, most Americans are unaware that obesity will increase their risk of developing or dying from cancer.

Dr. Jennifer Ligibel

Dr. Clifford Hudis

“When we started this effort, the goals were to make the oncology community more aware of the connection between obesity, inactivity, and cancer risk, and find ways to help providers talk to patients about this,” Jennifer A. Ligibel, MD, of the Dana-Farber Cancer Institute, said. “The research shows that when people are diagnosed with cancer, they are more open to changing their lifestyle and losing weight, which makes this a teachable moment.”

“There was growing evidence from basic and translational science that obesity was a contributing factor to various cancers,” ASCO Chief Executive Officer Clifford A. Hudis, MD, FACP, FASCO, said.

This motivated ASCO’s Board of Directors in 2013 to “elevate the issue of obesity strategically and put ASCO resources to work in addressing it,” Dr. Hudis said. The board’s strategic obesity initiative focused on raising public awareness, research, policy, and advocacy.

In October 2017, as a result of the continued need for ASCO’s involvement in obesity awareness and prevention, the temporary Energy Balance Work Group became the Obesity and Energy Balance Subcommittee, a permanent branch of the Cancer Prevention Committee. Dr. Ligibel, who chairs the subcommittee, told the ASCO Daily News that the subcommittee met in December 2017 to “consider where ASCO should focus its efforts in this area, and how ASCO’s unique role representing oncology professionals could have the biggest influence in reducing the impact of obesity on cancer risk and outcomes.”

The Obesity and Energy Balance Subcommittee developed plans for a number of new initiatives over the next few years, including:

• A survey of ASCO members to determine whether they are discussing physical activity and weight management with patients during and after cancer treatment, and to identify tools and resources that could help support oncology providers in these discussions;
• Development of guidelines that would incorporate physical activity, weight management, and dietary intake at different points during the cancer trajectory; and
• Development of initiatives to educate oncology professionals at all career stages about the relationship between obesity and cancer, as well as strategies to help patients lose weight and make other lifestyle changes during and after treatment.

ASCO’s Previous Obesity Efforts

ASCO’s new initiatives to combat obesity build upon an already robust effort by the Society. For example, in recognition that a broad-based collaboration needed to tackle this public health crisis, ASCO hosted the Summit on Addressing Obesity Through Multidisciplinary Collaboration in 2016. “We brought different professional organizations together that have been working in this area to look at where we can synergize and harmonize our efforts. We realized that by coordinating our efforts, we could avoid duplication, reach a broader audience, and have more of
an impact than working on our own,” Dr. Ligibel said.

The subcommittee’s efforts were in addition to the resources and events developed by the original Energy Balance Work Group in 2014, including:

• ASCO’s “Position Statement on Obesity and Cancer,” published in the Journal of Clinical Oncology (JCO). The statement outlines ASCO’s interest in obesity and cancer, its priorities, and its initiatives to increase awareness of the links between obesity and cancer.³
• The Obesity Toolkit, designed to educate oncologists and patients about the role weight management and healthy lifestyle behaviors play in cancer. The toolkit was updated in 2015 and has been translated into Spanish and French. For more information, visit asco.org/obesity.
• ASCO’s Research Summit on Advancing Obesity Clinical Trials in Cancer Survivors, held in 2014 to identify the unmet needs and opportunities for research regarding obesity, weight loss, and cancer. “Most of the research studies up to this point have been observational. We looked at what types of additional data will be needed to establish weight loss and physical activity as a standard part of cancer care,” Dr. Ligibel said. The recommendations from the summit were published in JCO in November 2015.⁴

“ASCO has recognized that obesity is an area of increasing research. Having high-quality research will enable us to determine what policies we should advocate for on behalf of our patients with cancer and enable oncology providers to give patients evidence-based information to make the necessary lifestyle changes to reduce obesity,” Dr. Ligibel said.

–Christine Lehmann, MA

References:

1. Centers for Disease Control and Prevention. Obesity Trends Among US Adults Between 1985 and 2010. cdc.gov/obesity/downloads/obesity_trends_2010.pdf. Accessed March 9, 2018.
2. National Cancer Institute. Obesity and Cancer. cancer.gov/cancertopics/factsheet/risk/obesity. Updated January 17, 2017. Accessed March 9, 2018.
3. Ligibel J, et al. J Clin Oncol.
   2014;32:3568-74.
4. Ligibel J, et al. J Clin Oncol.
   2015;33:3961-7.

https://bit.ly/2Hgdjpv

Advaxis Data on Prostate Cancer Med To Be Presented at #ASCO18

 Advaxis, Inc. (NASDAQ:ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, today announced preliminary data from the ongoing metastatic, castration resistant prostate cancer (mCRPC) Phase 1/2 KEYNOTE-046 study, conducted in conjunction with Merck (known as MSD outside the United States and Canada) evaluating ADXS-PSA, Advaxis’s Listeria monocytogenes (Lm)-based immunotherapy, alone and in combination with KEYTRUDA^®(pembrolizumab), Merck’s anti-PD-1 therapy.

Findings will be highlighted in a poster discussion at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting underway in Chicago, on Saturday, June 2, from 4:45 pm to 6:00 p.m. CDT (Location: Hall A; Poster #246; Abstract #5019). Principal Investigator and author Naomi Haas, MD, Director of the Prostate and Kidney Cancer Programs and Associate Professor of Medicine at the Hospital of the University of Pennsylvania will be presenting.

ADXS-PSA was tested alone or in combination with KEYTRUDA in an advanced and heavily pretreated patient population who had progressed on androgen deprivation therapy. A total of 13 and 37 patients were evaluated on monotherapy and combination therapy, respectively. Overall, the safety profile was consistent with findings from prior clinical studies using the Lmplatform. Treatment-related adverse events (TRAEs) were mostly mild or moderate constitutional symptoms such as fever, chills, rigors, hypotension, nausea and fatigue, consistent with immune activation and manageable with standard care. One patient in the monotherapy arm was discontinued from the study due to a grade 4 TRAE related to cytokine release, which resolved within 24 hours using medical management. There were no new toxicities observed with the combination therapy. In all treated patients, those who received the combination therapy experienced the longest overall survival (OS) at data cut-off, with the median not having been reached at 13 months of follow-up.

“Improvements in the care and treatment of highly refractory prostate cancer, a traditionally difficult type of cancer to treat, are vital. These early results show a safe and tolerable profile for ADXS-PSA alone or in combination with KEYTRUDA,” said Dr. Haas. “Albeit the study was not designed to compare monotherapy to combination therapy, the survival rates in the combination therapy arm are encouraging, especially given the reduction in PSA levels observed in this group, and mature data in the following 6 months will help better define the role of ADXS-PSA in combination with KEYTRUDA in mCRPC.”

Key Findings from KEYNOTE-046 (as of March 30, 2018):

• The advanced patient population in the study had a median Gleason score of 8.3, and was heavily pretreated, with greater than 70% having received three or more prior lines of therapy.
• Median overall survival had not been reached in the combination arm after 13 months of follow-up (95%CI 7.16-NR), and was 7.79 months (95%CI 3.52-11.9) in the monotherapy arm.
• 56.8% of patients on combination therapy and 38.5% of patients on monotherapy did not experience disease progression.
• The percentage of patients with PSA declines from baseline in the combination therapy arm was 40.5%, and 15.4% in the monotherapy arm.
• In all treated patients, an improvement in survival was observed in patients with PSA declines from baseline of 50% or greater vs. those with PSA declines of less than 50%. There were 7 patients in the combination arm with 50% or greater declines in PSA from baseline, and none in the monotherapy arm.

Previously presented immunologic data from the monotherapy arm of this trial showed that ADXS-PSA induced or enhanced T cell responses not only to PSA, but also to other prostate cancer antigens that were not expressed by the Lm-based vector, which is indicative of antigen cascade or antigen spreading (SITC 2017; Hayes et al. J Immunother Cancer. 2017;5(Suppl 2)86:P2). Correlative immunologic analyses and overall survival for the combination therapy patients are underway.

About KEYNOTE-046

KEYNOTE-046 (NCT02325557) is a Phase 1/2 open-label, multicenter dose determination and expansion trial that evaluates the safety, tolerability and preliminary clinical activity of ADXS-PSA as monotherapy (Part A; n=14 [13 treated]), and in combination with KEYTRUDA (Part B; n= 37) in heavily pretreated patients with progressive and refractory mCRPC. Patient accrual in the study is complete, with 5 patients still receiving treatment, all in Part B, and being followed for survival analysis.

About ADXS-PSA

ADXS-PSA, one of Advaxis’s Listeria monocytogenes (Lm) based immunotherapies, utilizes live, attenuated, bioengineered Lm as a vector to deliver PSA directly to antigen presenting cells. Development is being pursued in a clinical trial collaboration and supply agreement with Merck.

https://bit.ly/2xE8w1O

#ASCO18: Grail’s cancer blood test shows ‘proof of principle,’ but challenges remain

A long way to go, but getting there — that’s the verdict on the highly anticipated data Grail released Saturday about its liquid biopsy for cancer.

The Illumina spinoff is almost as well known for its executive departures and ability to raise buckets of money as for its out-of-the-park goal: detecting tumors super-early, when even cancers with a horrible prognosis might be treatable, by analyzing DNA that has escaped its cells and is floating in the blood.

There are still years of work before Grail has a cancer blood test ready for clinical use. But the four studies it presented at the annual meeting of the American Society of Clinical Oncology demonstrate “a proof of principle,” said geneticist Fergus Couch of the Mayo Clinic, a co-author of a study using Grail’s system to detect breast cancer. “These methods are better for some cancers than others, and there are some cancers we didn’t pick up. But it bodes well that we can detect cancers and not make many mistakes in terms of telling someone she has cancer when she doesn’t.”

The basic idea of circulating cell-free DNA is that tumor cells constantly burst and die, releasing their DNA into the blood. If that DNA contains tumor-specific mutations or other abnormalities, it might reveal the presence of cancer. The challenge is to differentiate cancer-marking DNA from DNA that might look suspicious but doesn’t come from malignant cells.

The early data from Grail’s Circulating Cancer Genome Atlas study suggest that the problem of such “false positives” is tractable. CCGA is enrolling 15,000 participants (it has just over 12,000 so far), 70 percent with cancer and 30 percent without. After a blood sample is drawn at one of the 142 participating medical institutions, Grail analyzes it three ways: detecting mutations in 507 cancer-associated genes; with DNA sequencing to detect gene duplications or losses, which can indicate cancer; and by an assay for abnormal DNA activation, called methylation patterns.

“This is the most exhaustive sequencing you can imagine,” said Dr. Geoffrey Oxnard of Dana-Farber Cancer Institute, who led the lung cancer part of CCGA. “The scope is groundbreaking, because we don’t want to miss any cancer.”

For its ASCO data, Grail analyzed a subset of CCGA including 878 participants with newly diagnosed untreated cancer (20 types) and 749 healthy participants.

Of these, 127 people had lung cancer. After setting the bar for what counts as a cancer signal high enough to keep false positives below 2 percent, the three assays picked up lung cancer about equally well. The methylation test detected 41 percent of early-stage (I-IIIA) lung cancers and 89 percent of late-stage (IIIB-IV) ones. Genome sequencing picked up 38 percent and 87 percent, while the 507-gene assay found 51 percent of early-stage cancers and 89 percent of late-stage ones.

That cell-free DNA picks up advanced lung cancers better than early ones is no surprise, since advanced tumors are larger, among other things. But it’s also a problem. The whole point of cancer blood tests is to detect cancers super-early.

Oxnard called detecting 50 percent of early lung cancers “awesome,” since it might give such patients a much better chance at survival than if their lung cancer is found later.

Outside experts aren’t so sure. “I’m looking for something higher,” said Dr. Debra Patt of Texas Oncology. Low-dose CT finds just under 90 percent of early lung cancers, she pointed out, making it the number to beat. “Ultimately [Grail’s test] is likely to be a better mousetrap, but it still has to evolve.”

Dr. Otis Brawley, chef medical officer of the American Cancer Society, said he’s optimistic that Grail can get its sensitivity numbers up to the 75 percent to 80 percent range, “but it’s going to take time.”

Thoracic oncologist Dr. Naiyer Rizvi of NewYork Presbyterian Columbia University Medical Center, who is not involved in the Grail study, wonders if “early” detection might still be too late: “If a tumor is already shedding DNA into the blood, it might be acting like advanced disease” in terms of the threat it poses. He said the true measure of a test like Grail’s is whether people identified “early” have a higher cure rate than those diagnosed only after they have symptoms. “I view this as very preliminary data,” Rizvi said.

On the positive side, the rate of false positives in Grail’s test seems low. The company had previously announced that the assays detected cancer-like signals (incorrectly, it seemed) in only five of 580 healthy volunteers — but two of those were soon diagnosed with cancer (ovarian and endometrial). That suggests Grail’s tests could have a false positive rate below 1 or 2 percent.

Part of Grail’s secret sauce is subtracting out “this-might-be-cancer” signals from white blood cells. Through aging and stress, those cells accumulate mutations at high rates but in fact never become, say, leukemia. Some 54 percent of the mutations detected in the lung cancer part of CCGA were from white blood cells, not tumors.

“You have to get rid of those to get down to your true tumor-associated mutations,” said Mayo’s Couch. “I’m not aware of anyone else [developing cancer blood tests] who’s doing this.”

The breast cancer part of CCGA, which included 358 women with invasive breast cancer, ran the same three assays. The methylation assay detected 56 percent of triple-negative breast cancers, 34 percent of HER2-positive ones, and 11 percent of hormone-receptor-positive/HER2-negative tumors, all in stages I to III.

“That’s a little lower than we would like,” said Couch. “We’d like to be above 80 percent. But this is just a first pass to show how the three methods do.”

CCGA is also reporting data from 1,627 participants on detecting 20 tumor types at any stage. Again setting the bar high enough to keep false positives below 2 percent, the assays detected 63 percent of colorectal cancers, 58 percent of esophageal, 56 percent of head and neck, 80 percent of ovarian, and 60 percent of pancreatic, in each case for stages I to III. But the test flopped, detecting less than 10 percent, in cancers of the thyroid, uterus, and kidney.

“In some other cancers we do have a lower signal,” said Dr. Anne-Renee Hartman, Grail’s vice president of clinical development. But CCGA is intended to identify the most promising of the assays and optimize them, she said. “We do not intend to bring all three assays into the final product.”

An even bigger challenge than detecting cancer early is distinguishing tumors that are so indolent they will never threaten health. Ideally, a blood test would not flag those cancers, since a diagnosis would send patients for more testing and, in many cases, risky treatment for no purpose. Research to determine that lies well in the future.

https://bit.ly/2xyKUvC

Top Colorectal Cancer Studies at #ASCO18

It is time for the annual meeting of the American Society of Clinical Oncology (ASCO), and for those of you going for the first time, you will enjoy a meeting of fantastic scientific quality. Plan ahead. Think of why you really want to go, and focus. Do not exhaust yourself; instead, pace yourself. I can say that as a veteran of many of these meetings. But clearly, ASCO, as well as the annual meeting of the European Society for Medical Oncology (ESMO), provide great breaking news and high-quality work. Enjoy yourselves.

I wanted to mention a few abstracts that caught my eye. In abstract 3509, Michael Geissler, MD, PhD, and colleagues^[1] report on a very interesting study of triple chemotherapy with anti-EGFR, looking at combinations of a modified FOLFOXIRI regimen plus panitumumab versus FOLFOXIRI alone in chemotherapy-naive, front-line, nonresectable, RAS wild-type metastatic colorectal cancer patients.

It’s a nice study design in terms of how you move the regimen forward. There was a 2-to-1 randomization of 96 patients. What really caught my eye was the extraordinary response rate in the combination arm: 85.7% versus 54.5% in the chemotherapy-alone arm.

It is fantastic that if we select patients appropriately, we can achieve response rates at this level. Clearly, this is a regimen that could be very effective in certain patient groups. There are also some subgroup analyses with relatively small numbers, which we should therefore treat with caution. But it’s a study to watch for.

In another interesting abstract, 3507, Katherine Clifton, MD, and colleagues^[2]have done a very nice study using a clever methodology to look at new copy number circulating DNA. They looked for driver mutations in a very large cohort of colorectal cancer patients; almost 5000 patients underwent molecular profiling with a plasma-based, next-generation sequencing assay.

The assay encompassed driver mutations like ROS1, RET, ALK, and some of the FGF receptor fusions. In this well-designed study, they found 41 patients in whom they could detect DNA driver mutations. It was a huge effort and very well done; however, quite a small payback given the effort. Of course, there is no evidence as yet—at least in the abstract—as to whether those driver mutations were of any clinical use.

This raises the question of how much work is still to be done in terms of using next-generation sequencing in precision medicine. There is extraordinary potential for using gene sequencing, but can it actually be parlayed into significant, practical clinical benefit?

Another abstract that caught my eye was 3505, reported by an excellent Italian group with lead author Filippo Pietrantonio, MD.^[3] This study addresses the question of maintenance chemotherapy in patients with RAS wild-type, unresectable, metastatic colorectal cancer. The patients received FOLFOX and panitumumab for eight cycles of induction therapy and then they were randomized to two different maintenance regimens: panitumumab alone or panitumumab plus infusion of 5-FU/leucovorin. They had 229 patients randomized equally across each arm. The study showed a benefit from maintenance with chemotherapy and panitumumab.

This is an area that still fascinates me. In the old days, we published a couple of papers in the Lancet from the United Kingdom in which we randomized patients who were responding or had stable disease to stop or continue chemotherapy until progression. In those rather old-fashioned studies, having a complete chemotherapy break did not interfere or reduce overall survival. And not surprisingly, it was associated with improved quality of life.

Of course, there have been more recent studies from Italy, France, and the Netherlands in which some form of de-intensified maintenance chemotherapy is associated with prolongation of progression-free survival. This is more or less what was shown here—that rather than just use panitumumab on its own, if one is de-intensifying chemotherapy, then use the infusion of 5-FU/leucovorin.

In our clinic, we tend to use capecitabine. And we tend to select patients for maintenance treatment who have a higher metastatic burden or tumor load on presentation; who present with relatively oligometastatic disease that is, for whatever reason, not technically ablatable or operable; and who have a good response to chemotherapy.

For the elderly, the frail, and those who have suffered toxicity with chemotherapy, we would give them a chemotherapy break and reintroduce chemotherapy on progression of disease.

In younger, fitter patients who are tolerating chemo and who had a big initial burden of disease, we would offer a maintenance treatment. A fluoropyrimidine and anti-EGFR inhibitor in RAS wild-type disease would seem entirely reasonable. But think about the possibility of a complete chemotherapy break for those who have more indolent disease and perhaps are less tolerant of chemotherapy.

https://wb.md/2JkNc62

#ASCO18 Highlights: Melanoma

As part of of our coverage of the 2018 American Society of Clinical Oncology (ASCO) meeting, being held June 1–5 in Chicago, we spoke with Ryan J. Sullivan, MD, about several melanoma presentations of interest at the meeting, as well as questions of major clinical importance in the management of melanoma today. Dr. Sullivan is a medical oncologist at Massachusetts General Hospital, Boston, Mass., who specializes in the care of patients with advanced melanoma. He is also leading clinical trials investigating the development of predictive biomarkers in the treatment of patients with melanoma.

Cancer Network: Are there one or two key presentations of clinical trial data at the meeting that you feel could potentially be practice-changing?

Dr. Sullivan: This is another year when the practice-changing trial results are not part of the oral abstract and poster sessions, and may or may not find their way into the poster sessions. The main issue with melanoma right now is sorting out the best way to treat patients upfront, and there are ongoing trials addressing that. Some abstracts at the ASCO meeting are presenting economic analyses of sequencing therapies and comparing different treatment approaches head-to-head.

The trials that will truly be practice-changing are the ones looking at how to treat patients after upfront immune checkpoint inhibitor therapy, because well over 50% of our patients are progressing on those treatments and we need to have better therapies for these patients. Some of these trials are early-stage, some in melanoma but some are single-agent [studies] or combinations of novel immune-targeting agents plus, usually, an anti-PD1 antibody. And ultimately, some of those strategies will be moved forward if the preliminary data hold up.

So there are a number of abstracts, some in the melanoma program and some probably in the developmental therapeutics immunology program, that give us a better sense of what types of therapies are being studied and [will provide] the preliminary evidence to understand whether we should move those approaches forward into larger trials.

Cancer Network: Are there other, specific presentations at the meeting that you would like to highlight?

Dr. Sullivan: There are some melanoma trials with additional follow-up data. One is [overall survival data from] COLUMBUS, which is a phase III trial of encorafenib (an oral BRAF inhibitor) plus binimetinib (an oral MEK inhibitor) vs vemurafenib or encorafenib in patients with BRAF-mutant melanoma. [The] phase II [data on] epacadostat (an IDO inhibitor) plus nivolumab trial data will be interesting to see, although in the context of the epacadostat-plus-pembrolizumab phase III trial that failed to show an improvement in metastatic melanoma patients compared to pembrolizumab alone, I am not sure how exciting the data will be. [I’m also in interested in] the phase III data on pembrolizumab plus epacadostat.

The 4-year survival data on patients who were on pembrolizumab for 2 years and then went off treatment [will be useful]. I always like seeing these types of data—on the patients who stopped treatment after 2 years and continued to be followed—in order to see how long these patients can go before needing new therapy and [experiencing] progression. These data are absolutely practice-affirming, because we are stopping patients who are on an anti-PD1 [programmed death 1] therapy and are having great responses. And any additional data help support us in speaking to patients and saying “here are the data, and we feel more comfortable than ever because we have these additional data.” Every year that [this type of outcome] is presented, I am thrilled, because [such findings provide] more and more confidence that it is ok to stop these therapies in patients after a while.

Also, an analysis of the COMBI-AD phase III data on adjuvant dabrafenib plus trametinib, a BRAF-inibitor plus MEK-inhibitor combination based on the AJCC 8 [American Joint Committee on Cancer 8th edition Cancer Staging Manual] classification will [likely provide some useful information]. This will not change the dataset, but at least we will be able to apply the data that are presented in the contemporary AJCC staging system—whereas the trial itself was run under the prior staging system, which is important but not particularly exciting. It will help in the day-to-day management of patients, to translate those data into this current era. In addition, [there are] updated data from the Checkmate 238 adjuvant trial of nivolumab vs ipilimumab. And it’s always great to window shop at the poster session, to see what researchers are working on that I didn’t know about. That is certainly something I am looking forward to.

Cancer Network: Are there any trials you are a part of that will be presented at the meeting and which you could highlight?

Dr. Sullivan: There is a trial of entinostat (an HDAC [histone deacetylase] inhibitor) and pembrolizumab that is part of the poster session, which is a dose-expansion study in melanoma as part of a phase Ib trial. There’s also a trial, in the developmental therapeutics section, of an oral PI3-gamma inhibitor, IPI-549, plus nivolumab (as part of a poster discussion session). There will not be any melanoma patient data [from the study] presented at this meeting, but this is an example of an emerging combination that could be potentially useful in [treatment of] melanoma and other tumor types.

Cancer Network: Lastly, what is your perspective on how the treatment paradigm for patients with metastatic melanoma has changed in the last 10 years? It seems that there has been quite a bit of progress, but there are still unmet needs that have to be addressed.

Dr. Sullivan: It can’t be overstated that there has been a dramatic change in the way patients with metastatic melanoma are treated in the last 10 years. There are almost a dozen drugs approved or about to be approved [for treatment of melanoma], including combination therapies. We essentially went from not having anything for our patients to having many options, and this has translated to an increase in survival.

There was a study of melanoma patients enrolled in clinical trials [that was] published in 2008 and covered the span from 1975 to 2005. And the 1-year survival to begin with was about 25%, and it hadn’t changed much in the 3 prior decades. Then, when you look at the clinical trial data from some of the really large, randomized phase III trials such as COLUMBUS, Checkmate 067, and Keynote 006, the 2-year survival is at or above 50%, up from a 1-year survival of 25%; and the 3-year survival is somewhere between 40% and 50%.

We don’t know what the 5-year survival will be for some of these trials, but contrast the 5-year survival from that meta-analysis, where the survival at 5 years was 5% or less. And [in the future] we are probably going to be [achieving survival rates] 7 or 8 times that at 5 years, which is amazing. This really highlights [not only] that a lot of drugs were approved but also that these drugs had [a significant impact] on patients’ lives. The obvious first unmet need is that the majority of metastatic melanoma patients are going to die from their disease, and so the 5-year survival rate of 30% or 40% is not good enough, even though it is so much better than before we had these drugs.

So we need to get better at upfront therapy or sequencing there. We also need to [improve how we treat] toxicity, particularly because the safety profile of the immune checkpoint inhibitors is so different from that of chemotherapy or oral agents. And we have to get better at predicting who will develop these toxicities—and ideally get better at treating and maybe even preventing these toxicities. Also [we need to get better at] figuring out who to treat with what and when, and [what are the] optimal treatments. [Management considerations may include] selection of treatments such as post–immune checkpoint inhibitor therapy, and that really speaks to us needing to understand better the innate and adaptive immune resistance to these drugs, and to oral agents.

We also need to get better at treating patients with uveal melanoma, where there has not been much progress despite [our ability to] treat these patients with the drugs available for metastatic melanoma. But we need to identify effective therapies for uveal melanoma, because the current drugs don’t work all that well for this disease. And overall, we don’t have a great way to [develop] a treatment strategy for every patient who comes through the door that optimizes his or her chances of benefit.

https://tinyurl.com/yc6d6opd

Cleveland Clinic Cancer Center experts present data at #ASCO18

At the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, researchers from Cleveland Clinic Cancer Center will present data from several new studies, including a prospective clinical trial examining non-small cell lung cancer cells’ response to immunotherapy; research on germline testing for melanoma; and interim results from a study testing a vaccine for glioblastoma.

“Clinical research is critical to the development of treatment options we can offer patients that extend their lives and improve their quality of life,” said Brian Bolwell, M.D., FACP, chairman of Cleveland Clinic Taussig Cancer Institute. “Clinical trials, involving immunotherapy and genomics in particular, are a priority for our cancer center and the research we are presenting at ASCO is a testament to that.”

• Abstract 12001 title: Prospective clinical evaluation of blood-based tumor mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC): Interim B-F1RST results; Dr. Vamsidhar Velcheti, oral presenter; Tuesday, June 5Vamsidhar Velcheti, M.D., FACP, FCCP a medical oncologist at Cleveland Clinic, will announce, in an oral presentation, the interim results of the first prospective trial looking at blood-based tumor mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer. Patients on this clinical trial had a blood-based test for circulating tumor DNA mutation burden before participating in the trial, allowing researchers to perform a post-trial comparison on whether the cancer’s genomics were a predictor of response to immunotherapy. Early data, gathered from more than 20 sites, has shown progression-free survival.
  Dr. Velcheti is also an author on a study that was the first to examine ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer. A portion of the results were published in Lancet Oncology in April, and at ASCO, updates will be presented. Lastly, Dr. Velcheti was also one of the key investigators in a first-in-human phase 1 clinical trial of loxo-292, a drug targeting RET-fusion positive non-small cell lung cancer, which will be presented at ASCO. This treatment is showing promise in patients with lung cancer harboring this rare form of genomic alteration, and offers a therapeutic alterative with targeted therapy.
• Abstract 2041 title: Phase II trial of SurVaxM combined with standard therapy in patients with newly diagnosed glioblastoma; Dr. Manmeet Ahluwalia, poster presenter; Saturday, June 2Manmeet Ahluwalia, M.D., a Cleveland Clinic medical oncologist specializing in neuro-oncology, will present a poster on the interim results from a multicenter Phase II study of SurVaxM in patients with newly diagnosed glioblastoma. SurVaxM, is a first-of-its-kind, patented peptide mimic immunotherapeutic vaccine that targets survivin, a cell-survival protein present in most cancers, and is designed to control tumor growth and recurrence. Patients received four priming doses of SurVaxM (500 mcg) with Montanide and sargramostim (100 mcg) every two weeks, followed by adjuvant temozolomide and maintenance SurVaxM every 12 weeks until progression.
  Analysis of the first 55 patients showed progression-free survival was 96.3 percent measured from diagnosis and 62.8 percent from first immunization. The 12-month overall survival was 90.9 percent from diagnosis and 70.8 percent from first immunization. The regimen was generally well tolerated and immunization-related adverse events were mild with no serious adverse events attributable to SurVaxM. Researchers concluded standard therapy plus SurVaxM appears promising in glioblastoma compared to standard therapy alone, and the use of SurVaxM is safe in glioblastoma. A randomized, prospective trial of SurVaxM in glioblastoma is planned.
  Dr. Ahluwalia is also part of a multi-institutional team examining the efficacy of using tumor DNA to guide treatment for patients with glioblastoma. He and investigators from several leading institutions are participating in a new collaborative effort called ALLELE, to generate prospective clinical genomics and inform treatment decisions such as clinical trial participation in patients with newly diagnosed glioblastoma. The latest data from their work will be presented as an oral at ASCO.
• Abstract 1588 title: Multiplex germline testing in selected melanomas presenting to oncology clinic; Dr. Pauline Funchain, poster presenter; Saturday, June 2Also at ASCO 2018, Pauline Funchain, M.D., a Cleveland Clinic medical oncologist specializing in melanoma, will present a poster focused on multiplex germline testing in selected melanoma patients. Dr. Funchain’s objective was to establish the usefulness of germline testing in the oncologic melanoma population.
  In Dr. Funchain’s research, a cohort of patients selected based on family or personal history of multiple cancers were offered germline testing with a multiplex panel comprised of 12 genes related to melanoma and 69 additional cancer-related genes not known to be related to melanoma. Dr. Funchain and team concluded that multiplex germline testing in this group resulted in an 18.5 percent mutation-positive rate. Nearly half were identified in genes not previously associated with melanoma, and all genes identified related to increased risks of other cancers. She concluded that patients with melanoma, particularly with a personal or family history of other cancers, may benefit from germline testing, and more data will be required to further refine testing guidelines for melanoma.

https://bit.ly/2sB3Wvj