Δευτέρα, 26 Ιουνίου 2017

NO BENEFIT OF NIVOLUMAB IN FIRST LINE TREATMENT OF NSCLC

The programmed death 1 (PD-1) immune-checkpoint-inhibitor-antibody nivolumab (Opdivo, Bristol-Myers Squibb) did not yield longer progression-free survival (PFS) than platinum-based chemotherapy when used as a first-line therapy in patients with untreated stage IV or recurrent non–small cell lung cancer (NSCLC), the open-label phase 3 CheckMate 026 trial now shows.
Furthermore, overall survival (OS) was similar between groups, report lead author David Carbone, MD, PhD, of the Ohio State University Comprehensive Cancer Center in Columbus, and colleagues in a study published online June 22 in the New England Journal of Medicine.
However, nivolumab had a favorable safety profile with no new or unexpected safety signals, the team also says.
Among NSCLC patients with a PD ligand 1 (PD-L1)–positive expression level of 5% or more, median PFS was 4.2 months in patients who received nivolumab vs 5.9 months for those treated with chemotherapy (hazard ratio [HR] for disease progression or death, 1.15; = .25). The median OS was 14.4 months vs 13.2 months (HR for death, 1.02).
"The primary result was a surprise," Dr Carbone said in an interview with Medscape Medical News. "I fully expected there to be an improvement in progression-free survival," he explained, noting that there was "no difference in the patient population that we chose. We included anybody with any expression of the PD-L1 marker."
Earlier results with nivolumab in two phase 3 trials demonstrated significantly longer OS than was seen with docetaxel (Taxotere, Sanofi-Aventis) in patients with metastatic NSCLC who experienced disease progression during or after platinum-based chemotherapy. The OS advantage in patients treated with nivolumab was independent of PD-L1 expression level, although it was enhanced in patients with nonsquamous NSCLC with increasing PD-L1 expression.
These findings are in marked contrast to outcomes of the KEYNOTE-024 trial, in which the rival anti-PD-1 antibody pembrolizumab (Keytruda, Merck) was used as first-line treatment in patients with NSCLC with a PD-L1 expression level ≥50%, Dr Carbone and colleagues note. KEYNOTE-024 demonstrated a median PFS of 10.3 months for patients who received pembrolizumab compared to 6.0 months for patients who received chemotherapy, with response rates of 45% and 28%, respectively.
The reasons behind these different outcomes with two similar drugs "remain unclear and cannot be attributed to a single factor," the study authors say.
In an accompanying editorial, Edward B. Garon, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, suggests that the reason the efficacy of these similar drugs differed so greatly may be the result of "imprecise" patient selection.
"Could an effort to enhance the selection of patients fail on the basis of the inclusion of too broad a population, coupled with a PD-L1 assay that discriminates poorly at certain values? Absolutely, as is clearly shown in a trial of the PD-L1 inhibitor atezolizumab in patients with previously treated NSCLC in which atezolizumab was superior to chemotherapy," he writes.
The selection strategy in CheckMate 026 may have torpedoed the trial, he suggested. "Despite limitations, there is efficacy for first-line chemotherapy in non–small cell lung cancer," Dr Garon said in an email to Medscape Medical News. "A positive study based on a progression-free survival endpoint in first-line non–small cell lung cancer requires identification of a population with enhanced benefit from PD-1 inhibitors. The selection strategy in this study did not appear to sufficiently identify such a population," he said.
"Despite limitations, there is efficacy for first-line chemotherapy in non–small cell lung cancer," he added.
Noting that the KEYNOTE-024 trial used a different selection strategy and showed a benefit for pembrolizumab, Dr Garon recommended that "the successful strategy (assessing for PD-L1 using the 22C3 antibody) should be adopted by clinicians."
Many approaches are currently underway to improve outcomes, he noted.
"Ideally, ongoing phase 3 trials of combinations including inhibitors of PD-1 or PD-L1 in a broad population will improve outcomes," he told Medscape Medical News."Whether these phase 3 studies are positive or negative, it will be important to work to identify which patients are benefiting more from the addition of agents to a PD-1 or PD-L1 inhibitor."
In a statement, Martin J. Edelman, MD, chair of the Department of Hematology/Oncology at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, reminded clinicians of the shortcomings of immunotherapy. "The message from this and other studies is that immunotherapy is active in a significant fraction of patients with advanced lung cancer. However, despite this, the majority of patients, even those identified with various biomarkers, do not benefit or benefit for only a short period of time."
To extend the benefits of immunotherapy, new agents and strategies that combine new drugs with chemotherapy and radiotherapy are also being evaluated, he pointed out.

Deeper Data

Of 1325 patients enrolled in CheckMate 026 between March 2014 and April 2015, only 541 (41%) with a PD-L1 expression level ≥1% underwent randomization. Randomization was stratified on the basis of PD-L1 expression level of <5 and="" as="" histology.="" nonsquamous="" or="" p="" squamous="" tumor="" well="">
Baseline characteristics were balanced between the treatment groups. However, there were more women and more patients with a PD-L1 expression level of ≥50% in the nivolumab group than in the group receiving chemotherapy (32% vs 45% and 32% vs 47%, respectively).
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A total of 271 patients were allocated to receive nivolumab, administered intravenously at a dose of 3 mg/kg body weight once every 2 weeks; 270 patients were allocated to receive platinum-based chemotherapy once every 3 weeks for up to six cycles.
Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab, with 18% experiencing events of grade 3 or 4 severity. In the chemotherapy group, 92% of patients had treatment-related adverse events, with 51% experiencing events of grade 3 or 4 severity.
At the time of disease progression, determined in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 128 of 212 patients in the chemotherapy arm (60%) crossed over and received nivolumab as subsequent therapy.
Results from the study's exploratory biomarker analysis also demonstrated that tumor mutation burden may play a role in both response and PFS. It was conducted in 312 patients (58%) who underwent randomization. It showed that those with a high tumor-mutation burden did better with immunotherapy than with chemotherapy.
"This wasn't the primary endpoint, but it does need to be prospectively tested," Dr Carbone explained.
In patients with a high-mutation tumor burden, the response rate in those receiving nivolumab was higher than in those given chemotherapy (47% vs 28%), and PFS was longer (median, 9.7 vs 5.8 months; HR for disease progression or death, 0.62). In patients who had both a high tumor-mutation burden and a PD-L1 expression level ≥50%, the response rate to nivolumab jumped to 75%.
In the presence of just one of these two factors, however, response to nivolumab diminished significantly. The rate was 32% in patients who had a high-tumor burden only, and it was 34% in those with only a PD-L1 expression level of ≥50%. Without either of these factors, the response rate was 16%, the study authors say. They acknowledge that the comparison was not powered for statistical analysis.
However, Dr Carbone said these results "just add to the weight of evidence that molecular testing of blood cancer tumors should be done before any treatment. We should be looking for mutation burden, and expression of the PD-L1 marker should be part of the standard workup."
This kind of genetic testing is not readily available in community settings, he admitted, adding, "We need to educate community physicians to do testing and make more economical testing available right across the country."
Assessment of mutation quality to select mutations most responsive to therapy "will be the next thing to look at," he predicted. "It's not perfect, but it's better than just counting the number of mutations."
Dr Garon called the analysis "intriguing" but said that results are "akin to an algorithm developed today that predicts last season's World Series victory by the Cubs. Although potentially meritorious, its ability to pick this season's champion is unclear."

IMMUNOTHERAPY IN EARLY BREAST CANCER

Immune checkpoint blockade may have a role in the presurgery treatment of high-risk, early-stage breast cancers, according to results from a phase 2 trial presented here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
Currently, no cancer immunotherapy is approved for use in breast cancer, either metastatic or early-stage disease. But multiple studies are exploring the possibility, including several with pembrolizumab (Keytruda, Merck).
Earlier research in the metastatic setting found that single-agent pembrolizumab had "modest" activity, with a response rate less than 10% among heavily pretreated patients with triple-negative breast cancer (TNBC), said Rita Nanda, MD, a medical oncologist at the University of Chicago in Illinois.
In the new I-SPY 2 trial, the setting is early-stage breast cancer, including TNBC, and pembrolizumab was used as part of a combination therapy.
Lead author Dr Nanda reported that four cycles of neoadjuvant pembrolizumab, when added to conventional chemotherapy, improved estimated pathologic complete response (pCR) rates among 69 patients compared with chemotherapy alone among 180 patients with high-risk, early-stage disease.
pCR was the study's primary endpoint and was defined as no evidence of residual invasive cancer in the breast or lymph nodes.
In the trial, pembrolizumab was studied in three human epidermal growth factor receptor 2 (HER2)–negative biomarker "signatures" (all HER2–, hormone receptor [HR]+/HER2–, HR–/HER2–). The results, which are estimates because of the study's novel "adaptive" randomization, varied by signature.
Table. Estimated pCR Rates 
SignaturePembrolizumab + Standard Chemotherapy (%)Standard Chemotherapy (%)
All HER2–4516
HR–/HER2– (TNBC)6020
HR+/HER2–3413
There was a tripling of the estimated pCR rate in the triple-negative (HR–/HER2–) patients and a near tripling in HR+/HER– patients, emphasized Dr Nanda in her conclusion.
She also told the ASCO audience that pembrolizumab had "graduated" for all 3 HER2– signatures on the basis of these results, which means that there is a greater than 85% predictive probability of success in a 300-patient randomized phase 3 trial.
Priyanka Sharma, MD, a medical oncologist at the University of Kansas in Kansas City, agreed with that move. Phase 3 trials should be pursued, said Dr Sharma, who acted as meeting discussant of the study.
 But she questioned the choice of standard chemotherapy in the trial.
The trial schema called for randomization to 12 weeks of paclitaxel (T) — with or without the experimental pembrolizumab — followed by doxorubicin/cyclophosphamide (AC) every 2 to 3 weeks for four cycles.
Was AC/T "the best neoadjuvant chemotherapy backbone?" wondered Dr Sharma. After all, in I-SPY 2's chemotherapy-alone group, the pCR rate was only 13% to 20% among the various signatures.
Other chemotherapy regimens have shown efficacy in the neoadjuvant setting among patients with TNBC, observed Dr Sharma.
For example, in an early-stage TNBC study comparing a taxane with and without carboplatin followed by AC found a 54% pCR rate in the group with carboplatin vs a rate of only 41% in the no-carboplatin group (J Clin Oncol2014;33:13-21), she said.
Dr Sharma observed that some practitioners believe that the addition of a platinum agent (carboplatin or cisplatin) to neoadjuvant chemotherapy for TNBC is advisable. 
Another expert provided additional context with regard to early-stage TNBC.
"The current standard of therapy is to treat with combination chemotherapy in the neoadjuvant or adjuvant setting. In the neoadjuvant setting, 40% to 50% of patients achieve pCR," said Mateusz Opyrchal, MD, PhD, a medical oncologist at the Roswell Park Cancer Institute in Buffalo, New York.
Asked for comment, Dr Opyrchal also explained the significance of pCR as a measure in this setting. "We know that patients who do not achieve pCR are at much higher risk for recurrence," he said. Other experts have pointed out that, in neoadjuvant studies, pCR is an intermediate endpoint that is important because tumor eradication is desired before surgery proceeds
Overall, the pembrolizumab study results are "encouraging," Dr Opyrchal said, "but larger and randomized studies are needed to discover a true benefit from the combination." 

First Report of Certain Toxicities in Early-Stage Breast Cancer

Dr Nanda reported select adverse events from the trial. Overall, the safety profile among the pembrolizumab-treated patients was consistent with that observed in previously reported studies in the advanced-stage setting.
The pCR advantage came at the cost of some adverse events (pembrolizumab vs control). For example, for all grades, more vomiting (34.8% vs 18.3%), diarrhea (49.3% vs 37.8%), and peripheral motor neuropathy (13% vs 4.0%) occurred in the pembrolizumab group.
Dr Nanda also highlighted that rates of grade 3 to 5 fatigue and nausea were higher in the pembrolizumab-treated patients than in controls (5.8% vs 0.6% and 4.3% vs 0%, respectively).
Among adverse events of "special interest," including immune-related toxicities, the pembrolizumab group, not surprisingly, also fared worse.
For example, the pembrolizumab group had higher rates of hypothyroidism (8.7% vs 0.6%, all grades) and hyperthyroidism (4.3% vs 0%, all grades).
But Dr Nanda gave the most focus to adrenal insufficiency, which was observed in 8.7% (all grades) and 7.2% (grades 3 to 5) of patients in the pembrolizumab group vs none in the control group. Most of the cases presented after completion of AC (10 to 12 weeks after the last pembrolizumab dose), she also observed. "Patients are doing well on replacement therapy,"  said Dr Nanda.
This is the first report regarding the immune-related toxicities in early-stage breast cancer, she also pointed out.
Adrenal insufficiency is a known toxicity of pembrolizumab, but, in patients with metastatic cancer, the rates have been less than 1%, said Dr Nanda.
Because of these toxicities, serial screening of morning cortisol levels has  been incorporated into the trial along with serial thyroid function testing.
Dr Sharma wondered whether, in the early-stage setting, a "more conserved host immune system" is leading to "heightened immune toxicities."

More on I-SPY 2

To date, 13 agents have been studied in multiple concurrent arms and more than 2000 patients have enrolled in I-SPY 2, which stands for Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2. Patients are required to have a breast tumor 2.5 cm or greater in diameter on examination or a tumor 2 cm or greater in diameter on breast imaging.
Biomarker assessment, based on HER2 status, HR status, and a 70-gene profile using MammaPrint (Agendia), was performed at baseline to classify patients according to prospectively defined breast cancer subtypes.
In phase 2, the trial is "adaptively randomized," with the goal of efficiently identifying agents to take to phase 3, and it minimizes the number of patients needed to determine efficacy, said Dr Nanda.
A detailed review of the I-SPY 2 trial design and its merits and shortcomings was reported last year by Medscape Medical News.
The trial is supported by multiple pharmaceutical companies as well as private foundations. Dr Nanda and Dr. Opyrchal have disclosed no relevant financial relationships. Dr Sharma has financial ties with multiple drug companies. 
American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstract 506. Presented June 5, 2017.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
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TUMOR SIDENESS LESS PROGNOSTIC IN EARLY COLORECTAL CANCER

The recent observation that tumor sidedness is associated with survival in advanced colorectal cancer may not extend to patients with early-stage disease, according to a new study from Canada.
In a population-based cohort study from the Ontario Cancer Registry, there was no association between tumor sidedness and overall survival or cancer-specific survival in patients with stage I to III colon cancer.
“While there seems to be a convincing argument that primary tumor sidedness may have both prognostic and predictive implications for patients with advanced disease, as the authors of the present report have shown, the same may not hold true for early-stage disease,” write the authors of an editorial published with the study online June 8 in JAMA Oncology.
Dr. Safiya Karim from Queen's University Cancer Research Institute in Kingston and colleagues identified 6,365 patients with early-stage colon cancer (49% female). Their median age was 72 years and 52% had right-sided disease. About 18% had stage I disease, 38% stage II, and 43% stage III disease.
Patients with right-sided colon cancer were more likely to be older, female and to have greater comorbidity. Right-sided cancers were more likely to be T4 and poorly differentiated but less likely to be node positive compared with left-sided cancers.
But after adjusting for these factors, there was no difference in long-term survival for right-sided compared with left-sided colon cancer. The hazard ratios were 1.00 (95% CI, 0.92-1.08) for overall survival and 1.00 (95% CI, 0.91-1.10) for cancer-specific survival.
This lack of association with laterality persisted when the survival analyses were restricted to stage III disease, with hazard ratios of 1.03 (95% CI, 0.93-1.14) for overall survival and 1.10 (95% CI, 0.97-1.24) for cancer-specific survival.
Summing up, Dr. Karim and colleagues say their study found “no strong association between disease laterality and outcome of early-stage resected colon cancer. Results of previously published studies are not consistent; therefore, the extent to which disease laterality is prognostic remains uncertain.”
“Future research that can incorporate molecular and genetic elements of disease will provide important insights into how tumor location is associated with patient outcome,” the authors note.
In their editorial, Dr. George Chang from University of Texas MD Anderson Cancer Center in Houston and Dr. Mithat Gonen from Memorial Sloan Kettering Cancer Center in New York make the point that “sidedness in (tumors) that harbor whatever biologic drivers that . . . led to the development of recurrence . . . seems to have a very different interaction than in tumors that are cured by initial treatment.”
“This is another important lesson not only about the molecular heterogeneity of colorectal cancer but also about how these underlying differences affect treatment outcomes of patients at different stages of disease manifestation. Whenever it seems that all has been figured out, it is often humbling to know how much there is still to learn,” they conclude.
The study had no commercial funding. One author disclosed relationships with Amgen and Lilly.
SOURCE: http://bit.ly/2solWvv and http://bit.ly/2sorTbR
JAMA Oncol 2017.

LEVANTINIB FOR HCC

A new first-line treatment for advanced hepatocellular carcinoma (HCC) appears to be on the horizon. The current standard is sorafenib (Nexavar, Bayer), but a new study has found that lenvatinib (Lenvima, Eisai) was noninferior in this setting.
The results come from the phase 3 REFLECT study and were presented here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
Lenvatinib showed noninferiority in overall survival (OS) compared with sorafenib in patients with unresectable HCC. "Lenvatinib also demonstrated statistically significant and clinically meaningful improvements in secondary endpoints, including progression-free survival, time to progression, and objective response rates," said lead study author, Ann-Lii Cheng, MD, PhD, from the National Taiwan University Hospital. So are these results  practice changing?
"Well, not yet, as lenvatinib is not approved yet for liver cancer," commented Tanios Bekaii-Saab, MD, a medical oncologist at the Mayo Clinic in Phoenix, Arizona. "But it's clear that lenvatinib may become another first-line option for patients with advanced HCC," he added.
Lenvatinib is currently approved for use in thyroid cancer and renal cell carcinoma. The manufacturer has said that it plans to apply for approval of lenvatinib for first-line use in unresectable HCC on the basis of the findings from the REFLECT study.
Speaking at a "Highlight of the Day" session, Dr. Bekaii-Saab emphasized that this study was powered for noninferiority and not superiority, "so the only thing we can conclude is that lenvatinib is not worse than sorafenib, and we cannot make any conclusions about it being better."
The study met its primary endpoint and was not inferior, and there were suggestions that in progression-free survival and overall response rate — which were secondary endpoints — they were superior with lenvatinib, he noted. "But again, with a cautious note, these were secondary endpoints and cannot be considered other than exploratory."
"However, it certainly goes along with the fact that lenvatinib is as good as sorafenib," Dr. Bekaii-Saab added.

Promising Results

HCC remains a large unmet need, commented Dr Cheng. It is the second leading cause of cancer death worldwide, and sorafenib is currently the only approved systemic therapy proven to extend OS in the first-line setting.
"Over the past 10 years, four global phase 3 trials have failed to meet the primary endpoints of noninferiority or  superiority to sorafenib in overall survival," he said. " Lenvatinib showed promise in a previous phase 2 trial in patients with advanced HCC, and now this is the first positive study in 10 years' time."
The REFLECT trial randomly assigned 954 treatment-naive patients with unresectable HCC to lenvatinib at either 8 mg or 12 mg once per day (n = 478) or sorafenib at 400 mg twice daily (n = 476). Two thirds of patients had macrovascular invasion (MVI) and extrahepatic spread (EHS).
The median time to progression was 8.9 months with lenvatinib compared with 3.7 months with sorafenib (hazard ratio [HR], 0.63; P < .00001).
"This was a highly significant difference," said Dr Cheng.
In addition, lenvatinib demonstrated a significantly higher overall response rate compared with sorafenib (24% [n = 115] vs 9% [n = 44]; odds ratio, 3.13; P < .00001). 
in the lenvatinib group, there were 6 complete responses (CRs) and 109 partial responses (PRs), while 246 patients achieved stable disease and 71 had progressive disease (46 patients had unknown status).
For sorafenib, there were 2 CRs, 42 PRs, and 244 patients with stable disease, while 147 had disease progression (status for 41 was unknown).
OS was similar in the two groups: Median OS was 13.6 months with lenvatinib compared with 12.3 months with sorafenib (HR, 0.92).
Dr Cheng pointed out that the forest plot of OS favored lenvatinib in subanalyses except in the western population and among those with MVI and EHS. The forest plot favored all subgroups for progression-free survival.
As for adverse events, Dr. Cheng noted that the "safety profiles of lenvatinib and sorafenib in this study appear consistent with those previously reported in patients with HCC."
Grade 3 and higher events were more common with lenvatinib than with sorafenib (57% vs 49%), with hypertension (23% vs 14%), decreased weight (8% vs 3%), decreased platelet count (6% vs 3%), elevated aspartate aminotransferase (5% vs 8%), decreased appetite (5% vs 1%), diarrhea (4% vs 4%), and palmar-plantar erythrodysesthesia (3% vs 11%) being the most common.
Quality of life was similar in both groups, and after treatment, scores declined in both study groups.
"Role functioning, pain, and diarrhea scores worsened earlier and nutrition and body image deterioration was observed earlier in patients treated with sorafenib," he said.

On the Horizon

Dr Bekaii-Saab explained that ongoing studies are looking at other options in HCC.
"We are excited to see studies that are looking at immunotherapy in the first- and second-line setting," he said, "And we hope to include immunotherapy, as more treatment options are needed.
"There is currently an ongoing phase 3 study of nivolumab [Opdivo, Bristol-Myers Squibb] vs sorafenib in the first-line setting, so this may add a PD1 [programmed cell death 1] inhibitor into the mix," he said. "In second line there is an ongoing phase 3 study with another immunotherapy agent pembrolizumab [Keytruda, Merck] vs supportive care."
He added that if all of the agents currently being studied are eventually approved, there may even be options for patients in the third-line setting. "Which is exciting, since this is HCC and a few years ago we didn't even think we had a first line and now we are talking about perhaps a third line and even more. So these are exciting times for HCC — if all of these options pan out the way we hope they do."

IMMUNOTHERAPY EFFECTIVE FOR MELANOMA BRAIN METASTASES

New data on brain metastases in melanoma are practice changing, and clinicians can now consider systemic therapy alone and not use local therapy such as radiation," Tara C. Gangadhar, MD, assistant professor of medicine at the Abramson Cancer Center of the University of Pennsylvania, told attendees here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
Treatment of melanoma brain metastases is a critical, unmet need, because such metastases are a common clinical presentation and are associated with a poor prognosis, she commented.
Speaking at a Highlights of the Day session, Dr Gangadhar summarized data from CheckMate 204 (abstract 9507) and the Australian Anti-PD1 Brain Collaboration (ABC) study (abstract 9508), which showed a high degree of intracranial responses (50% to 60%) in patients with metastatic melanoma treated with the combination of two checkpoint inhibitors, ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb). These responses were durable, she noted.
Data from the COMBI-MB study (abstract 9506), which used the targeted combination of BRAF and MEK inhibitors, also showed high intracranial responses (75%) in a similar patient population with BRAF V300E melanoma. However, the responses in this study were not durable, she said.
All three presentations were discussed at the meeting by Lynn Schuchter, MD, C. Willard Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania, who put the new data in the context of clinical practice.
Currently, when a melanoma patient presents with brain metastases, there is consultation with neurosurgery and radiation oncology to determine whether surgery and/or radiotherapy, such as stereotactic radiotherapy or whole-brain radiotherapy, are appropriate. These patients are generally excluded from enrolling in clinical trials, she noted. "And while we consider systemic therapy, we don't have a good understanding of its role in this patient population," she added.
All the presentations addressed up-front treatment of melanoma brain metastases in asymptomatic patients. CheckMate 204 and the ABC study evaluated the combination of ipilimumab and nivolumab at standard doses. The ABC study evaluated nivolumab monotherapy in asymptomatic and symptomatic patients. The COMB-MB study evaluated the combination of dabrafenib (Tafinlar, Glaxo-Smith Kline) and tremitinib (Mekinist, Glaxo-Smith Kline) in asymptomatic patients.
The three studies enrolled remarkably similar groups of patients. The median age of the patients was 59 years. Notably, patients in CheckMate 204 and COMBI-MB had three to five brain metastases; more patients in the ABC study had more than four brain lesions. In addition, all patients in the COMBI-MB study had BRAF V300E mutant melanoma; this mutation was present in a little more than 50% of patients in the other two studies, Dr Schuchter noted.
Intracranial disease was measured using gadolinium contrast-enhanced MRI. Responses were measured using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Extracranial disease was measured using contrast-enhanced CT or MRI.
Across the three studies, intracranial clinical benefit rates (complete response [CR] + partial response [PR] + stable disease of longer than 6 months) were similar: 60% in CheckMate 204; 50% in the ABC study; and 78% in the COMBI-MB study. Corresponding objective response rates were 54% (CR, 21%), 42% (CR, 15%), and 58% (CR, 4%), respectively.
Extracranial clinical benefit rates were generally in concordance with the intracranial responses: 52%, 67%, and 79% in Checkmate 204, the ABC study, and the COMBI-MB study, respectively.
In CheckMate 204, responses were ongoing in 93% of patients who responded. In the COMBI-MB study, median duration of response was 6.5 months. Median progression-free survival (PFS) was not reached for patients in the CheckMate 204 study; it was 5.6 months for patients in COMBI-MB. Six-month PFS rates were 67%, 62%, and 44% in the Checkmate 204 study, the ABC study, and the COMBI-MB study, respectively.
The overall response rate (ORR) for asymptomatic patients who received nivolumab monotherapy in the ABC cohort was lower, at 20%, than in patients who received the combination immunotherapy; it was lower still for patients with symptomatic brain metastases (ORR, 6%).
"Overall, these are very well-done studies, asking the critically important question in clinically relevant patient population," Dr Schuchter said.
These new data are sufficient to warrant up-front systemic therapy for patients with melanoma brain metastases, Dr Schuchter commented.
"Yes, they are practice changing," she said. "Our approach for this patient population was to think of local therapy first. With these data, we can think of using up-front systemic therapy as our initial approach to these patients," she added.
She stressed, however, that this is applicable to asymptomatic patients only, and added that "there is concern about concurrent steroid use in limiting the activity of immunotherapy."
A number of questions remain, she said. For example, what should be the sequence of these treatments in clinical practice? Dr Schuchter noted that in the ABC study, responses to immunotherapy were low in a subset of patients who had received prior therapy with BRAF and MEK inhibitors (intracranial response rate, 16%) and were higher in treatment-naive patients (intracranial response rate, 50%). Longer follow-up is needed to define the best way to sequence these therapies, she observed.
She noted that in clinical practice, several variables need to be considered, such as whether the patient has a solitary metastasis or multiple metastases, the extent of extracranial disease, the presence of BRAF mutation, the patient's performance status, and whether the patient has received prior radiotherapy.
In combining local therapy with systemic therapy, Dr Schucher noted that in light of reports of CNS radiation necrosis when radiation is given concurrently with BRAF inhibitors, the recommendation is to withhold targeted therapy for several days prior to radiotherapy. To help in wound healing, the same applies for the combination of targeted therapy and surgery.
In general, immunotherapy appears safe when combined with radiotherapy, she said. She noted that efficacy may be enhanced when radiotherapy and immunotherapy are combined. "However, there is concern about concurrent steroid use in limiting the activity of immunotherapy," she concluded.
Dr Gangadhar receives honoraria from Bristol-Myers Squibb, Merck, Medscape, and Novartis and receives institutional research funding from Bristol-Myers Squibb, Incyte, Roche, and Merck. Dr Schuchter is a paid consultant for Incyte and receives institutional research funding from Bristol-Myers Squibb, Glaxo-Smith Kline, and Merck.

ATEZOLIZUMAB FOR NSCLC

In the phase II BIRCH trial, atezolizumab (Tecentriq) was found to produce higher response rates as first-line or subsequent therapy in patients with advanced non–small cell lung cancer (NSCLC) with higher levels of programmed cell death ligand 1 (PD-L1) expression. Study findings were reported by Peters et al in the Journal of Clinical Oncology.
Study Details
The study included 659 evaluable patients with advanced NSCLC and no central nervous system (CNS) metastases who received atezolizumab at 1,200 mg intravenously every 3 weeks as first-line (cohort 1, n = 139), second-line (cohort 2, n = 268), or third- or higher-line therapy (cohort 3, n = 252). Only patients with PD-L1 expression on ≥ 5% of tumor cells (TC; TC2/3) or tumor-infiltrating immune cells (ICs; IC2/3) on the SP142 immunohistochemistry assay were enrolled.
Expression levels ≥ 50% on TCs or ≥ 10% on ICs were defined as TC3 or IC3. Overall, 46% to 47% of patients in each cohort had TC3 or IC3 expression status. The primary endpoint was objective response rate on independent review.
Response Rates and Overall Survival
At a minimum of 12 months of follow-up, the objective response rates were 22%, 19%, and 18% in cohorts 1, 2, and 3 and 31%, 26%, and 27% in the TC3 or IC3 subgroups of the cohorts, respectively. Responses were observed irrespective of EGFR or KRAS mutation status. Median durations of response were 9.8 months, not estimable, and 11.8 months in the 3 cohorts and 10.0 months, not estimable, and 7.2 months in the TC3 or IC3 subgroups, respectively.
In a survival analysis with a minimum follow-up of 20 months, median overall survival was 23.5 months (26.9 months for TC3 or IC3 patients), 15.5 months (16.6 months) , and 13.2 months (17.5 months) in the 3 cohorts, respectively.
The safety profile was similar among the three cohorts and consistent with that observed in previous atezolizumab monotherapy trials.
The investigators concluded: “BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1–selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.”
The study was supported by a National Institutes of Health grant and Genentech (a member of the Roche Group).

ASPIRIN FOR PATIENTS WITH COLORECTAL CANCER

The benefit of taking aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) after colorectal cancer (CRC) diagnosis depends on tumor subtype, new research suggests.
Among long-term CRC survivors, regular use of NSAIDs after diagnosis was significantly associated with improved overall survival (OS) only in patients with KRAS wild-type tumors. That subtype accounts for a majority of CRCs.
"This study is unique in examining the previously observed benefits of NSAIDs on colorectal cancer survival according to tumor subtype," study investigator Polly Newcomb, PhD, president, American Society of Preventive Oncology, told Medscape Medical News.
"We found that patients who had tumors that didn't have mutation in KRAS (about 70% of all colorectal cancers) experienced improved survival — about a 40% reduction in mortality. In our study there was no survival benefit of these common medications in patients that had KRAS mutation," said Dr Newcomb, from the Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
"The results of this study support the hypothesis that mutations in KRAS activate pathways that may lead to pro-proliferative/antiapoptotic effects that cannot be inhibited by NSAIDs," she added.
Timing also seems to matter. Patients who started aspirin therapy after diagnosis had improved OS, while both aspirin initiators and continued users seemed to be associated with more favorable CRC-specific survival.
The study was published online June 15 in the Journal of Clinical Oncology.
Regular use of aspirin is associated with improved survival for patients with CRC, but until now, the timing of and the subtype of CRC that would provide the most survival benefit  have been unclear, the authors note.
To investigate, they used population-based cancer registries in the United States, Canada, and Australia to identify 2419 patients aged 18 to 74 years diagnosed with incident invasive CRC from 1997 to 2008.
After a median of 10.8 years of follow-up since diagnosis, 381 of the patients had died (100 due to CRC).
Overall, compared with nonusers, patients who used aspirin-only after CRC diagnosis had more favorable OS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.59 - 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 - 0.71).
The association between aspirin use and OS and CRC-specific survival was more pronounced in those who initiated aspirin therapy after diagnosis. For OS, the HR was 0.64 (95% CI, 0.47 - 0.86) and for CRC-specific survival, it was 0.40 (95% CI, 0.20 - 0.80).
The association between any NSAID use after diagnosis and OS differed significantly by KRAS mutation status (P interaction = .01). Use of any NSAID after diagnosis was associated with improved OS in patients with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 - 0.80) but not in those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 - 1.96).
"Although both observational and randomized studies provided convincing evidence of aspirin as an effective chemopreventive agent for CRC, aspirin is not generally recommended for primary prevention of CRC for people at average risk of [cardiovascular disease] CVD because of the potential risks," Dr Newcomb and colleagues note in their article.
"Aspirin for secondary prevention of CRC, particularly in subgroups such as those with KRAS wild-type tumors, is supported by our study. Future studies are needed to find the best timing, dose, and duration of aspirin use and to identify subgroups of patients with CRC for whom the benefits of aspirin outweigh its risk," they conclude.

"Very Interesting" Study

Gerrit Jan Liefers, MD, PhD, and Martine Frouws, MD, PhD candidate, from Leiden University Medical Centre in the Netherlands, who reviewed the study for Medscape Medical News, called it "very interesting" and said it generally supports their own research.
In a 2012 retrospective cohort study in the Journal of the American Geriatrics Society, Dr Liefers and colleagues reported that aspirin use after colon cancer diagnosis in older adults was associated with longer survival.
At the 2015 European Cancer Congress, Dr Frouws reported an analysis of prescribing data of almost 1400 patients with gastrointestinal cancer that found low-dose daily aspirin almost doubled survival among those patients. Almost half of the patients in the analysis had colon cancer. 
However, determining the subtype of CRC that benefits most from aspirin in relation to survival is "difficult" to do in a retrospective cohort, Drs Liefers and Frouws commented. "This year, in PLOS Oneone of our studies could not confirm an effect of KRAS or BRAF mutations on the effect of aspirin on survival. This contradiction has been the case in many retrospective studies in the past decade, and no decisive answers have been found."
In their view, the current study "confirms two very important issues" in this field of research: (1) the necessity for large, worldwide cohorts and (2) the importance to study this in a randomized, placebo-controlled setting."
Currently, Dr Liefers and Dr Frouws are performing a large randomized controlled trial (RCT) on the effect of aspirin on survival in 1588 patients with colon cancer in the Netherlands, and very soon also in Belgium. "This RCT is being done in close cooperation with other RCT's worldwide (UK, India, Singapore, Sweden, Switzerland) in order to pool these cohorts in the future, so we will be able to perform further studies in the future on molecular mechanisms involved in the effect of aspirin on cancer survival," the researchers said.
Dr Newcomb has disclosed no relevant financial relationships. One author holds a use patent for the colorectal chemopreventive use of aspirin. 
J Clin Oncol. Published online June 15, 2017.  Abstract

BLOOD TEST TO TARGET PROSTATE CANCER

A new 3-in-1 blood test could revolutionise the treatment of prostate cancer, say scientists, and help pave the way for personalised patient treatment.
The key to the new treatment is the ability to test for cancer DNA in a person's bloodstream. This so-called 'liquid biopsy' has the advantage of being cheaper and less invasive than traditional biopsies.
Clinical Trials
The blood test is still in early clinical trials involving only a few patients but scientists say it could be used in 3 ways:
  1. Men with advanced prostate cancer could be checked to see if they would benefit from treatment with new drugs called PARP inhibitors – which can help stop cancer cells from repairing themselves, causing the tumour cells to die
  2. An analysis of DNA in people's blood after they had started a specific course of treatment can check whether it is working and if not, switch them to an alternative treatment
  3. Monitor a patient's blood throughout treatment to check whether the cancer is evolving to become resistant to the drugs being used
The team from The Institute of Cancer Research (ICR) in London and The Royal Marsden NHS Foundation Trust say it is the first time a test has been developed to aid targeted cancer therapy for specific genetic faults within cancer tumours.
They say it could one day lead to a PARP inhibitor called olaparib becoming standard treatment for advanced prostate cancer.
Some patients respond to treatment with olaparib for years but in other patients, the treatment either fails early, or the cancer evolves resistance. This means that cancer cells regain the ability to repair themselves, causing tumours to grow.
Reducing Cancer DNA in the Blood
Using the new blood test, the researchers report that patients who responded to olaparib saw an average fall in the levels of circulating cancer DNA of 49.6% after just 8 weeks of treatment. This compared to an average rise of 2.1% in patients who did not respond to the drug.
Men whose blood levels of DNA had decreased at 8 weeks after treatment survived an average of 17 months, compared with only 10.1 months for those whose cancer DNA levels remained high.
The study, in the journal Cancer Discovery, involved samples taken from 49 men at The Royal Marsden with advanced prostate cancer enrolled in a phase II clinical trial of olaparib.
'Truly Revolutionary'
The results have drawn comments from several experts in the field. Professor Paul Workman, chief executive of the ICR, says "Blood tests for cancer promise to be truly revolutionary. They are cheap and simple to use, but most importantly, because they aren’t invasive, they can be employed or applied to routinely monitor patients to spot early if treatment is failing – offering patients the best chance of surviving their disease."
Professor David Cunningham, director of clinical research at The Royal Marsden NHS Foundation Trust, comments: "This is another important example where liquid biopsies – a simple blood test as opposed to an invasive tissue biopsy – can be used to direct and improve the treatment of patients with cancer."
Dr Matthew Hobbs, deputy director of research at Prostate Cancer UK says: "To greatly improve the survival chances of the 47,000 men diagnosed with prostate cancer each year, it’s clear that we need to move away from the current one-size-fits-all approach to much more targeted treatment methods.
"The results from this study and others like it are crucial as they give an important understanding of the factors that drive certain prostate cancers, or make them vulnerable to specific treatments.
"However, there is still much more to understand before the potentially huge benefits of widespread precision treatment for prostate cancer will reach men in clinics across the UK."

TWICE DAILY RT FOR LIMITED SCLC

Once-daily radiotherapy is not superior to twice-daily treatment for patients with small-cell lung cancer (SCLC) receiving concurrent chemoradiotherapy, according to a study published in The Lancet Oncology.1
SCLC, which is highly aggressive even from an early stage and carries a poor prognosis, tends to respond to concurrent chemoradiotherapy. Although radiation is typically administered in 2 daily doses, researchers hypothesized that once-daily higher-dose radiotherapy would improve outcomes in this setting.
For the randomized phase 3 CONVERT trial (ClinicalTrials.gov Identifier: NCT00433563), researchers enrolled 547 patients with SCLC to receive radiotherapy 1.5 Gy twice-daily for 30 fractions over 19 days or 2 Gy once-daily for 33 fractions.
Patients in both groups received concurrent cisplatin-etoposide for 4 or 6 cycles.
Of 274 and 273 patients assigned to receive twice-daily and once-daily chemoradiotherapy, respectively, 249 and 240 underwent concurrent treatment. Almost all initially assigned patients were, however, included in the survival analysis.
Patient characteristics were similar in the 2 groups: in the twice-daily group and the once-daily group, respectively, median age was 62 and 63 years, 96% and 97% of patients were Caucasian, and 98% and 99% of patients were former or current smokers.
Median follow-up was 45 months. In the twice-daily group and once-daily group, median overall survival was 30 months vs 25 months, respectively; 2-year overall survival rates were 56% and 51%, respectively.
RELATED: Maintenance Pembrolizumab Does Not Improve PFS in Small-cell Lung Cancer
Toxicity was similar in both groups, though grade 4 neutropenia was more common in the twice-daily group. There were 3 treatment-related deaths in the twice-daily group and 8 in the once-daily group.
The authors concluded that “from a pragmatic perspective, once-daily radiotherapy could be considered when delivery of twice-daily radiotherapy is impossible because of departmental logistics or patient choice.”

NEOADJUVANT PEMBROLIZUMAB IN HEAD-NECK CANCER

The data are early and the sample size small, but pembrolizumab (Keytruda, Merck & Co) used in the neoadjuvant and adjuvant setting showed antitumor activity in locally advanced head and neck squamous cell carcinoma (HNSCC), according to new findings.
No serious drug-related adverse events or unexpected surgical delays or complications occurred, explained lead author, Ravindra Uppaluri, MD, PhD, director, Head and Neck Surgical Oncology at the Dana Farber Cancer Institute, Boston, Massachusetts, who presented the findings here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
"We also have an early signal of potential clinical efficacy," he said. "The numbers are small, but there were no local regional relapses or distant metastases for 14 patients at or more than one year after surgery, in this very high risk subgroup of patients."
"But most intriguingly, we’ve seen a pathologic response in 42% of patients with just a single dose," he added. "This was a finding we were surprised to see."
The Food and Drug Administration approved pembrolizumab in 2016 for patients with recurrent or metastatic HNSCC who experienced disease progression during or after platinum-containing chemotherapy. It has also been approved for use in melanoma and non-small cell lung cancer.
But outside the metastatic setting, Dr Uppaluri noted that previous studies have provided level 1 supporting the use of adjuvant chemoradiotherapy in patients with resected, high-risk, locally advanced HNSCC. But despite this, 35% of patients develop recurrent and metastatic disease in high-risk HNSCC within 1 year after postoperative adjuvant chemoradiotherapy.
"Given that, the question is if the addition of pembrolizumab can improve these outcomes, Dr Uppaluri said.
In the current phase 2 trial, patients receive a single dose of neoadjuvant pembrolizumab and then undergo surgery 2 to 3 weeks later.
Postoperative treatment largely depended on the patient.  Those who were low risk or intermediate risk, such as those with negative extracapsular extension (ECE)  margins received standard of care, while patients with high-risk features, including positive ECE margins, underwent adjuvant chemoradiotherapy followed by maintenance pembrolizumab.
The primary endpoint of the study is to reduce the rate of local regional relapse and distant metastasis from 35% to 15%. Secondary endpoints are safety and correlative biomarkers and genomic assessment in the pre-/post-treatment blood and tumor tissue.

Patient Details

The trial is ongoing and thus far has accrued 25 patients. All patients were originally treated at Washington University, St Louis, Missouri, but the trial now also includes the Dana Farber Institute.
Most patients had tumors in the oral cavity (n = 18), followed by the larynx/hypopharynx (n = 5) and oropharynx (n = 2).
The cohort in this trial is human papillomavirus negative and predominantly male (n = 18), with "significant histories of tobacco and alcohol abuse," Dr Uppaluri said.
Except for one patient with stage III disease, all patients had stage IV tumors.  In addition, 92% had clinical stage T4 disease, "which is consistent with this high-risk subgroup of patients."

Promising Results

Dr Uppaluri noted that none of the 14 patients have had any recurrence to date, and all of them had T4 disease.
"We define tumor response as a change in the tumor on exam or on CT scan or pathology," he said. "And 50% of patients had some sort of evidence of a response in the neoadjuvant phase."
For example, patient 20, who had stage IV disease, has since been downstaged to stage I disease (pT1NO).
Another finding was the extent of the "treatment effect," which is defined as tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in more than 10% of tumor area. "Overall, 42% of patients had some sort of a treatment effect either in the primary tumor or lymph nodes," he noted.  "In addition, 25% had a major effect of more than 50%."
There was also a significant correlation between baseline programmed cell death ligand 1 (PD-L1) expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient = 0.72; P = .0005).
A preliminary analysis also showed a correlation between treatment effect and CD8 cells (P = .0051), PD-L1 + CD8 T cells (P = .022), and CD4 T cells (P = .048).
Dr Uppaluri pointed out that the patient numbers are small and it is early data. "But there are significant  implications with the signals we have seen," he said, "including reduced need for postoperative adjuvant chemoradiation, potential to reduce the extent of surgery, and reduction in relapse risk."

It's All About Timing

In a discussion of the paper, Antonio Jimeno, MD, PhD,  professor in the Division of Medical Oncology at the University of Colorado, Denver, explained that one of the key questions about integrating immunotherapy in the treatment regimen is the timing.
"There are factors that favor preoperative immune modulations, such as the potential for downstaging and de-intensification of radiation therapy and chemoradiation therapy," Dr Jimeno said. "But there are also factors favoring use in the postoperative setting. Debulking has been advocated as a favorable factor for immune modulation."
But several ongoing studies are investigating peri- or postsurgery immune-directed therapy, he explained. "In the absence of strong rationale, randomized studies are needed to identify the optimal sequence."
Overall, the addition of immune modulation appears to be feasible in contemporary HNSCC. "With the caveat of being nonrandomized, it added minimal toxicity, there were favorable comparisons with historical outcomes data, and pathologic indications of an antitumor effect," said Dr Jimeno.
"Importantly, it did not lead to delays in curative intent surgery," he added. "But robust translational investigations are needed to develop rational patient selection strategies and to continue investigating optimal timing of immune modulation."
The study was funded by Merck, V Foundation, and National Institutes of Health. Dr Uppaluri has disclosed a financial relationship with Merck. Dr Jimeno has disclosed relationships with Merimack andSuvica, as well as  the Gates, Mordecai, Grant, and Karsh Family Foundations.
American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.  Abstract 6012. Presented June 6, 2017.

BRCA CANCER RISK ESTIMATES

While it has been well established that carriers of the BRCA1 and BRCA2 mutations face a higher risk for breast and ovarian cancer, most studies to date have been retrospective.
A new prospective study on several assessment variables, published online June 20 in JAMA, has further clarified which women face the highest risks.
"This large prospective cohort of women with BRCA1 and BRCA2 mutations has enabled us to obtain the most precise estimates of age-specific breast and ovarian cancer risks to date," said lead study author, Antonis Antoniou, PhD, from the Centre for Cancer Genetic Epidemiology, University of Cambridge, United Kingdom. "These should provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2 genes."
The ideal epidemiologic study for estimating cancer risks is a prospective study, he explained. In that model, healthy women with genetic faults are followed over time and overcome potential biases. However, to date, published prospective studies have been very small.
The present study used data from a prospective cohort of women with BRCA1 and BRCA2 mutations who were recruited from 1997 to 2011 and were followed over time. The study included almost 10,000 women and was made possible through collaborations among scientists from Europe, North America, and Australia. 
"The prospective study design explains why it has taken 20 years of hard work to get these results," Dr Antoniou told Medscape Medical News. "Most importantly, it took an enormous long-term contribution and commitment from the women themselves to allow the scientists to be able to assemble this dataset."

Family History Implications Differ by Cancer Type

A novel finding in this study is that breast cancer risk for women with faults in BRCA1 and BRCA2 increases rapidly at a young age then remains at a constant high level for the rest of their lives.
"It peaks in the 40s for BRCA1 mutation carriers and in the 50s for BRCA2 carriers, but carriers of mutations in both genes are at about the same high risk in later life," Dr Antoniou explained. "This is important information to inform the clinical management also of women with mutations over the age of 60 years old."
Some clinics, he noted, have discharged women with mutations when they reached older ages, but the "current study suggests that this may not be appropriate."
The researchers found that the cumulative risk for breast cancer risk up to age 80 years was 72% for BRCA1 mutation carriers and 69% for BRCA2 carriers.
For ovarian cancer, the cumulative risk to age 80 years was 44% for BRCA1 and 17% for BRCA2 carriers.
Another important finding was the role of family history in estimating risk.
This has only been studied indirectly in the past and, again, only in retrospective studies. "The results from the current study show clearly and for the first time in a prospective study, that the cancer risks for women with BRCA1 and BRCA2mutations depend on the extent of the woman's family history of cancer," Dr Antoniou explained.
Advances in genetic technologies have opened up the potential of screening all women for BRCA1 and BRCA2 mutations, and currently there is considerable debate as to whether to offer universal mutation screening.
"The cancer risk estimates from our study will provide critical information for informing such policies," he said.  "For example, our results show clearly that women without family history of cancer are likely to be at lower breast cancer risk than women with strong cancer family history who had been typically seen in clinical genetics centers."
The results showed that the risk for breast cancer for both BRCA1 and BRCA2carriers increased along with the number of first- and second-degree relatives who had been diagnosed with the disease.
However, a similar association was not observed for ovarian cancer.
A third key point was that a significantly higher breast cancer risk when the mutations were located in certain regions for both BRCA1 and BRCA2, but mutation position did not appear to affect ovarian cancer risk.
Dr Antoniou pointed out that only a small number of retrospective studies have shown that cancer risks vary by mutation location within BRCA1 and BRCA2. However, a major limitation of those studies was that researchers could not estimate the cancer risks associated with mutations at different locations, mainly because of the retrospective nature of the studies and the inherent biases in the study designs.
"Therefore, it has been unclear how to apply those findings in clinical practice and how to incorporate those in the risk assessment of women with mutations," he said. "The results from this study show clearly, and again for the first time in a prospective study, that the cancer risks for women with BRCA1 and BRCA2 mutations depend on the  position of the specific fault within the gene."
"Moreover, the study provides for the first time cancer risk estimates for mutations at different locations," he added. "Therefore, mutation location can now be confidently incorporated in the risk assessment of women with BRCA1 and BRCA2  mutations."

Adding to Knowledge Base

Commenting on the study, Charles Shapiro, MD, from the Tisch Cancer Institute at Mount Sinai Medical Center in New York City, agreed that a very important aspect of this study is that it was prospective.
"Most previous studies have been retrospective, so this is really an important point," he told Medscape Medical News.
And one of the key points is that this is an example of data sharing. "Patients often think that everyone shares data, but that's not the case," Dr Shapiro said. "One institution may not be able to get enough numbers, but if 3 get together, then they have enough for the study."
That is essentially what they did in this paper in order to be able to draw data from such a large cohort, he noted. "This is something that we really need to do more of."
The findings from this study are already known, in that certain mutations convey risks. "But what we don't know yet is why," Dr Shapiro said. "And that is where more investigation is needed."
The study also found that carriers with a family history of cancer have a higher risk, but that wasn't anything new, he noted.
"What is important is that we need to refer every patient who needs to be referred for screening," Dr Shapiro said. "And we need to get a family history on all patients, as that is a recommendation from guidelines."

Study Details

The cohort comprised 6036 women who were BRCA1 carriers and 3820 with BRCA2, who were recruited through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry, and the Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer.
During the follow-up period, 426 participants were diagnosed with breast cancer, 109 with ovarian cancer, and 45 with asynchronous contralateral breast cancer.
The incidence of breast cancer for BRCA1 carriers increased between 21 to 30 years and 31 to 40 years but then remained stable at 23.5 to 28.3 per 1000 person-years for ages 31 to 70 years (P = .97 for trend). Peak incidence occurred in carriers aged 31 to 50 years (28.3 per 1000 person-years).
BRCA2 carriers showed a similar pattern, with peak incidence among those aged 51 to 60 years and incidence of 21.9 to 30.6 per 1000 person-years across ages 41 to 80 years (P = .57 for trend).
For contralateral breast cancer, the risk for a second breast cancer up to 20 years after the first cancer was 40% for BRCA1 carriers and 26% for BRCA2 carriers (hazard ratio [HR], comparing BRCA2 vs BRCA1 carriers, 0.62; = .001), with the risk for a second breast cancer higher among women whose first breast cancer was at a young age (<40 p="" years="">
The incidence of ovarian cancer increased with age up to 61 to 70 years for both mutations but was higher for BRCA1 carriers (HR comparing BRCA1 vs BRCA2, 3.6; P < .001). The cumulative risk for ovarian cancer to age 80 years was 44% for BRCA1and 17% for BRCA2.
A family history boosted the risk for breast cancer. The risk increased as the number of first- and second-degree relatives with breast cancer increased for both BRCA1(HR for 2 vs 0 affected relatives, 1.99; P < .001 for trend) and BRCA2 carriers (HR, 1.91; P = .02 for trend).
The risk for breast cancer was also higher if the mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 carriers (HR, 1.46; P = .007) and c.2831-c.6401 in BRCA2 (HR, 1.93; P < .001).
Conversely, risk for ovarian cancer was not associated with a family history of ovarian cancer or position of the mutation.
This work was supported by Cancer Research–UK grants. Dr Antoniou has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. 

COMBINATION IMMUNOTHERAPY FOR MERCKEL CELL CARCINOMA

A novel cellular approach that recruits three separate pathways involved in the oncogenesis of Merkel cell carcinoma (MCC), a rare and aggressive form of skin cancer, is leading to unprecedented and seemingly durable objective responses in patients with advanced MCC, early-stage trial results suggest.
"We hypothesized that the combination of adoptive transfer of Merkel cell polyomavirus (MCPyV)–specific T cells with HLA upregulation and programmed death (PD)-1 axis blockade would be more effective than either approach alone," lead author, Kelly Paulson, MD, oncology fellow, Fred Hutchinson Cancer Research Center,  Seattle, Washington, reported during the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
The phase 1/2 trials involved a total of eight patients with metastatic MCC with no preexisting immune deficiencies, including four who received triple therapy (enhanced T-cell therapy plus HLA upregulation plus the anti-PD-ligand 1 agent avelumab [Bavencio, EMD Serono]).
"Three out of 4 patients who received triple therapy achieved a complete response and are alive at a medium follow-up of 10 months," she added, "while one patient had a partial response." Follow-up is now out to approximately 13 months and complete responses are still sustained, she added.
Dr Paulson explained that 80% of MCCs are caused by MCPyV oncoproteins, which, when present, are associated with good outcomes in patients with MCC. Importantly, all eight patients in the phase 1/2 trials had MCPyV-associated metastatic MCC. The T-cell therapy targets MCPyV.
HLA was upregulated in all eight patients by delivering single-fraction radiotherapy or interferon β to a single lesion.
 In the double therapy (enhanced T-cell therapy plus HLA upregulation) group (n = 4), three  patients progressed after treatment and one patient responded with a complete response that lasted 14 months before disease progression. Two patients subsequently died.
In the triple therapy group, the avelumab dose was 10 mg/kg given intravenously every 2 weeks.
Dr Paulson reported that both the double and the triple therapy regimens had an acceptable toxicity profile. Adverse events were similar in both groups and included a transient lymphopenia and cytokine release syndrome lasting less than 24 hours (manageable on the general ward).
No grade 3 or 4 toxicities were linked to avelumab among patients receiving triple therapy.
"The number of patients treated was small, but the efficacy observed was promising," Dr Paulson concluded.
"And correlative studies suggest that avelumab enhances the T-cell response to MCC."
As Dr Paulson noted in a statement, their study is ongoing and their next goal is to engineer patients' cells to recognize the cancerous oncoprotein that drives MCC growth, potentially broadening the therapy to more patients.
"I love working on Merkel cell cancer, but I also know that the most impact is going to be made by spreading what we know about Merkel to other cancers," she said in the same statement.
Historical 5-year survival rates for patients with metastatic MCC are under 10%.
The study was funded by the National Institutes of Health, MCC Patient Gift Fund at the University of Washington, and the EMD Serono Biomarkers Award.
American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstract 3044. Presented June 5, 2017.