Molecular testing of patients with colorectal cancer (CRC) should be incorporated into standard practice to establish the mutations each patient has that would affect their response to treatment with EGFR-targeted therapies, according to new guidelines from the American Society for Clin- ical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO).

Together the ASCP, CAP, AMP, and ASCO convened a panel of experts to determine a set of guidelines that establish molecular biomarker testing to guide personalized care for patients with CRC who are being considered for treatment with anti-EGFR therapies and/or conventional chemotherapy.

&ldquo;The evidence-based recommendations for these guidelines focused on molecular biomarkers identified as the most useful in patients with CRC, in order to select patients who can benefit from enhanced treatment with targeted therapies,&rdquo; said Antonia R. Sepulveda, MD, PhD, of Columbia University in New York City, the project co-chair on behalf of AMP, in a statement.

While EGFR-targeted therapies continue to be a mainstay in treating patients with CRC, certain mutations affect responses to them. KRAS mutations, for example, have been associated with resistance to these therapies. The identification of this negative predictive biomarker several years ago led to an uptake in testing for other potential biomarkers in this patient population.

A retrospective analysis of the effects of

mutations on response to treatment with cetuximab (Erbitux), an anti-EGFR monoclonal antibody, and chemotherapy demonstrated that

exon 20 mutations were also associated with lower responses in patients with chemotherapy-refractory metastatic CRC.

&ldquo;While many existing recommendations cover the application of individual molecular biomarkers in colorectal cancer, this guideline fills the need for an overarching set of recommendations spanning the breadth of current knowledge,&rdquo; said Wayne W. Grody, MD, PhD, of the University of California Los Angeles School of Medicine, the project co-chair on behalf of ASCP, in a statement.

To identify patients with mutations who may not benefit from treatment with anti-EGFR agents, the panel highly recommended that all patients with CRC undergo testing for RAS mutations, especially KRAS and NRAS codons 12 and 13 of exon 2, codons 59 and 61 of exon 3, and codons 117 and 146 of exon 4. These specific RAS mutations were singled out in a meta-analysis of the effect of extended RAS mutations on survival with anti-EGFR therapies.

Patients harboring any of these RAS mutations were unlikely to achieve a significant benefit from an anti-EGFR monoclonal antibody, whereas patients with RAS wild-type tumors showed a significant progression-free survival and overall survival (OS) benefit. The results were consistent whether patients received cetuximab or panitumumab (Vectibix), another anti-EGFR therapy, with or without chemotherapy.

V600 mutations, including in tumors with mismatch repair (MMR)-deficiency with loss of 1

in patients who potentially may have Lynch syndrome.

mutation demonstrated decreased outcomes when treated with anti-EGFR therapy compared with those with unmutated tumors. However, the guidelines also noted that the poorer outcome could be a result of a decreased OS after relapse rather than a suggestion of an increased likelihood of relapse. The authors noted that patients with

mutations could instead benefit from treatment with a BRAF inhibitor in addition to EGFR-targeted therapy, which has shown promise in early trials. Specifically, though,

V600 mutations alone could not be considered a biomarker for response to EGFR inhibitors due to conflicting evidence.

The guidelines noted that MMR status may have a predictive role in evaluating for Lynch syndrome. The incidence of Lynch syndrome can often be attributed to a germline mutation of 1 of the 4 MMR genes: MLH1, MSH2, MSH6, and PMS2.4 Identification of the syndrome has important implications for the patient&rsquo;s family members because their risk of developing cancer would be significantly increased.

Also, testing for microsatellite instability (MSI) would help identify patients for treatment with immunotherapy, such as pembrolizumab (Keytruda), which is currently undergoing a review from the FDA for the treatment of patients with MSI-high cancer.

A post hoc analysis of the PETACC-8 trial demonstrated that patients with

mutations and microsatellite-stable disease were more likely to have a shorter disease-free survival and OS when treated with FOLFOX-based chemotherapy, with or without cetuximab, than patients with MSI disease,

Insufficient evidence was found supporting

mutations as a biomarker for therapy selection outside of a clinical trial.

Although several analyses have shown worse responses and PFS rates among patients with a PIK3CA mutation, primarily in exon 20, the impact of the mutation has been inconsistent across disease stages and various studies. However, the authors did note that a benefit has been seen from treatment with aspirin in patients with a

mutation; more prospective studies are underway to investigate this result.

Articles

Clinical Articles

Molecular testing of patients with colorectal cancer should be incorporated into standard practice to establish the mutations each patient has that would affect their response to treatment with EGFR-targeted therapies.

Guidelines Establish the Role of Molecular Testing in Treatment of Patients With CRC

Representative Doug Collins (R, Georgia) has proposed a bill that would increase the transparency of payment methodologies to pharmacies. The Prescription Drug Price Transparency Act (H.R. 1316) was introduced in the House of Representatives on March 2, with the intent of requiring pharmacy benefit managers (PBMs) to disclose their generic drug pricing information.

The Community Oncology Alliance (COA) offered its support for the bill and its co-sponsors. &ldquo;If passed, the Prescription Drug Price Transparency Act, and other legislation like it, will finally help curb PBM abuses. Increasing PBM transparency and fees will also finally move our country closer to solving rising drug costs,&rdquo; Ted Okon, executive director of COA, said in a statement.

If the bill is passed, it would require PBMs to provide updates and disclosures on the maximum allowable costs (MAC) on drugs to pharmacies every 7 days and the sources used for making each update. The MAC lists help to determine the generic reimbursements that pharmacies receive.

The bill would also prevent PBM-owned pharmacies from sharing patient information and mandating that patients use their affiliated pharmacies, unless a patient has chosen to fill their prescription at that pharmacy.

COA noted that in recent years, PBMs have introduced new fees that have raised costs, created complex bureaucracies that often denied patients access to necessary medications, and limited patients&rsquo; access to certain pharmacies that were not affiliated with a PBM.

The organization also recently produced a report in conjunction with Frier Levitt, LLC, that revealed the effect that PBMs have on community oncology practices and the resulting rise in drug costs.

The report suggested that PBMs have been collecting both direct and indirect remuneration (DIR) fees as a percentage of drug costs from pharmacy providers through rebates and pharmacy concessions and DIR fees after beneficiaries have received the drugs.

The Pharmaceutical Care Management Association (PCMA), responded that the report commissioned by COA was a &ldquo;thinly veiled attempt to protect certain oncologists&rsquo; profits at the expense of patients and the Medicare program.&rdquo; The organization, which supports PBMs, stated that DIR fees reduce premiums for Medicare Part D beneficiaries, leading to lower costs for the government.

In a statement, the PCMA suggested that the bill would in fact cut competition and lead to increased prescription drug costs.

&ldquo;Now is not the time for new government mandates that raise prescription drug costs and undermine competition,&rdquo; said Mark Merritt, president of PCMA, in a statement.

The PCMA noted that the legislation would ruin the use of the MAC lists, which are significant in containing Medicaid drug costs, and suggested that these lists be strengthened instead of weakened. An analysis conducted by Visante for the PCMA indicated that legislation against MAC could increase the cost of affected generic prescriptions by 31% to 56%.

The association also suggested that the bill would risk the safety of patients with chronic conditions by undermining their use of mail order pharmacies.

Collins spoke out about the negative practices of PBMs when the legislation was introduced: &ldquo;PBMs engage in practices designed to boost their own profit margins at the expense of insurers, contracting pharmacies, patients, andin their relationships with federal programs&mdash;taxpayers. The lack of transparency in their operations has allowed them to control the market unjustly, with the result that these companies withhold savings that they have promised to pass on.

&ldquo;I&rsquo;m introducing a bipartisan bill to ensure that PBMs update their MAC lists for Medicare Part D, TRICARE, and FEHBP [Federal Employee Health Benefits Program] every 7 days to protect competitive pricing and to preserve pharmacy access and choice for patients. The Prescription Drug Price Transparency Act provides essential oversight to prevent waste, fraud, and the abuse of taxpayer funds, and [it] better protects patient privacy,&rdquo; he said.

The bill also had suppor from Representative Dave Loebsack (D, Iowa) as the Democratic co-sponsor, as well as from Reps Brian Babin (R, Texas), Rod Blum (R, Iowa), Buddy Carter (R, Georgia), John Duncan, Jr. (R, Tennessee), Cathy McMorris Rodgers (R, Washington), and John Sarbanes (D, Maryland).

&ldquo;As a pharmacist for more than 30 years, I saw firsthand the distress of families attempting to balance their healthcare needs with their bottom line when the cost of their prescription medications was on the rise and unpredictable,&rdquo; Carter said in a statement on his support for Collins&rsquo; bill. &ldquo;That is why the Prescription Drug Price Transparency Act is so important. The legislation will provide some light on how PBMs determine the pricing reimbursement of prescription drugs, which will provide greater transparency on how drug prices are set so patients can finally get the truth about drug pricing increases.&rdquo;

Frier Levitt LLC. PBM DIR fees costing Medicare and bene ciaries: investigative white paper on background, cost impact, and legal issues. Commissioned by Community Oncology Alliance. https:// www.communityoncology.org/wp-content/uploads/2017/01/COA_White_Paper_on_DIR-Final. pdf. Published February 1, 2017. Accessed March 23, 2017.

Visante. Proposed MAC legislation may increase costs of a ected generic drugs by more than 50 per- cent. Pharmaceutical Care Management Association website. https://www.pcmanet.org/wp-content/ uploads/2016/08/visante-pcma-mac-legislation-study-2015-update.pdf. Published January 2015. Ac- cessed March 23, 2017.

Representative Doug Collins (R, Georgia) has proposed a bill that would increase the transparency of payment methodologies to pharmacies.

COA Lauds the Introduction of the Prescription Drug Price Transparency Act

V212, a new inactivated varicella zoster virus vaccine, lowered the cumulative incidence rate of herpes zoster (HZ) infections and HZ-related complications for patients undergoing autologous stem cell transplantation (ASCT), according to findings from a phase III study presented at the 2017 BMT Tandem Meetings.

After 2.3 years of follow-up, confirmed cases of HZ by polymerase chain reaction were seen in 42 of 538 patients (7.8%) treated with the vaccine versus 113 of 535 patients (21.1%) who received a placebo (P <.0001). After adjusting for age and antiviral prophylaxis, the vaccine was estimated to be 63.8% effective against HZ (95% CI, 48.4-74.6).

&ldquo;The study demonstrates that the inactivated varicella vaccine is very effective for prevention of HZ after autologous transplant,&rdquo; summarized Drew J. Winston, MD, from the University of California Los Angeles Medical Center, during his talk at the meeting. &ldquo;The vaccine also reduces the incidence of moderate-to-severe pain, post-herpetic neuralgia, and HZ complications after autologous transplantation.&rdquo;

In the trial, patients received V212 (n = 560) and a matching placebo (n = 564) at 0.5 mL subcutaneously approximately 30 days prior to ASCT (range, 5-60), followed by 3 subsequent injections on days 30, 60, and 90 post transplant. An additional arm looked at a high-antigen version of the vaccine (n = 106). The high-antigen arm was not included in the efficacy analysis but was part of the safety assessment.

Patient characteristics were well balanced between the groups. In the investigational arm, the most common underlying diseases were non-Hodgkin lymphoma (42%), multiple myeloma (44%), and Hodgkin lymphoma (10%). Ninety percent of patients received conditioning chemotherapy.

Post transplant maintenance therapy was received by one-third of patients, most commonly lenalidomide (15%), bortezomib (11%), and rituximab (7%). Post treatment antiviral therapy was utilized for &le;3 months for one-third of patients, with 20% receiving these therapies for 3 to 6 months and 37% for >6 months. Twelve percent of patients did not receive antiviral therapy.

The primary endpoint was the incidence of HZ, which was deemed statistically improved if the lower end of the confidence interval was greater than 25%. Secondary endpoints focused on the severity of HZ-associated pain, HZ complications, and the incidence of post herpetic neuralgia (PHN). Only those who went on to receive ASCT and the vaccine were included in the efficacy analysis.

Moderate-to-severe HZ-related pain was experienced by 3.5% of those in the vaccine arm versus 11.4% in the placebo group, showing the vaccine was 69.5% effective for this endpoint (95% CI, 0.490-0.818). PHN occurred in just 0.5% of those in the vaccine arm versus 3.4% in the placebo group (83.7% efficacy; 95% CI, 0.446-0.952). HZ complications occurred in 2.2% versus 8.2% of those in the vaccine and placebo arms, respectively (73.5% efficacy; 95% CI, 0.498-0.860).

In those aged <50 years, in the vaccine arm (n = 154) the HZ incidence was 4.5% compared with 17.9% in the placebo arm (n = 151). Whereas, in those &ge;50 years, in the vaccine group (n = 384) the HZ rate was 9.1% versus 22.4% in the placebo arm (n = 384).

In those who received antivirals for &le;3 months, in the vaccine arm (n = 228) 9.7% had an HZ infection versus 21.3% in the placebo group (n = 239). In those treated with antivirals for 3 to 6 months, the HZ rate was 7.1% in the vaccine group (n = 310) versus 20.9% in the placebo group (n = 296).&rsquo;

Vaccine-related adverse events (AEs) occurred in 32.6% of patients in the investigational arm versus 12.6% in the placebo group, and many of these events were associated with the high-antigen vaccine. Most of the events reported were injection-site reactions (29.1% vs 6.5%). The rates of serious AEs were similar between the vaccine and placebo arms, at 32.9% and 32.7%, respectively. Serious vaccine-related AEs were 0.8% and 0.9%, in the V212 and placebo arms, respectively.

&ldquo;These results indicate that V212 might offer a way to help reduce the risk of HZ and HZ-related complications in this vulnerable, immunocompromised patient population,&rdquo; Eliav Barr, MD, senior vice president of Merck Research Laboratories, the company developing the vaccine, said in a statement. &ldquo;We look forward to exploring these data further and to reviewing the results of an additional phase III study that is underway in immunocompromised patients with malignancies.&rdquo;

A larger phase III study is examining the efficacy, safety, and tolerability of V212 for patients with solid tumors or a hematologic malignancy. The trial is comparing the vaccine with placebo across 5307 patients, with primary endpoints of reduction in HZ cases and safety. The study is fully enrolled with an estimated completion date in April 2017 (NCT01254630).

Winston DJ, Mullane KM, Boeckh MJ, et al. A phase III, double-blind, randomized, placebo-controlled, multicenter clinical trial to study the safety, tolerability, e cacy, and immunogenicity of inactivated vzv vaccine (ZVIN) in recipients of autologous hematopoietic cell transplants (Auto-HCTs). Presented at: BMT Tandem Meetings; February 22-26, 2017; Orlando, FL. Abstract 6.

V212, a new inactivated varicella zoster virus vaccine, lowered the cumulative incidence rate of herpes zoster (HZ) infections and HZ-related complications for patients undergoing autologous stem cell transplantation.

V212 Lowers Incidence of Herpes Zoster Infections After Transplant

During a satellite symposium at the 2017 BMT Tandem Meetings (the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation [ASBMT]), presenters reviewed the experience of using new and emerging therapies for treating patients with acute and chronic graft-versus-host disease (GVHD). The presenters detailed the existing options, including B-cell depletion, interleukin (IL)-2, T-cell trafficking modulators (ie, inhibitors of JAK1/JAK2, JAK1-specific inhibitors), extracorporeal photopheresis (ECP), and ibrutinib (Imbruvica), the Bruton&rsquo;s tyrosine kinase inhibitor.

Initial treatment for acute GVHD is prednisone, according to ASBMT&rsquo;s 2012 guidelines, but steroid-refractory acute GVHD remains a problem. No approach has been associated with improved GVHD control or overall survival (OS) compared with second-line therapy with high-dose steroids.

The first portion of the session was delivered by John F. DiPersio, MD, PhD, chief, Division of Oncology, Washington University School of Medicine in St. Louis, Missouri, on new targets for acute GVHD. JAK1 and JAK2 are mediators of interferon gamma receptor signaling; in mouse models, pharmacologic inhibition with JAK1/2 inhibitors decreased expression of the chemokine receptor CXCR3, reduced the incidence of GVHD, and improved survival after allogeneic hematopoietic stem cell transplant.

In a retrospective survey of 19 stem cell transplant centers in the United States and Europe, outcomes data from 95 patients who had received ruxolitinib (Jakafi) as salvage therapy for steroid-refractory GVHD showed an overall response rate (ORR) of 81.5% and a complete response (CR) rate of 46.3% for acute GVHD, and an ORR of 85.4% for chronic GVHD. One-year OS in the overall population of 95 patients (acute and chronic GVHD) was 92.7%, and the estimated median OS was not reached.

The IL-6 pathway appears to be mediated by JAK1/2 signaling, and blockade of this pathway has an important effect on mitigating GVHD, said DiPersio. Tocilizumab (Actemra), an IL-6 inhibitor, was associated with very low rates of acute GVHD and high survival rates when administered with standard prophylaxis in patients undergoing T-replete HLA-matched allogeneic hematopoietic stem cell transplant (HSCT).

Integrin inhibitors are undergoing investigation as another strategy to improve GVHD control; alpha-4 is involved in GVHD pathology, likely by facilitating the migration of alloreactive T cells to GVHD target organs. Selective inhibition of the alpha4beta1 integrin was recently shown to be effective in preventing GVHD in a mismatched allogeneic HSCT model.

New approaches to treating chronic GVHD were discussed by David Miklos, MD, PhD, associate professor of medicine, Blood and Marrow Transplantation, Stanford University Medical Center. The incidence of chronic GVHD is increasing as early transplant-related mortality is falling, requiring long-term therapy and being associated with quality of life and functional deficits. Corticosteroids remain the initial therapy for chronic GVHD. Alternatives have failed to improve outcomes.

&ldquo;There is no current consensus on optimal second-line treatment,&rdquo; Miklos said. Many retrospective and prospective studies suggest high response rates with ECP, rituximab (Rituxan), imatinib (Gleevec), mycophenolate mofetil, and mTOR inhibitors in the second-line setting, but the results are difficult to interpret because of suboptimal study designs.

ECP plus standard therapy in patients with cutaneous chronic GVHD manifestations not adequately controlled by steroids showed that the surface area of involved skin at week 12 decreased by 14.5% compared with 8.5% with standard treatment alone.

Some 8.3% of patients in the ECP group had &ge;50% reduction in steroid doses from baseline and &ge;25% reduction in Total Skin Score compared with 0% of the patients with standard therapy. &ldquo;One of our goals is to find and identify steroid-sparing therapies,&rdquo; Miklos said.

Because the B cell has a role in the pathogenesis of chronic GVHD, B-cell depletion with rituximab 375 mg/m2/week for 4 weeks was studied in 21 patients who had extensive steroid-refractory chronic GVHD. The ORR was 70% at 1 year, and the median steroid dose was reduced from 40 mg/day at study entry to 10 mg/day following rituximab (P <.001).6 Significant changes were also reported for skin involvement, the oral pharyngeal score, ocular Schirmer&rsquo;s test, and rheumatologic symptoms.

The rationale for use of low-dose IL-2 is that impairment of regulatory T-cell (Treg) function is associated with chronic GVHD and IL-2 is critical for normal Treg development, expansion, activity, and survival. In 35 patients with extensive refractory chronic GVHD, partial responses (PRs) occurred in 61% and were observed in the liver, skin, lung, joint/fascia, and gastrointestinal system.

Ibrutinib may selectively target chronic GVHD pathogenic cells while preserving cytotoxic T cells and Tregs, Miklos said, noting the results of a multicenter open-label phase II study of ibrutinib given after failure of corticosteroids in 42 patients with chronic GVHD. In that study, investigators observed an ORR of 67%, with 9 CRs, 19 PRs, and a sustained response rate at &ge;20 weeks of 71%.8 Only 3 patients had chronic GVHD progression, and 14 came off therapy due to treatment-emergent adverse events.

A supplemental new drug application for ibrutinib as a treatment for patients with chronic graft-versus-host-disease after failure of &ge;1 lines of systemic therapy is pending with the FDA. The agent previ- ously received a breakthrough therapy designation in this setting.

Experts review the experience of using new and emerging therapies for treating patients with acute and chronic graft-versus-host disease.

Approaches to Targeting Acute and Chronic GVHD

Responses to treatment with avelumab (Bavencio) monotherapy can increase in certain subtypes of patients with metastatic Merkel cell carcinoma (mMCC), per an analysis of the phase II JAVELIN Merkel 200 trial that was presented during the ASCO-SITC Clinical Immuno-Oncology Symposium.

Although a predictive biomarker of response to avelumab therapy could not be determined in the analysis, several factors contributing to increased progression-free survival (PFS) rates were defined.

Patients with a lower disease burden showed a median PFS of 7.1 months and the median PFS had not yet been reached in patients with positive PD-L1 expression on their tumor. Both groups exceeded the median PFS of 2.7 months in the overall population.

&ldquo;In this analysis, we could not definitively define a predictive biomarker to identify patients, although we did see a trend toward better response in patients who did have PD-L1 expression on their tumor,&rdquo; said lead investigator Howard L. Kaufman, MD, FACS.

Patients with mMCC who had progressed following &ge;1 prior line of chemotherapy in the metastatic setting were treated with 10 mg/kg of avelumab every 2 weeks in the phase II JAVELIN Merkel 200 study. The results of the multicenter, single-group, open-label trial were presented at the 2016 ASCO Annual Meeting

and led to breakthrough therapy, fast track, accelerated approval, and orphan drug designations from the FDA for avelumab. The agent received approval on March 23, for the treatment of adult and pediatric patients (&ge;12 years) with metastatic MCC, including those who have not received prior chemotherapy.

In the trial, 88 patients were treated. Their median age was 72.5 years (range, 33-88), most (73.9%) were male, and 55.7% had an ECOG performance status (PS) of 0, with the remainder having a PS of 1. Enrolled patients were required to have received 1 prior therapy; 26 patients (29.5%) had received 2 prior therapies and 10 (11.4%) had received &ge;3 therapies.

Patients were enrolled regardless of their PD-L1 status, but 19 (21.6%) were measured as having PD-L1 expression of &ge;5% in the tumor cells by immunohistochemistry. Fifty-five patients (62.5%) were negative for PD-L1 expression and 14 (15.9%) were not evaluable. Enrollment was not dependent on polyomavirus (MCPyV) status, but 46 patients (52.3%) had the virus.

In the overall population, the objective response rate (ORR) was 31.8% (95% CI, 22.3-42.6) with complete responses in 9.1% and partial responses in 22.7%. The median duration of response was not reached, and the 6-month PFS rate was 40%.

&ldquo;These responses occurred quite rapidly and...the vast majority of patients who respond seem to remain in response,&rdquo; said Kaufman, associate director for clinical science, Rutgers Cancer Institute of New Jersey. He also noted that avelumab was well tolerated in the trial, with most treatment-related adverse events of grade 1 or 2 and no observed grade 4 or 5 events.

The investigators looked to the subgroups established at baseline to see which patients responded better to the treatment.

&ldquo;Now that we have a minimum follow-up of 6 months or more in all the patients, we did a post hoc analysis to see if we could identify potential predictive biomarkers that would help us to better select patients who might benefit from avelumab treatment,&rdquo; Kaufman said.

In patients who had only received 1 prior systemic therapy, the ORR was higher than that of the overall population (40.4% vs 31.8%), and of patients who had received &ge;2 therapies (40.4% vs 19.4%). Patients with less tumor burden also had a higher ORR of 41.0% (95% CI, 25.6-57.9) compared with 26.3% (95% CI, 13.4-43.1) for those with bulkier tumors. And patients with positive PD-L1 expression had an ORR of 52.6% (95% CI, 28.9-75.6) compared with 23.6% (95% CI, 13.2-37.0) in patients with <5% PD-L1 expression.

Responses to avelumab were durable across all subgroups. The &ge;6-month duration of response rate was 92% for the overall population with similar proportions of responses noted across all subgroups. &ldquo;Avelumab monotherapy showed durable antitumor activity across several of the important subgroups of patients with mMCC in the second-line setting,&rdquo; Kaufman said.

PFS rates did vary by subgroup, with patients who had only received 1 prior therapy demonstrating a median PFS of 3.5 months (95% CI, 2.0-9.7 months) compared with 1.4 months (95% CI, 1.3-2.8) for patients who had &ge;2 prior therapies. Patients with a lower tumor burden showed a much higher PFS rate than patients with a higher tumor burden (7.1 vs 1.4 months). However, patients with positive PD-L1 expression did not reach a median PFS compared with patients with negative PD-L1 expression in their tumor cells who had a median PFS of 1.6 months. No trends were noted based on MCPyV status or primary tumor location.

Although the trend favoring patients with positive PD-L1 expression was of interest, it was not defined as a potential predictive biomarker for patient response to avelumab.

An ongoing multicenter trial is evaluating avelumab monotherapy in the frontline for patients with mMCC, and Kaufman noted that the investigators hope to present findings from this trial at the 2017 ASCO Annual Meeting.

Kaufman HL, Russell J, Hamid O, et al. Avelumab in chemotherapy-refractory metastatic Merkel cell carcinoma: subgroup analysis of e cacy. J Clin Oncol. 2017;35(suppl 7S; abstr 80).

Kaufman H, Russell JS, Hamid O, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: results of the phase 2 JAV- ELIN Merkel 200 trial. J Clin Oncol. 2016;34(suppl; abstr 9508).

Responses to treatment with avelumab monotherapy can increase in certain subtypes of patients with metastatic Merkel cell carcinoma, per an analysis of the phase II JAVELIN Merkel 200 trial that was presented during the ASCO-SITC Clinical Immuno-Oncology Symposium.

Intriguing Biomarker Results in Study of Avelumab in Merkel Cell Carcinoma

Immunotherapy agents have shown great promise for the treatment of patients with head and neck cancer; however, only a small subset of patients reap these benefits. Thus, the question becomes: which patients are more likely to benefit from these therapies, and why? As such, researchers are investigating potential predictive biomarkers of response to identify the patients who would respond best to these agents.

&ldquo;Squamous cell carcinoma of the head and neck [SCCHN] is an immunosuppressive disease, with lower absolute lymphocyte counts than those found in healthy subjects, impaired natural killer cell activity, and poor antigen-presenting function. Impairment of tumor-infiltrating T lymphocytes has also been reported in SCCHN and other cancers, with a strong impact on clinical outcome. Therefore, immunomodulatory therapies that overcome immune suppressive signals in patients with SCCHN have therapeutic promise,&rdquo; Robert L. Ferris, MD, PhD, said in a report published in the

Two checkpoint inhibitors have already been approved as immunotherapy agents for patients with head and neck cancer. Pembrolizumab (Keytruda) is for the treatment of patients with platinum-refractory SCCHN, and nivolumab (Opdivo) is for patients with recurrent or metastatic SCCHN with disease progression on or after a platinum-containing regimen. Both are inhibitors of PD-1, which is a T-cell molecule that binds to the ligands PD-L1 or PD-L2.

In the KEYNOTE-012 trial, pembrolizumab was investigated in patients with recurrent and/or metastatic SCCHN, and patients showed durable responses to the treatment. The objective response rate (ORR) was 18% by central review and 20% by investigator review.

Patients were not selected for the trial based on biomarkers, but were tested for human papillomavirus (HPV) and PD-L1 expression. Twenty-one percent were associated with HPV; among this group, the ORR was 32%. Expression of PD-L1 was noted in 77.9% of all patients.3 PD-L1positive patients (&ge;1% expression in the tumor cells alone) showed an ORR of 18% (95% CI, 12-26) versus 19% (95% CI, 10-30; P = .461) in PD-L1&ndash;negative patients (<1% expression). When measuring PD-L1 expression as a composite score from both tumor cells and inflammatory cells, PD-L1&ndash;positive patients had an ORR of 21% (95% CI, 15-28) compared with 6% (95% CI, 1-19) in PD-L1&ndash; negative patients (P = .023). A similar trend was noticed with progression-free survival (PFS) and overall survival (OS).

PD-L1 expression is a potential biomarker that has received a great deal of attention, as it can be found in &ge;50% of patients with SCCHN.

However, there are con icting reports of its significance. HPV-associated disease also holds interest as a possible biomarker of response. Ferris, co-leader of the Cancer Immunology Program, University of Pittsburgh Cancer Institute, and chief in the Division of Head and Neck Oncologic Surgery, University of Pittsburgh School of Medicine, noted that tumor infiltration by PD-1positive regulatory T cells may be more common among patients with HPV-associated SCCHN than in patients with HPV-negative disease. In a group of patients with SCCHN, 55% had high levels of PD-L1 expression, yet there was no association between the PD-L1 expression and the HPV status in the tumor.

The utilization of PD-L1 expression as a biomarker is complicated by the factors that go into measuring PD-L1 expression levels.

Trials often use different cutoff points to indicate PD-L1 positivity in a patient, with the base starting at &ge;1%, as in the KEYNOTE-012 trial. However, improved survival rates in patients with PD-L1 expression of &ge;50% in the tumor cells was noticed in the KEYNOTE-024 study, which investigated pembrolizumab in patients with nonsmall cell lung cancer.

A true verification of the predictive value of PD-L1 expression may require a more standardized approach.

Expression levels are also often measured using different assays or by testing different cells. KEYNOTE-012, and the ongoing KEYNOTE-055 trial, which presented preliminary results during the 2016 ASCO Annual Meeting, de ned PD-L1 positivity as expression of &ge;1% on tumor and inflammatory cells, using the Dako assay.

KEYNOTE-055 also showed a difference in ORRs (17% vs 8%, respectively) between patients with positive and negative PD-L1 expression at this cutoff point.

However, a recent report suggested that PD-L1 expression is only a &ldquo;favorable&rdquo; prognostic biomarker when measured using tumor-infiltrating immune cells instead of tumor cells in head and neck cancer.

The analysis investigated PD-L1 expression on tumor cells and tumor-in ltrating immune cells, divided into 4 groups based on degree of expression (TC0/1/2/3 and IC0/1/2/3), and the abundance of tumor-infiltrating lymphocytes in 402 patients with SCCHN.

The study showed that there was no significant difference in recurrence-free survival (RFS; P = .206) or OS (P = .317) rates between patients with PD-L1positive or &ndash;negative expression when measured on tumor cells alone. On the other hand, higher RFS and OS rates were noted for PD-L1&ndash;positive patients when measured on immune cells compared with patients with negative expression. This association continued even after adjusting for factors such as sex, smoking, age, pathologic stage, and HPV infection.

Kim et al suggested that this was because the frequency of higher PD-L1 expression was greater in immune cells than in tumor cells, with little to no overlap. In these patients with the highest PD-L1 expression levels (TC3 or IC3), expression levels of effector T-cell markers, including interferon-gamma and GZMB, were found to be higher in the IC3 group of patients compared with the TC3 group.

PD-L2 expression as a biomarker was also investigated in an analysis by Laura Quan Man Chow, MD, and colleagues of responses to pembrolizumab treatment in patients with head and neck cancer. In patients with positive PD-L2 expression on their tumor and inflammatory cells, the ORR was 23% (95% CI, 15-31) versus 10% (95% CI, 4-20) in PD-L2negative patients (P = .022). The ORR among patients who were positive for both PD-L1 and PD-L2 expression was 23% (95% CI, 16-32).

&ldquo;We believe that PD-L2 expression on both tumor and inflammatory cells was predicative of response to pembrolizumab,&rdquo; Chow, associate professor of medical oncology at the University of Washington School of Medicine, said when presenting the ndings during the 2016 ASCO Annual Meeting.

When looking for further predictive biomarkers to treatment with pembrolizumab, investigators tested a 6-gene interferon-gamma (IFN-&gamma;) signature, consisting of the genes (CXCL9, CXCL10, IDO1, IFNG, HLA-DRA, and STAT1) that had been identified in a cohort of patients with melanoma from the KEYNOTE-001 study, as a composite score.

The biomarker analysis demonstrated that the gene signature was associated with an inflamed tumor phenotype and diverse immunoregulatory activities, including immune tolerance.

There was a significant association with best overall response (P = .0047) and PFS (P = .0009) for the composite score, which demonstrated a positive predictive value of 40% and a negative predictive value of 95%. The authors noted that the composite score could be used to identify patients who would not respond to treatment with pembrolizumab, although further validation was recommended. The study of a potential association between the IFN-&gamma; signature and PD-L1positive expression was also suggested as patients with higher PD-L1 expression levels and IFN-&gamma;&ndash;related genes showed greater antitumor activity.

In the phase III CheckMate-141 trial, 361 patients with recurrent SCCHN were treated with second-line therapy of nivolumab or standard therapy. The PD-1 inhibitor showed a median OS of 7.5 months (95% CI, 5.5-9.1) over 5.1 months for patients treated with standard therapy (HR, 0.70; 97.73% CI, 0.51-0.96; P = .01). Estimated 1-year OS rates were 36% with nivolumab versus 16.6% with standard therapy.

PD-L1 expression was evaluated on tumor cells in a prespecified analysis of the trial, in which 57.3% of the 260 evaluable patients demonstrated PD-L1 expression of &ge;1%. PD-L1 expression was grouped into different levels of positivity: &ge;1%, &ge;5%, and &ge;10%. The median OS did not differ significantly between the 3 groups (8.7, 8.8, and 8.7, respectively). Alternatively, patients with <1% expression showed a median OS of 5.7 months while patients with <5% and <10% expression levels showed median OS rates of 7.0 and 7.2 months, respectively (

The analysis also investigated tumor HPV status by p16 immuno-histochemical testing in 178 evaluable patients. Regardless of p16 status (&ge;1% or <1%), the median OS was longer with nivolumab compared with standard therapy. Yet patients with p16-positive tumors showed a median OS of 9.1 months compared with 7.5 months for patients with p16-negative tumors and 4.4 months for p16-positive patients treated with standard therapy. However, p16-negative patients did better with standard therapy than p16-positive patients.

The HPV status was especially important among patients with oropharyngeal cancer, as HPV-positivity is more frequently noted in oropharyngeal cancers.

In the analysis by Kim et al, the authors also noted that PD-L1expressing immune cells were more frequently noted in patients with HPV-positive oropharyngeal cancer than in patients with HPV-negative oropharyngeal cancer.

Combined, p16 status and PD-L1 expression levels showed the greatest effect on response in patients with positive p16 and negative PD-L1 expression on tumor cells (n = 24), for a median OS of 10 months. Patients with positive PD-L1 expression &ge;1% and negative p16 status (n = 17) showed the lowest hazard ratio of 0.44 (95% CI, 0.18-1.10).

&ldquo;Although we observed preliminary evidence that patients with a tumor PD-L1 expression level of 1% or more or p16-positive tumors (or both) may have a greater magnitude of effect from nivolumab therapy than those whose PD-L1 level was less than 1% or who had p16-negative tumors, the interactions were not significant and were not corrected for multiple comparisons,&rdquo; Ferris et al wrote in their conclusion.

When analyzing for additional potential predictive biomarkers of response to nivolumab treatment, Ferris et al investigated peripheral blood lymphocytes both at baseline and during treatment and found that levels of CD8-positive T cells were higher in the patients who responded to treatment with nivolumab than in those who did not respond (23% vs 13%, respectively), both at baseline and during treatment (P <.05).

Patients who responded to nivolumab also showed a decrease in CTLA-4-positive CD8-positive effector T cells while on treatment. However, responders and nonresponders both showed a 2-fold decrease in PD-1-positive CD8-positive and PD-1 CTLA-4-positive CD8-positive effector T cells following treatment with nivolumab (P <.05). PD-1-positive regulatory T cells (Tregs) were found to be at lower levels in responders than in nonresponders both at base- line (19% vs 33%, respectively; P <.01) and during treatment (12% vs 20%; P <.001). Also, levels of Ki67-positive Tregs at baseline were lower in nonresponders than responders (P <.05).

The authors suggested that both PD-1 and CTLA-4 pathways be targeted in patients with SCCHN to overcome suppressive signals in CD8-positive effector T cells and Tregs that express both PD-1 and CTLA-4. The ongoing CheckMate-651 trial is doing just that, investigating nivolumab in combination with ipilimumab (Yervoy), a CTLA-4 inhibitor, against the standard of care in patients with recurrent or metastatic SCCHN (NCT02741570).

Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33(29):3293- 3304. doi: 10.1200/JCO.2015.61.1509.

Chow LQM, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34(32):3838-3845. doi: 10.1200/JCO.2016.68.1478.

Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPVassociated head and neck (H/N) cancer. J Clin Oncol. 2014;32(15):6011. doi: 10.1200/jco.2014.32.15_suppl.6011.

Chow L QM, Mehra R, Haddad RI. Biomarkers and response to pembrolizumab (pembro) in recurrent/met- astatic head and neck squamous cell carcinoma (R/M HNSCC). J Clin Oncol. 2016;34 (suppl; abstr 6010).

C Badoual, S Hans, N Merillon, et al. PD-1-expressing tumor-in ltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73(1):128-138. doi: 10.1158/0008- 5472.CAN-12-2606.

Addeo R, Caraglia M, Iuliano G. Pembrolizumab: the value of PDL1 biomarker in head and neck cancer. Expert Opin Biol Ther. 2016;16(9):1075-1078. doi: 10.1080/14712598.2016.1211635.

Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi:10.1056/NEJMoa1606774.

Bauml J, Seiwert TY, P ster DG, et al. Preliminary results from KEYNOTE-055: Pembrolizumab after plati- num and cetuximab failure in head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2016;34(suppl; abstr 6011).

Kim HR, Ha SJ, Hong MH, et al. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci Rep. 2016;6:36956. doi: 10.1038/srep36956.

Seiwert TY, Burtness B, Mehra R, Weiss J, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956-965. doi: 10.1016/S1470-2045(16)30066-3.

Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856-1867. doi: 10.1056/NEJMoa1602252.

Ferris RL, Concha-Benavente F, Blumenschein GR, et al. Characterization of potential predictive biomark- ers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol. 2017;35(suppl 7S; abstr 5).

Immunotherapy agents have shown great promise for the treatment of patients with head and neck cancer; however, only a small subset of patients reap these benefits. Thus, the question becomes: which patients are more likely to benefit from these therapies, and why?

Searching for the Key to Immunotherapy Response in Head and Neck Cancer

Patients with hematologic malignancies who receive a hematopoietic stem cell transplant (HSCT) still risk treatment failure through relapse. As part of a conditioning regimen prior to allogenic HSCT, strategies are emerging to improve HSCT outcomes by reducing the risk of relapse. Several of these conditioning regimens were reviewed during a satellite symposium to the 2017 BMT Tandem Meetings (the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation).

The spectrum of conditioning regimens ranges from low-intensity to high-intensity, with the former relying on a graft-versus-host disease (GVHD) effect with decreased regimen-related toxicity while the latter increases the immediate antitumor effect at the cost of higher toxicity.

&ldquo;We can reduce nonrelapse mortality by reducing the intensity of the regimen and relying on a GVHD effect, but we pay a price by increasing the risk of relapse,&rdquo; said Sergio A. Giralt, MD, chief, Adult Bone Marrow Transplant Service and the Melvin Berlin Family Chair in Multiple Myeloma, Memorial Sloan Kettering Cancer Center, New York City, during the satellite symposium.

Strategies that allow for exploiting dose intensity without increasing nonrelapse mortality are needed. The best way to improve outcomes is early referral, but even that may not affect results in individuals with primary induction failure who still represent about 30% to 40% of patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), said Giralt. New graft sources could lower relapse rates, and the use of KIR genotype-advantaged donors and cord blood (as opposed to haploidentical transplant) are currently being explored.

New preparative regimens, including novel drugs and targeted radiotherapy, may help eliminate cells that could be resistant to current conditioning strategies, Giralt said. Adding targeted agents, such as Iomab-B, a radiolabeled antibodydrug conjugate targeted against CD45, and rituximab (Rituxan), an antibody directed against CD20, to the pretransplant conditioning regimen has the potential to increase the antitumor effect.

Targeting the CD45 antigen is currently being explored as a way to deliver high-dose radiation to the bone marrow. Some 85% to 90% of acute leukemias express CD45 and, importantly, it is absent from nonhematopoietic tissues. Iomab-B, an iodine-131 anti-CD45based conditioning regimen, followed by allogeneic HSCT in patients with advanced AML or MDS, was developed at Fred Hutchinson Cancer Research Center in Seattle and has been tested in patients &ge;50 years with relapsed/refractory disease who were not candidates for a standard transplant.

Fifty-eight patients with active disease were treated (mean age, 63 years). In the first stage, single patients were treated at doses escalating in 2-Gy increments until the first dose-limiting toxicity (DLT). In the second stage, cohorts of 4 patients were started at the next lower dose, which was escalated in increments of 2 Gy if no DLT occurred. An additional cohort of 4 patients was treated at the same level if 1 patient experienced a DLT.

It was possible to deliver 12 to 26 Gy to the bone marrow; the estimated maximum tolerated dose (MTD) was 24 Gy. Ten days following the treatment, patients received reduced-intensity fludarabine (30 mg/m

/day) and low-dose total body irradiation (TBI). The mean doses delivered to the marrow and spleen were 36.1 Gy and 101.5 Gy, respectively. At 1 year, the rate of nonrelapse mortality was 22%, the relapse rate was 40%, and overall survival (OS) was 41%.

&ldquo;These are patients who have more resistant disease, but at the same time have less tolerance for traditional cytotoxic chemotherapies,&rdquo; said Partow Kebriaei, MD, in an interview with

A multicenter, pivotal, randomized, 2-arm, crossover phase III trial (SIERRA) of Iomab-B CD45 versus conventional care prior to HSCT in patients &ge;55 years with active, relapsed, or refractory AML has been designed, with a primary endpoint of durable complete remission (CR) at 6 months (NCT02665065).

&ldquo;We&rsquo;re very interested in the trial, which is using a radiolabeled anti-CD45 antibody and targeted radiation to help patients who are older and have active leukemia. It&rsquo;s a way to allow us to use a reduced-intensity conditioning regimen, but one that&rsquo;s still very targeted and focused to their disease,&rdquo; said Kebriaei, associate professor, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, who is also an investigator on the SIERRA trial.

Optimizing the delivery of currently used agents is another possibility, such as pharmacokinetic-directed therapy with intravenous busulfan (Busulfex, Myleran). A 50% reduction in the dose of busulfan in the conditioning regimen in patients with advanced AML or MDS is associated with a significant decline in 18-month relapse-free survival compared with a high-intensity regimen. By adjusting the dose of busulfan to target an average daily area under the curve of 6000 mcmol/min, a significant benefit in event-free survival is realized in patients with active disease.

Increasing radiation to the tumor can also reduce the risk of relapse, particularly the risk of early relapse in patients with active disease. TBI, however, cannot be safely dose-escalated. A novel method to deliver high-dose radiation to the tumor bed is targeted skeletal radiotherapy using Holmium-166-DOTMP, a beta-emitting radiophosphonate. A phase I/II study found very high rates of CR among 41 patients treated with this technique, but also high rates of hypertension and grade 3/4 elevated creatinine at 9 months.

Use of the radioimmunoconjugate iodine-131 tositumomab combined with B-BEAM (carmustine, etoposide, cytarabine, and melphalan) was not successful at improving OS compared with rituximab plus BEAM in patients with relapsed diffuse large B-cell lymphoma.

The BMT Tandem Meeting Symposium was sponsored by an unrestricted educational grant from Actinium Pharmaceuticals, Inc, which is developing Iomab-B.

Giralt SA. Clinical outcomes of new and emerging targeted conditioning regimens. Presented at: 2017 BMT Tandem Meetings; February 23-26, 2017; Orlando, FL.

Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after con- ditioning with 131I-anti-CD45 antibody plus udarabine and low-dose total body irradiation for el- derly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27):5444-5453. doi: 10.1182/blood-2009-03-213298.

Christoforidou AV, Saliba RM, Williams P, et al. Results of a retrospective single institution analysis of targeted skeletal radiotherapy with (166)Holmium-DOTMP as conditioning regimen for autologous stem cell transplant for patients with multiple myeloma. Impact on transplant outcomes. Biol Blood Marrow Transplant. 2007;13(5):543-549. doi: 10.1016/j.bbmt.2006.12.448.

Vose JM, Carter S, Burns LJ, et al. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed di use large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013;31(13):1662-1668. doi: 10.1200/JCO.2012.45.9453.

Patients with hematologic malignancies who receive a hematopoietic stem cell transplant (HSCT) still risk treatment failure through relapse. As part of a conditioning regimen prior to allogenic HSCT, strategies are emerging to improve HSCT outcomes by reducing the risk of relapse. Several of these conditioning regimens were reviewed during a satellite symposium to the 2017 BMT Tandem Meetings.