ASCO 2015-ELECTIVE NODE DISSECTION FOR EARLY ORAL CANCER

CHICAGO, IL — Optimal management of the neck in early oral cancers has been a matter of debate, but the results of a large randomized phase 3 trial have now settled the question, say the authors.

"Elective neck dissection [END] should be the standard of care for early node negative squamous cell cancers," said lead study author Anil D'Cruz, MBBS, professor and chief, Department of Head and Neck Surgery, Tata Memorial Centre, Mumbai, India.

An interim analysis of the first 500 patients showed that END improved overall survival by 12.5% in absolute numbers compared with therapeutic neck dissection (TND). END also reduced the relative risk for death by 36% and of recurrence by 55%.

Dr D'Cruz presented the results of his study during the plenary session here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

The study has also been published in the New England Journal of Medicine to coincide with the ASCO presentation.

"This study provides long-awaited answers to a question doctors worldwide have struggled with," commented ASCO expert Jyoti D. Patel, MD. "We never want to do more surgery than we have to, but for patients with early oral cancer, we now know that more extensive surgery prolongs lives."

But another expert questioned the generalizability of the results.

Hisham Mehanna, MD, from the University of Birmingham, United Kingdom, who acted as discussant of the study, said at this time, END should be standard of care — but for cancers of a certain depth.

Two Schools of Thought

To date, there have not been any strong clinical practice recommendations advocating neck dissection for early oral cancers, and thus there has been a wide range of variability in practice. Dr D'Cruz noted that the treatment of early oral cancer has been a matter of considerable debate among physicians — one that has spanned 5 decades.

The management of early oral cancers is primarily surgical, and there are two schools of thought: the "watch and wait" approach, which has TND as a progressive option as needed, and END.

According to Dr D'Cruz, TND has never shown a conclusive survival advantage, and patients must undergo an additional surgical procedure, which increases the risk for morbidities.

END, however, has been associated with better control and survival and involves only one surgical procedure.

Improved Overall and Disease-Free Survival

The primary end point of the study was overall survival, and the secondary end point was disease-free survival.

The trial, which was conducted at Tata Memorial Centre between 2004 and 2014, randomly assigned 596 patients with lateralized stage T1 or T2 oral squamous cell carcinomas to END or TND. An interim intent-to-treat analysis of 500 patients (255 TND, 245 END) with a minimum follow-up of 9 months was performed as mandated by the center's Data and Safety Monitoring Committee.

In this group, there were 427 tongue, 68 buccal mucosa, and 5 floor-of-mouth tumors; about half (n = 221) were TI, and 279 were T2.

There were 81 recurrences and 50 deaths in the elective surgery group, and 146 recurrences and 79 deaths in the therapeutic surgery group.

At 3 years, END resulted in an overall survival rate of 80% compared with 67.5% for TND (hazard ratio for death, 0.64 in the elective surgery group; P = .01).

At that time, the END group also had a higher rate of disease-free survival compared with the TND group (69.5% vs 45.9%; P < .001).

The rates of adverse events were 6.6% in the END group vs 3.6% for those in the TND group.

"For every eight patients who undergo [END], one death is prevented," said Dr D'Cruz, "And for every four patients who undergo the procedure, one recurrence is prevented."

Important...but Not Ready to Change Standard

This is an important study because it was a large randomized trial, and one that would have been difficult to conduct in the United States, commented Lori J. Wirth, MD, medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital in Boston.

"In the US, neck dissection is done in early-stage oral cancer, but the decision to do it is based on the depth of the cancer," she told Medscape Medical News. "So it is part of the standard of care for those cases, and we have seen that it can improve survival, but its importance appears to be greater than we may have previously thought."

However, although the data are important, Dr Mehanna does not believe END should be standard of care for everyone.

"END should be used for early oral cancer with tumors that have a depth of more than 3 mm," he said during his discussion. "There is inadequate evidence currently about ultrasound surveillance, and while we await further results, sentinel node biopsy can be used."

Sentinel node biopsy can help avoid neck dissection in about 70% to 75% of cases, Dr Mehanna explained, but acknowledged that it can be logistically difficult, resource-intensive, and may not be useful in resource-poor settings.

"In the future, biomarkers can hopefully be used to help determine the presence of occult metastasis," he added.

"This was an ambitious study with difficult randomization and has helped resolve one of the important controversies," Dr Mehanna concluded. "The study has potential to resolve even more of them."

The study was funded by the Department of Atomic Energy, Clinical Trial Center. Dr. D'Cruz, disclosed that he is with the Speakers' Bureau with Merck Serono and received research funding (institutional) from GlaxoSmithKline 

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Presented May 30, 2015. Abstract LBA 9002.

ASCO 2015-UPFRONT CHEMOTHERAPY FOR PROSTATE CANCER

CHICAGO, IL — Chemotherapy, which has traditionally been considered a treatment of last resort for prostate cancer, continues to inch closer to the therapeutic frontline, according to new research presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

On the heels of several recent trials (CHAARTED and STAMPEDE) suggesting a role for docetaxel chemotherapy in metastatic prostate cancer, a new trial — Radiation Therapy Oncology Group (RTOG) 0521 — now suggests it may have even greater benefit at an earlier stage: in high-risk, localized disease.

"Our study included nonmetastatic, potentially curable prostate cancer," lead investigator Howard M. Sandler, MD, from Cedars-Sinai Medical Center in Los Angeles, California, told Medscape Medical News.

"This is the first study that shows a potential survival benefit to using chemotherapy in this high-risk patient subset, and I think that for the right patient, the right physician, there will be justification — based on these results — for adding adjuvant docetaxel."

His words echoed those of STAMPEDE's lead investigator, Nicholas David James, MD, PhD, from Queen Elizabeth Hospital Birmingham, United Kingdom, who said during the same session that in addition to considering routine docetaxel in the metastatic setting, it should also "be considered for selected men with high-risk nonmetastatic disease," given the "substantial prolongation of failure-free survival" his trial showed in this patient population.

However, although some experts welcome the news of an earlier role for chemotherapy in prostate cancer, concerns about the toxicity of docetaxel and the robustness of the RTOG 0521 results have other experts urging caution.

As discussant for both the STAMPEDE and RTOG 0521 studies, Ian Tannock, MD, PhD, from Princess Margaret Cancer Centre, University of Toronto, Ontario, Canada, added a dissenting voice to the plenary session.

Although a newly published trial, Groupe d'Étude des Tumeurs Uro-Génitales (GETUG) 12, shows no benefit to upfront chemotherapy (hazard ratio [HR], 0.71) in high-risk localized disease, according to relapse-free survival rates ( Lancet Oncol. Published online May 28, 2015), and STAMPEDE shows a strong benefit in this same measure (HR, 0.57), relapse-free survival "does not inevitably mean improved overall survival," Dr Tannock pointed out.

Questioning RTOG's one-sided statistics and failure to meet its prestated criteria for an overall survival benefit, he said, "if there is no effect on overall survival, then chemo delayed is toxicity delayed, and is the preferred strategy."

Although he said his opinion might change with longer follow-up, for the time being, Dr Tannock put a damper on some of the enthusiasm for earlier chemotherapy. He recommends that "men with localized nonmetastatic prostate cancer who are to receive local treatment with radiotherapy should not be offered docetaxel in addition to androgen-deprivation therapy."

Study Details

RTOG 0521 enrolled 563 patients (mean age, 66 years) with high-risk localized prostate cancer. Patients were randomly assigned to receive standard therapy, which consisted of 24 months of androgen suppression and 8 weeks of external radiotherapy, or standard therapy plus chemotherapy, which consisted of six 21-day cycles of docetaxel plus prednisone starting 28 days after radiotherapy.

After a median follow-up of approximately 6 years, the 4-year overall survival rate was significantly higher in the chemotherapy group (93% vs 89%; P = .04; HR, 0.70, although this did not meet the prestated HR goal of 0.49).

Other endpoints such as distant metastasis and disease-free survival were also significantly better in the chemotherapy group compared with the control group.

Although there were more deaths in the control group, the causes of death were "strange," noted Dr Tannock.

There were seven more prostate cancer deaths in the control group, but this was counter-balanced by six deaths in the experimental group resulting from toxicity or unknown causes compared with none in the control group.

Speaking at a press conference, Dr Sandler described docetaxel as "a relatively familiar and well-tolerated systemic chemotherapy regimen." However, toxicity should be the main concern for practicing clinicians considering upfront chemotherapy, another expert told Medscape Medical News.

"Death in the adjuvant setting is sobering," said Marc B. Garnick, MD, professor of medicine at Harvard Medical School in Boston, Massachusetts. "With any adjuvant program comes the balance of risk of relapse vs toxicity of the treatment program. These patients may have been cured with the standard therapy, yet may have been exposed to a fatal outcome in the adjuvant setting."

Cause of Death	Androgen Suppression + Radiotherapy (n = 59)	Androgen Suppression + Radiotherapy + Chemotherapy (n = 43)
Death resulting from cancer under study	23	16
Death resulting from protocol treatment	0	2
Death resulting from other cause	24	16
Death resulting from secondary primary	12	5
Unknown cause of death	0	4

Dr Granick, who is also editor-in chief of the Harvard Medical School Annual Report on Prostate Diseases, also commented that "wiith the introduction of any new treatment programs, the devil will be in the details."

He added, "While Sandler et al need to be congratulated for carrying out this complicated study, final assessment of its importance will by necessity require details, details, and more details, along with greater follow-up."

He also cautioned that because very few of the data have been published in full-length, peer-reviewed manuscripts, "we are left with many unanswered questions and uncertainties before the touted results can be taken as fact."

Reaction was more positive from Christopher Sweeney, MD, whose CHAARTED study, presented last year at this meeting, helped shape the debate about upfront chemotherapy in prostate cancer.

"It is both reassuring and indeed very encouraging to see the results of RTOG 0521," Dr Sweeney, from the Dana-Farber Cancer Institute in Boston, told Medscape Medical News, emphasizing what he called the "consistency of accumulating evidence" for docetaxel in prostate cancer.

"All in all, we are in the medical profession to decrease the number of people who die of cancer," he said. "Multimodality and multidisciplinary care attacking cancer from different angles has been a winning proposition for many other cancers. It is very, very exciting to see we are starting to see strong and consistent evidence that we are achieving the same with high-risk localized prostate cancer treated with radiation plus testosterone suppression plus docetaxel. These are men who have aggressive prostate cancer, and left untreated, many die of this type of prostate cancer. As such, they need proactive treatment. As these results mature, we will not sit on our laurels but are enthusiastic about assessing the other agents which are active in these earlier settings, either in combination with docetaxel or as alternatives for patients who are not fit for chemotherapy."

ASCO expert Charles J. Ryan, MD, professor of medicine at the University of California, San Francisco, School of Medicine, was also enthusiastic.

"Adjuvant chemotherapy has delivered major survival gains to people with several of the most common types of cancer, and now we're finally seeing the same with prostate cancer. Here we have a powerful new use for a long-established therapy," he said.

In fact, RTOG 0521 is the first prostate cancer study ever to show a benefit for "adjuvant" chemotherapy in the strict definition of the word, he added.

In both CHAARTED and STAMPEDE, the chemotherapy was "not adjuvant as we define it in most cases," he told Medscape Medical News. "Adjuvant applies, typically, to medical therapy added to treatments given with curative intent, and RTOG 0521 used radiation with curative intent."

The RTOG 0521 study received funding from the National Institutes of Health, Sanofi, and AstraZeneca. Dr Sandler reported no conflicts of interest, but several coauthors report relationships with pharmaceutical companies, as detailed in the abstract.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA 5002. Presented May 31, 2015.

ASCO 2015-IMMUNOTHERAPY COMBINATION FOR MELANOMA

CHICAGO — Two cancer immunotherapies are significantly better than one in slowing the progression of advanced melanoma, new phase 3 study results indicate.

The results likely represent yet another sea change in the treatment of this disease because, to date, single-agent immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) has been the gold standard in the first-line treatment of non-BRAF-mutated disease.

This study shows that first-line nivolumab (Opdivo, Bristol-Myers Squibb), either in combination with ipilimumab or used alone, produced a longer progression-free survival than ipilimumab alone.

Patients were free of disease for twice as long with nivolumab alone as with ipilimumab alone, and nearly four times as long as with the combination.

But the two drugs together are much more toxic than either single agent, and the combination would be very expensive, cautioned study observers. Together, ipilumumab and nivolumab cost nearly $300,000.

Figuring out who is an optimal candidate for potent combination therapy is "the heart of the issue," said lead study author Jedd Wolchok, MD, PhD, from the Memorial Sloan Kettering Cancer Center in New York City, during a press briefing here at the American Society of Clinical Oncology 2015 Annual Meeting.

"We need to carefully define who will benefit from the combination and from nivolumab as a single agent because, as a society, we cannot afford to treat everyone with the combination," said Frances Collichio, MD, from the University of North Carolina in Chapel Hill, who was not involved with the study.

But these data are a good starting place, said Dr Collichio, who told Medscape Medical News that results are "thrilling."

"We now have a disease we can cure in the stage IV setting," she said.

The investigators of the CheckMate 067 trial randomized 945 patients with previously untreated stage III or IV melanoma with either no or mild symptoms to receive ipilimumab, nivolumab, or a combination of the two.

After a follow-up period of at least 9 months, median progression-free survival was 2.9 months for ipilimumab alone, 6.9 months for nivolumab alone, and 11.5 months for the combination.

Thus, patients were free of disease for twice as long with nivolumab alone, and nearly four times as long as with the combination.

Use of the combination resulted in a 58% reduced risk for progression or death compared with ipilimumab alone (hazard ratio [HR], 0.42; P < .001). Use of nivolumab alone reduced these risks by 43% compared with ipilimumab alone (HR, 0.57; P < .001).

Despite the fact the study was not designed to make the comparison, Dr Wolchok reported that the twosome reduced the risk for progression by 26% compared with nivolumab alone (HR, 0.74).

The combination also had superior rates of complete and partial responses in the study, which was simultaneously published online in the New England Journal of Medicine.

Overall survival data will be forthcoming, said Dr Wolchok.

History suggests that there will be a survival benefit, said Steven O'Day, MD, from the Los Angeles Skin Cancer Institute, who acted as expert commentator at the press briefing.

"What strikes us is this progression-free survival difference between [nivolumab] monotherapy and the combination of almost 5 months. Historically, that has correlated well with survival," said Dr O'Day.

The key data will be survival at 2 or 3 years, he said. "If [a survival benefit with the combination] holds up at a high plateau compared to monotherapy, then it will be obvious what we need to do," explained Dr O'Day, referring to combination therapy.

In the short term, the combination data are "incredibly encouraging," he added.

But does that mean all fit patients with advanced disease should undergo treatment with the combination of two checkpoint inhibitors?

A fledging biomarker suggests not.

In the study, patients who had higher levels (>5%) of the PD-1 ligand, which is a protein on immune cells, did no better, on average, with regard to disease progression when treated with combination therapy. That is, patients with PD-L1-positive tumors who were treated with either the combination or nivolumab alone had the same median progression-free survival of 14 months.

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In short, combination therapy was better at delaying disease progression, but the benefit occurred largely in the patients with PD-L1-negative tumors. Patients with PD-L1-positive tumors appear less likely to benefit from this combination immunotherapy, which is in contrast to results from other studies.

Using a biomarker, the PD-1 ligand, is an effort "to try to introduce a precision aspect to immunotherapy," said Dr Wolchok. And it might enable conversations with patients "about whether the combination is right for them."

But PDL-1 is a "weak biomarker" that has a high rate of false negatives and a host of problems in the pathology lab, said Michael Atkins, MD, PhD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. He was not involved with the study and acted as discussant of the study at the meeting's plenary session.

The subset analysis in CheckMate 067 was not valid because the biomarker has too many shortcomings, he said.

Dr Atkins is not a fan of PD-L1, but he is high on combination therapy for advanced melanoma.

It is the treatment of choice in this setting, he said, unless toxicity is a "concern"; in that case, single-agent nivolumab is preferable.

In other words, ipilimumab is no longer the standard in the first-line treatment of advanced melanoma, he stated clearly.

The new trial is proof of this change, said Dr Atkins, as are the recent results from KEYNOTE-006, a head-to-head comparison that showed that pembrolizumab (Keytruda, Merck) significantly prolonged progression-free and overall survival and had less high-grade toxicity than ipilimumab in advanced melanoma.

ADJUVANT TAXANES AND RISK OF LYMPHEDEMA

Breast Cancer Res Treat. 2015 Jun;151(2):393-403. doi: 10.1007/s10549-015-3408-1. Epub 2015 May 5.

Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort.

Swaroop MN1, Ferguson CM, Horick NK, Skolny MN, Miller CL, Jammallo LS, Brunelle CL, O'Toole JA, Isakoff SJ, Specht MC, Taghian AG.

Author information

Abstract

Taxane-based chemotherapy for the treatment of breast cancer is associated with fluid retention in the extremities; however, its association with development of breast cancer-related lymphedema is unclear. We sought to determine if adjuvant taxane-based chemotherapy increased risk of lymphedema or mild swelling of the upper extremity. 1121 patients with unilateral breast cancer were prospectively screened for lymphedema with perometer measurements. Lymphedema was defined as a relative volume change (RVC) of ≥10 % from preoperative baseline. Mild swelling was defined as RVC 5- <10 1.14="" 1.56="" 1.63="" 2-year="" 2.15="" 29="" 5.27="" abstracttext="" adjuvant="" age="" an="" analyses="" analysis="" and="" are="" associated="" at="" axillary="" body="" both="" but="" by="" characteristics="" chemotherapy.="" chemotherapy="" clinicopathologic="" cohort="" compared="" comparison="" cox="" cumulative="" determine="" dissection="" docetaxel="" does="" experience="" factors.="" groups="" hazard="" higher="" however="" hr="" in="" incidence="" increased="" index="" into="" kaplan-meier="" lymph="" lymphedema.="" lymphedema="" mass="" may="" medical="" mild="" multivariate="" nbsp="" no="" node="" non-taxane="" not="" obtained="" of="" older="" on="" or="" overall="" p="" patients="" performed="" proportional="" rates="" receive="" receiving="" record="" respectively="" review.="" risk="" significant="" significantly="" subsequent="" surgery="" swelling="" taxane-based="" taxane="" the="" this="" those="" to="" translate="" treated="" via="" was="" were="" when="" who="" with="">

ASCO 2015- A SAFER DRUG FOR MYELOFIBROSIS?

CHICAGO, IL — A new drug for patients with myelofibrosis can be used even in patients with very low platelet counts, who currently have no other approved therapy. The product, pacritinib (CTI BioPharma), has completed a phase 3 trial that will be used for an approval submission.

"There is a huge unmet clinical need for patients with myelofibrosis. Only one drug is currently [approved by the US Food and Drug Administration] for the disease, and it is not safe for patients with low platelet counts," said lead study author Ruben A. Mesa, MD, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona. He was referring to ruxolitinib (Jakafi, Incyte), which, in 2011, was the first drug ever approvedfor myelofibrosis.

Dr Mesa presented results with pacritinib from a phase 3 study, known as PERSIST-3, here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

"We were encouraged to see that pacritinib was safe and effective in the trial, even in patients with severely low blood counts (<50 added.="" an="" between="" commented="" differentiator="" drugs="" he="" his="" in="" interview.="" is="" major="" p="" the="" two="" ul="">

About one third of patients with myelofibrosis have low platelet counts, Dr Mesa noted, and these patients tend to have shorter survival and are at higher risk for leukemic transformations. These patients would be particularly suitable for treatment with pacritinib, but the drug showed efficacy across all subsets of patients with myelofibrosis, he noted.

Ruxolitinib is associated with a fair amount of anemia and thrombocytopenia, whereas pacritinib showed no increase in either in the study, noted study discussant Lloyd Damon, MD, professor of medicine at the University of California, San Francisco. In fact, in the study, 25% of patients receiving pacritinib could stop having transfusions for their anemia he noted. The lack of these adverse effects also allows pacritinib to be used in patients with low platelet counts, in whom ruxolitinib cannot be used or is used at a lower dose. For these reasons, Dr Damon suggested pacritinib represented an advance in the treatment of myelofibrosis.

Why do the 2 drugs differ in this effect?

Pacritinib acts as an inhibitor of JAK2 and FLT3, whereas ruxolitinib acts as an inhibitor of JAK1 and JAK2, and there are also a variety of differences in the effect they have on cytokines and on the spleen, Dr Mesa explained. At the moment, it is not clear which of these differences is the most important, he said, as there are many factors that influence the low platelet counts. Laboratory studies are underway to explore the mechanisms involved, he added.

Myelofibrosis affects about 20,000 people in the United States. The disease develops when the bone marrow does not make enough normal blood cells, so the spleen takes over blood cell production and becomes enlarged, according to ASCO press materials. Patients also often experience tiredness, weakness, shortness of breath, fever, and weight loss. In about a third of patients, myelofibrosis transforms into acute leukemia.

There is currently no cure for myelofibrosis other than allogeneic hematopoietic (bone marrow) stem cell transplant, which is not a feasible option for many patients, and the only treatment approved by the US Food and Drug Administration is ruxolitinib.

Quarter of Patients Stopped Transfusions

In the PERSIST-3 trial, conducted in 327 patients with myelofibrosis, pacritinib was shown to be superior to best available therapy, which included drugs that are used off-label and commonly included the use of hydroxyurea. Ruxolitinib was intentionally excluded because this study included patients with very low platelet counts, for whom this drug is not deemed to be safe, the researchers note.

One of the main symptoms of myelofibrosis is spleen enlargement, which can be debilitating, as the enlarged spleen can press against other organs and cause problems with breathlessness and digestion. In this study, after 24 weeks of taking pacritinib, 9.1% of patients showed a reduction in spleen volume by 35% or more compared with 4.7% of patients receiving best available therapy (P = .0003).

Another symptom is anemia, which can be severe and require regular transfusions of red blood cells. In the trial, half of the patients receiving pacritinib achieve a 50% reduction or more in transfusions compared with 9.9% receiving best available therapy (P < .0001). In addition, 25.9% of patients taking pacritinib could stop having transfusions altogether.

"This is a big deal for patients," commented Dr Mesa. "Having transfusions involves a lot of hassle, and has a big negative impact on quality of life," he said. "It takes up 2 days every fortnight, with 48 hours to receive the transfusion; then you get diuretics and you spent the night passing off the excess fluid. So it is a big deal that the drug allows some patients to stop all that."

The effects of these drugs on the patients can be "very impactful," he said. They can provide dramatic relief of symptoms, but Dr Mesa said he believes they may also prolong patients' lives, because the disease is so debilitating. About 60% to 70% of patients die from complications of the disease, pneumonia infections, and heart failure; by alleviating symptoms, these drugs make the disease les debilitating, he said. In the trial, there was a hint that the patients who saw a reduction in spleen volume may have better overall survival, but there was just a hint of this, and longer follow-up is needed.

The most common adverse effects of pacritinib were diarrhea, nausea, and vomiting. Dr Mesa said these were manageable, with antimotility agents used by some patients. The symptoms typically lasted less than 1 week, and few patients discontinued treatment because of adverse effects, the researchers noted. Three patients discontinued and 15 patients reduced the dose because of adverse effects.

This study received funding from CTI BioPharma Corp. Dr Mesa reports receiving honoraria from Novartis and research funding from Incyte, Gilead Sciences, Celgene, and CTI. Dr Damon has disclosed no relevant financial relationships (although his disclosures list some relationships with pharmaceutical companies, he said they were all his wife's; she is a cardiologist).

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA109. Presented May 30, 2015.

ASCO 2015-FULL LYMPH NODE DISSECTION DOES NOT INCRESE SURVIVAL IN MELANOMA

CHICAGO, IL — Complete lymph node dissection (CLND) in patients with melanoma with positive sentinel lymph node biopsy does not improve survival, according to the results of a new study.

"This is the first study that tested the typical recommendation of complete lymph node dissection in patients with positive sentinel nodes, and we cannot confirm this recommendation," commented senior study author Claus Garbe, MD, a professor of dermatology at the University of Tübingen in Tübingen, Germany.

"And we expect that practice will change," Dr Garbe said at a press briefing held here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

Notably, only patients with micrometastases were included in this study. CLND will continue to be recommended for patients with larger, clinically detectable macrometastases, Dr Garbe noted.

At this time, CLND is considered the standard of care in patients with melanoma who are found to have sentinel node metastasis, and is recommended in National Comprehensive Cancer Network guidelines. But not all experts agree, citing mixed results about improved survival with the procedure and the risk for significant morbidities, such as lymphedema.

The results of this new randomized trial (n = 483) found no significant treatment-related difference in 5-year recurrence-free (P = .76), distant metastases–free (P = .76), and melanoma-specific (P = .86) survival between patients who underwent CLND and those who did not.

A total of 38 patients died of melanoma in the observation group compared with 36 who underwent CLND.

"We did not find any difference between the two study groups in terms of survival," said Dr Garbe. "The distant metastases–free survival was nearly identical for both groups."

At a median follow-up of 35 months, 14.6% of patients in the observation group developed lymph node regional metastases compared with 8.3% in the CLND group; the difference was not significant.

Only patients with micrometastases were included in this study, and CLND will continue to be recommended for those with larger, clinically detectable macrometastases, Dr Garbe noted.

Not Ready for Prime Time

It is still standard practice to suggest to patients with positive sentinel lymph nodes that they should undergo a second surgery, said ASCO expert Lynn Schuchter, MD, a melanoma specialist at the University of Pennsylvania in Philadelphia. But more and more, there have been questions about whether it is really necessary.

"I would say that this is a really important study, but it's a relatively small study, and I don't think we would make a complete change in our recommendations based on this data," she said. "I think we will wait in making definitive changes in our management until we have results from a larger study."

However, for patients who are concerned about lymphedema, this study does provide enough information to make them comfortable about a watch-and-wait approach, she added. Dr Garbe noted that lymphedema can occur in 20% of patients and can be long-term in about 5% to 10% of patients.

Another analysis of the current study is planned in 3 years, although Dr Garbe feels it is unlikely that the overall findings of the study will change, as prior research has shown that about 80% of melanoma recurrences happen in the first 3 years of initial diagnosis.

A larger ongoing CLND randomized trial, the Multicenter Sentinel Lymphadenectomy Trial II (MSLT-II), is also poised to answer this question and is designed to detect a 5% difference in survival. (The current study defined a significant difference in survival as 10% or greater.) However, the final results from MSLT-II are not expected until 2022.

More Questions Need Answers

The new study prompts investigation of a number of patient management issues, said another expert.

"The majority of stage III melanoma patients present with a positive sentinel lymph node, which means their nodal disease was diagnosed at a microscopic level, rather than when a large lump had developed that the patient or their doctor could detect," commented Vernon Sondak, MD, chair of the Cutaneous Oncology‎ Department at Moffit Cancer Center, Tampa, Florida. He was approached by Medscape Medical News for independent comment.

"Because nodal disease is being diagnosed earlier, surgical treatment of the lymph node basin by completion lymph node dissection is able to be done earlier, when there are often fewer side effects of surgery than if it is done for larger sized nodal tumors," he explained.

In contrast, if the nodal disease has been diagnosed early enough, then the melanoma may have only spread to the sentinel node, which has already been removed in the initial sentinel node biopsy procedure. "This means that completion lymph node dissection is likely unnecessary in a percentage of patients who are already cured by the biopsy," he said.

"Finally, some patients will eventually die of distant metastatic tumors that have already been seeded before the completion lymph node dissection can take place, meaning that the more radical surgery could not impact their survival," Dr Sondak continued.

"Unfortunately, we don't know which patients are already cured by their sentinel node biopsy procedure, which ones are destined to die no matter what surgery is done, and which ones might be saved from recurring and dying — or at least from extra surgical side effects — by early use of lymph node dissection," he said."

"Randomized trials like this one and the much larger [MSLT-II] will help answer these important questions over the next few years," he added.

This study was funded by German Cancer Aid. Several of the authors report relationships with industry, as noted in the abstract.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA 9002. Presented May 30, 2015.

ASCO 2015-NIVOLUMAB FOR NSCLC

CHICAGO, IL — The immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb) has beaten chemotherapy in another subset of patients with lung cancer in the second phase 3 trial to show an improvement in survival compared with docetaxel.

Results released today from the CheckMate 057 study, conducted in 582 patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC) who had progressed on platinum-doublet chemotherapy, show that treatment with nivolumab extended median overall survival by 3 months compared with docetaxel (12.2 vs 9.4 months; hazard ratio, 0.73; P = .00155).

Response rates were higher in the nivolumab group compared with in the docetaxel group (19.2% vs 12.4%). Responses also lasted significantly longer in the nivolumab group (17.1 vs 5.6 months, on average).

Lead author Luis Paz-Ares MD, PhD, from the Hospital Universitario Virgen Del Roccio in Seville, Spain, said he was hopeful that longer follow-up will show that the responses to immunotherapy in lung cancer are long-lasting, as they have shown to be in melanoma.

This is the second phase 3 trial to show a survival benefit with nivolumab. The other was CheckMate 017, which was conducted in patients with advanced squamous NSCLC. This trial has already resulted in the approval of nivolumab for squamous NSCLC in the United States; this indication was also recently recommended for approval in Europe.

These latest results also should result in an approval for the nonsquamous subset of NSCLC as well, predicts Dr Paz-Ares. He noted that nonsquamous subset is the larger of the two, accounting for around 60% of all patients with lung cancer, whereas the squamous subset accounts for some 25%. The remainder is made up of SCLC, he commented, which is a different disease.

Both trials are scheduled to be presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

Immunotherapy has the potential to shift the treatment paradigm of lung cancer, Dr Paz-Ares suggested. Some of the responses that have been seen with nivolumab are unprecendented, he told Medscape Medical News.

In the CheckMate 057 study, patients had their tumors tested for expression of the program death ligand 1 (PDL-1), and the study showed that patients with higher levels of PD-L1 experienced the greatest degree of benefit from nivolumab. Patients who had more than 1%, more than 5% and more than 10% PDL-1 expression levels showed a median overall survival of 17.2 to 19.4 months, which is unprecedented in this type of patient population. Usually, patients who are treated with second-line docetaxel have a median overall survival of 8 to 10.4 months, Dr Paz-Ares said.

However, he noted that although the responses and survival were much lower in the patients who had low PDL-1 expression, some of these patients did respond, so this biomarker is useful as a positive predictor of patients who are likely to respond, but not so useful as a negative predictor of those who are unlikely to respond.

In addition, in the other trial in squamous NSCLC, the PDL-1 biomarker appeared to be irrelevant: it was not associated with better responses rates in Checkmate 017.

Nivolumab was well tolerated, and treatment-related adverse events leading to discontinuation were reported in only 5% of patients compared with 15% of those receiving docetaxel.

The adverse effects seen with these immunotherapies are unique: They are immune-related adverse events, and they are much less significant than traditionally used chemotherapy, commented ASCO expert Lynn Schuschter, MD, a medical oncologist at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Immunotherapy is a "game changer" in lung cancer, commented Ben Creelan MD, assistant faculty in thoracic oncology at the Moffitt Cancer Center, Tampa, Florida.

Immunotherapy is a leap forward even when compared with targeted therapy, he added, because it can benefit more patients. The results so far suggest that in an unselected population of patients with NSCLC, about 20% will see tumor shrinkage, but about 20% will have stable disease, so the overall clinical benefit is seen in about 40% of patients.

In addition, the responses are long-lasting, whereas a big drawback with the targeted therapies is that the tumor becomes resistant, often within 6 months or so.

"We have been treating lung cancer patients with nivolumab and drugs like it since 2010, and we [have seen] patients since then who are still in remission 5 years later," Dr Creelan said. "The durability of these responses is astounding," he told Medscape Medical News. These patients were participating in early clinical trials and took nivolumab for 2 years only, and yet they remain in remission even though they are no longer taking the drug. "It has really changed the way we talk to our patients about their expectations," he added.

Docetaxel is the gold standard in second-line treatment of lung cancer, having been approved for that indication in 1999, and nothing has ever beaten it in NSCLC until nivolumab, he said.

And nivuolumab has now done it twice, in two separate phase 3 studies, in both squamous and nonsquamous subtypes of NSCLC.

Nivolumab is also much better tolerated than chemotherapy, he added. "Docetaxel can cause alopecia, nail problems, diarrhea, neuropathy, neutropenia, and fatigue, whereas nivolumab doesn't do any of that," Dr Creelan said.

Patients can get on with their lives and can return to work, and they say they feel and look like normal human beings, he commented. "They aren't defined by their disease anymore as much."

"And the attractive thing is, that they are doing this themselves," he added. Their immune system is holding the tumor in check, having been reset by the immunotherapy.

The CheckMate studies were funded by Bristol-Myers Squibb. Dr Paz-Ares reports receiving honoraria from Roche/Genentech, Lilly, Pfizer, Boehringer Ingelheim, Clovis Oncology, Bristol-Myers Squibb, and MSD. Some coauthors are company employees. Dr Creelan reports receiving research funding from Boehringer Ingelheim and serving as a speaker for Bristol-Myers Squibb.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA109, presented May 30, 2015; abstract 8009, presented May 31, 2015.

ASCO 2015-PEMBROLIZUMAB FOR HEAD-NECK CANCER

CHICAGO — In another noteworthy outcome for a PD-1 immunotherapy; nearly one-quarter of patients with advanced head and neck cancer responded to treatment with pembrolizumab (Keytruda, Merck), according to the KEYNOTE 012 trial.

The efficacy is "remarkable," said lead investigator Tanguy Seiwert, MD, from the University of Chicago, during a press briefing here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

Specifically, 29 of 117 (24.8%) patients in the expansion cohort of a phase 1 trial met the RECIST criteria for response; there were 28 partial responses and one complete response.

Notably, 25 of these responders continue to do so and, thus, are still on treatment and have a "durable" response; the average follow-up time is 5.7 months.

The overall response rate is double that of cetuximab (Erbitux, Bristol Myers-Squibb/Eli Lilly), which is the only targeted therapy for these patients, said Dr Seiwert.

"We have high hopes that immunotherapy will change the way we treat head and neck cancer," he noted in a press statement.

"This is yet another exciting example where PD-1 immunotherapy might work better and more reliably than existing drugs," said Gregory A. Masters, MD, a medical oncologist at Christiana Care's Helen F. Graham Cancer Center in Newark, Delaware, and an ASCO expert.

In the current study, the overall response rate is "on par" with that seen with immunotherapy in lung cancer, said Stephen Liu, MD, a medical oncologist at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who was not involved with the study.

"There are patients surviving 1 year and longer," he explained.

Dr Liu believes such benefits could occur in the head and neck setting. "That's why this is promising," he said. "We have a chance for durable responses that are meaningful in head and neck cancer too."

"It's a fun time," Dr Liu declared in interview with Medscape Medical News.

But the current treatment landscape is not inspiring, he noted. "While there are options, there are no good options," he said.

Currently, standard initial treatment involves platinum-based doublet chemotherapy with or without cetuximab. Second-line options include methotrexate, docetaxel, and cetuximab. Only 10% to 13% of patients respond to single-agent cetuximab.

Pembrolizumab is also effective in human papillomavirus (HPV)-negative and HPV-positive patients, said Dr Liu.

In their study, Dr Seiwert and colleagues found overall response rates with pembrolizumab of 27.2% in the 81 HPV-negative patients and 20.6% in the 34 HPV-positive patients.

This is notable because there appears to be less efficacy with EGFR inhibitors, such as cetuximab, in HPV-positive head and neck cancers, Dr Seiwert reported.

All the study patients had recurrent or metastatic squamous cell carcinoma of the head and neck and received a fixed dose of pembrolizumab 200 mg, administered as an infusion every 3 weeks. Average age was 58.9 years, and 83.3% of the patients were male.

Most of the study cohort was mostly heavily pretreated, and 59% had received at least two previous therapies.

Twenty-nine (24.8%) of the study participants had stable disease, said Dr Seiwert. Thus, when added to the overall response rate, there was a disease control rate of just about 50%.

Importantly, patients were not selected for the study on the basis of PD-L1 status. This biomarker predicts response to PD-1/PD-L1 immunotherapies such as pembrolizumab.

"The diversity of patients who responded is greater than in any previous clinical trial," Dr Masters said about the patient mix.

New treatments for advanced head and neck cancer are very much needed, said Dr Seiwert.

Recurrent/metastatic disease carries a poor prognosis; median overall survival is approximately 13 months.

Currently, standard initial treatment involves platinum-based doublet chemotherapy with or without cetuximab, according to ASCO press materials. Second-line options include methotrexate, docetaxel, and cetuximab. Only 10% to 13% of patients respond to single-agent cetuximab.

The most common adverse events of any grade were fatigue (15.2%), hypothyroidism (9.1%), and rash (7.6%). Adverse events of grade 3 or higher only occurred in 9.8% of patients. Two patients developed treatment-related pneumonitis of grade 3 or higher, and one developed treatment-related colitis of grade 3 or higher.

The adverse-event profile is better than that of current standard treatment, observed Dr Masters.

But more study is needed, he added. "We still need larger studies and longer follow-up to assess the impact of this treatment on patient survival."

Dr Seiwert also said that there might be a biomarker that helps predict which head and neck cancer patients will respond to immunotherapy. An interferon-gamma expression signature has shown promise and will be reported during the meeting (abstract 6017).

Currently, there are two ongoing phase 3 studies comparing pembrolizumab with standard treatment in patients with advanced head and neck cancer, according to meeting press materials.

The study was funded by Merck. Dr Seiwert reported financial relationships with pharmaceutical companies, including Merck. Some of the study authors are employees of Merck. Dr Masters has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA6008. To be presented June 1, 2015

ASCO 2015-MSI COLORECTAL TUMORS AND RESPONSE TO PEMBROLIZUMAB

Chicago — A mismatch repair (MMR) deficiency has been identified as the first genomic marker to predict response to the immunotherapy pembrolizumab (Keytruda, Merck).

"This is the first study to use genetics to guide immunotherapy," said lead study author Dung T. Le, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

Speaking during a press briefing here at the annual meeting of the American Society of Clinical Oncology, she noted that these data suggest that genomics may be more influential than histology for predicting which patients will respond to immunotherapy with drugs acting on the program death pathway.

MMR deficiency is found in 15% to 20% of sporadic colorectal cancer and in nearly all colorectal cancers that are associated with Lynch syndrome, which constitute up to 5% of all cases. MMR deficiency is also found in other tumor types including stomach, small bowel, endometrial, prostate, and ovarian cancers.

Right now, testing is standard of care in patients with colorectal cancer to check for the presence of Lynch syndrome. "It is in the NCCN [National Comprehensive Cancer Network] guidelines to check for that," she said, "and also in endometrial cancer."

As far as cost, Dr Le explained that testing can be done using different methods, but typically is not that expensive and runs "in the hundreds of dollars" and not thousands.

"We are beginning to pinpoint and predict which patients will benefit and [it is] important to precisely define who is going to benefit from immunotherapy and who isn't," commented Lynn Schuchter, MD, moderator of the briefing and chief of the hematology/oncology division at the University of Pennsylvania, Philadelphia.

"It is important to know who shouldn't be exposed to these treatments as they have a potential for side effects," she said.

MMR Deficiency Predicts Response

Pembrolizumab is currently approved by the US Food and Drug Administration to treat patients with advanced melanoma that has not responded to other standard therapies.

The study looking at MMR deficiency as a predictor of response was a phase II study conducted in a cohort that was divided into three groups: MMR-proficient metastatic colorectal cancer (n = 25), MMR-deficient metastatic colorectal cancer (n = 13), and other MMR-deficient cancers (n = 10).

Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to all patients, and the coprimary endpoints were immune-related objective response rate and immune-related progression-free survival at 20 weeks.

Among 48 patients with previously treated, progressive metastatic disease with and without MMR deficiency, 62% of those with MMR-deficient colorectal cancer had an objective response, and disease control was 92%.

The response and disease control rates were 60% and 70%, respectively, in patients with other types of MMR-deficient tumors.

However, for patients with MMR-proficient tumors, the response rate was 0% and the disease control rate was 16%.

The researchers found that the study met both primary endpoints for both MMR-deficient cohorts. The immune-related objective response rate and the immune-related progression-free survival at 20 weeks in MMR-deficient colorectal cancer were 40% and 78%, respectively, and for MMR-deficient other cancers the rates were 71% and 67%, respectively.

In contrast, for MMR-proficient colorectal cancer, the immune-related objective response rate and the immune-related progression-free survival at 20 weeks were 0% and 11%, respectively.

Among patients with MMR-deficient colorectal cancer, eight achieved a partial response to pembrolizumab, while four had prolonged, stable disease.

All 25 colorectal patients that were MMR-proficient failed to respond to the drug.

In the third group, where all patients were MMR-deficient (four with pancreatic/bile duct cancers, two with uterine cancers, two with small bowel cancers, one with stomach cancer, and one with prostate cancer), one uterine cancer patient achieved a complete response, five had partial responses, one had stable disease, and the remaining three patients had disease progression.

Median overall and progression-free survival in MMR-deficient colorectal cancer patients have not yet been reached, as several patients have continued to respond for more than 12 months, the authors note, and median follow-up is 36 weeks.

MMR-proficient colorectal cancer patients had a median overall survival of 7.6 months, and progression-free survival was 2.3 months, with a follow-up of 42 weeks.

In the third cohort, median overall survival has also not been reached, and median progression-free survival was 5.4 months after being followed-up for up to 42 weeks.

High Somatic Mutation Loads Predictive

Whole exome sequencing revealed an average of 1782 somatic mutations per tumor in MMR-deficient tumors compared with only 73 in MMR-proficient tumors (P = .0015). The high somatic mutation loads were associated with progression-free survival (P = .02).

"The 1700 mutations is like putting a red flag on a cancer cell and saying to the immune system 'here I am, and now allows the immune system to view these cancer cells as foreign," commented Dr Schuchter.

The next step is to reproduce the findings of this prospective study in a larger group of patients, according to Dr Le. She noted that the durability of response with little toxicity could eventually lead to testing this approach in initial treatment for these patients.

"This study helped identify a whole new population of patients who might benefit from PD-1 immunotherapy. MMR deficiency appears to be a predictor of response to pembrolizumab, and it's very encouraging that the responses in MMR-deficient tumors thus far have been long-lasting," said Smitha S. Krishnamurthi, MD, associate professor of medicine at Case Western Reserve University, Cleveland, Ohio, in a statement.

This study received funding from Swim Across America, The Commonwealth Fund, The Ludwig Center at Johns Hopkins, and the National Institutes of Health. Several of the authors report relationships with industry, as noted in the abstract. 

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA 100. Presented May 30, 2015.