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The National Comprehensive Cancer Network (NCCN) has issued the first-ever guidelines for the treatment of women with gestational trophoblastic neoplasia (GTN), a rare set of tumors that develop from placental cells. The guidelines recommend single-agent chemotherapy for most patients with low-risk disease; surgery and combination chemotherapy are advised for patients with high-risk GTN.

The rarity of these cancers makes it unlikely that most oncologists and other clinicians will develop enough hands-on experience with them to become expert in their management, which is why a team of NCCN panelists from nearly 30 institutes worked more than a year to develop these guidelines. The American Cancer Society (ACS) estimates that GTN develops in roughly 1 of 1000 pregnancies in the United States.

 GTN is more prevalent in Asian and African countries.

Sometimes known as gestational trophoblastic disease, GTN occurs during pregnancy. Nadeem R. Abu-Rustum, MD, chief of the Gynecology Service at Memorial Sloan Kettering Cancer Center in New York, New York, and vice chair of the NCCN GTN panel, said in an interview that even experienced gynecologic oncologists struggle to manage GTN. “Gestational trophoblastic neoplasia is a rare disease and a complex disease,” he said. “It’s not common, and you require centralization and high volumes to become an expert.”

“We felt it was important to develop guidelines for the treatment of these diseases [because] most practicing oncologists, whether they’re medical oncologists or gynecologic oncologists who will be seeing and treating these patients, have never seen one of these patients before,” added John R. Lurain, MD, the Marcia Stenn professor of Gynecologic Oncology at Northwestern University Feinberg School of Medicine in Chicago and a member of the guideline-writing committee. “Although there’s a pretty robust literature, we thought it was important to present this information in a concise form.”

Most GTN appears in the form of partial or complete noninvasive hydatidiform moles, a mass that can form inside the womb during early pregnancy, resulting in an abnormal fetus. Surgery, usually suction dilation and curettage, is often the only treatment necessary if the disease has not spread beyond the uterus. Hysterectomy is also an option for women who aren’t planning to have children in the future.

These women should be monitored by human chorionic gonadotropin (hCG) assay every 1 to 2 weeks until hCG levels are normal for 3 consecutive assays. The hCG levels should then be tested twice in 3-month intervals. If hCG continues to rise or the patient has extrauterine disease, she should proceed to the same chemotherapy regimen as women with low-risk (FIGO prognostic score <7) GTN (

These women are assigned to single-agent methotrexate or dactinomycin, or methotrexate/ leucovorin. The guidelines recommend a regimen of multiday methotrexate as frontline therapy. Because of its toxicity profile, dactinomycin is generally used in the second line for patients with methotrexate toxicity or effusions that contraindicate the use of methotrexate. NCCN recommends against using a dactinomycin pulse regimen as secondary therapy for patients with methotrexate- resistant disease or as primary therapy for choriocarcinoma.

These patients should undergo hCG assessment at the start of each treatment cycle. Those who have a good response to initial therapy and normal hCG levels can continue systemic therapy for 2 cycles, or 4 weeks, beyond hCG normalization, followed by an annual hCG assessment. The NCCN also recommends oral contraception for those patients.

The guidelines call for close hCG monitoring at all stages of disease and treatment. Abu-Rustum said the same test used to check for pregnancy also serves as the main blood test used to quantitatively monitor disease and indicate resolution.

Figure. NCCN Guidelines for Treatment of Gestational Trophoblastic Neoplasia

“[Human chorionic gonadotropin] is like the perfect tumor marker, which we don’t have with other disease,” Lurain said in an interview with 

. “We can use that to decide which patients need treatment based on the fall to normal [hCG levels] or persistent disease.

He added that these guidelines are also meant to be educational. Because GTN is rare, few oncologists, even gynecologic oncologists, are familiar with the disease. According to the ACS, almost all women with complete or partial moles and low-risk GTN can be cured, and cure rates are high for placental-site trophoblastic tumors. The prognosis is not as good if the disease metastasizes beyond the uterus, but even for high-risk GTD, cure rates range from 80% to 90%.

“Even when patients have widely metastatic disease to their lungs or brain or liver, you can still cure almost all these patients,” Lurain said. “[The guidelines] are an educational tool as well as a formula for appropriate approaches to patient care to result in the least morbidity and the highest chance of cure.”

Women with low-risk disease who have a good initial response to therapy followed by a plateau in hCG level should receive monotherapy with methotrexate or dactinomycin. Physicians should consider hysterectomy or salpingectomy if there is localized disease in the uterus and the patient is not concerned about preserving fertility.

Again, these patients should undergo hCG assessment every 2 weeks. Those who have normal hCG levels can continue systemic therapy for a total of 4 weeks beyond hCG normalization. Patients who experience <10% change in hCG levels for 2 cycles or whose hCG levels rise >10% for 1 treatment cycle should be assessed for metastatic disease and begin therapy with etoposide/ methotrexate/actinomycin D/cyclophosphamide/ vincristine (EMA/CO).

Women with low-risk disease who have a good initial response to therapy followed by a rapid increase in hCG of >10% or who have a poor response to initial therapy should be evaluated for metastatic disease and begin EMA/CO therapy. Hysterectomy and pulmonary resection may be options for patients with chemotherapy-resistant disease.

Patients who have normal hCG levels can continue systemic therapy for a total of 4 weeks beyond hCG normalization. Women who experience <10% change in hCG levels for 2 cycles or whose hCG levels rise >10% for 1 treatment cycle should begin chemotherapy with etoposide/ platinum-based regimens.

Women with high-risk GTN, FIGO stage IV or stage II/III and a prognostic score ≥7, should receive EMA/CO therapy. If the patient has brain metastases, the doses of methotrexate and folinic acid should be increased and brain radiotherapy is an option. Physicians should consider induction with low-dose etoposide and cisplatin for 1 to 3 cycles followed by EMA/CO for patients with extensive metastatic disease and a prognostic score >12.

Women whose hCG levels return to normal should continue systemic therapy for 2 to 3 cycles, followed by monthly hCG assessment for 12 months. For those who have good response followed by an hCG plateau at low levels or who relapse from remission should proceed to EMA in combination with etoposide and cisplatin.

The guideline recommends etoposide/ platinum-based chemotherapy in combination with bleomycin (Blenoxane), ifosfamide (Ifex), or paclitaxel (Abraxane) for high-risk patients who have incomplete response to treatment. Hysterectomy and pulmonary resection should be considered for chemotherapy-resistant disease.

Both Abu-Rustum and Lurain said that a woman can safely carry a fetus to term after being treated for GTN. Abu-Rustum added these patients should be evaluated as soon as possible to be sure there is no recurrence and that a second mole has not developed, but that is rare. If an ultrasound determines the pregnancy is normal, Lurain said that the expectant mother doesn’t need any special treatment. Six weeks after the end of the pregnancy, the woman should undergo an hCG test. Lurain said hCG levels should return to normal quickly.

“About 1% of patients will have recurrent or repeat disease in a subsequent pregnancy,” he said. “Ninety-nine times out of 100, the patients will do just fine. If it’s not normal, you need to do some more work to figure out why that is.

NCCN clinical practice guidelines in oncology—gestational trophoblastic neoplasia. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/default.aspx. Published August 9, 2018. Accessed September 4, 2018.

Treatment of gestational trophoblastic disease by type and stage. American Cancer Society website. cancer.org/cancer/gestational- trophoblastic-disease/treating/by-stage.html. Published November 28, 2017. Accessed September 4, 2018.

Articles

The National Comprehensive Cancer Network has issued the first-ever guidelines for the treatment of women with gestational trophoblastic neoplasia.

NCCN Issues Guidelines for Management of Rare Gestational Cancers

Although CD19 has proved to be an attractive and effective target for chimeric antigen receptor (CAR) T-cell therapies in hematologic malignancies, a significant subset of patients treated with this groundbreaking form of immunotherapy eventually relapse, with some developing a more aggressive and harder-to-treat form of their disease.

CAR therapies are composed of genetically engineered T cells designed to target tumor-associated antigens (TAAs). The 2 CAR T-cell therapies that the FDA has approved thus far, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta), target the CD19 protein, which is highly expressed in a variety of B-cell malignancies.

As investigators seek to understand the mechanisms of resistance that develop with these and other CD19-directed anticancer therapies, some are turning their attention to alternative targets that could offer a way to stay 1 step ahead of evolving cancers. In this respect, CD22 shows particular promise.

CAR T-cell therapies that target CD22 are beginning to demonstrate potential value, particularly in patients who have relapsed following treatment with CD19 CARs. Additionally, CD22 is becoming an important target in its own right in hematologic malignancies. Two novel therapies directed against CD22, inotuzumab ozogamicin (Besponsa) and moxetumomab pasudotox-tdfk (Lumoxiti), have gained FDA approvals during the past year.

CD22 is a glycoprotein and a member of the immunoglobulin G gene superfamily. It is expressed across all stages of B-cell differentiation but absent from mature plasma cells. Like CD19, CD22 expression is restricted to B cells and helps regulate the immune response through B-cell receptor signaling (FIGURE).

 Additionally, CD22 is highly expressed in B-cell malignancies. Importantly, CD22 expression is usually retained in tumors that have lost CD19 expression. In the earlier stages of B-cell development, CD22 is found inside the cell, though later on it is expressed on the membrane. It plays a number of different roles. Significantly, it has an inhibitory function in B-cell signaling, establishing a base-line level of antigen binding that must be exceeded prior to B-cell activation, to help keep humoral immunity in check.

CAR T-cell therapies directed at CD22 are being studied in a growing number of clinicaltrials throughout the world and in preclinical programs. In the United States, academic centers are leading several phase I trials testing novel approaches, including CAR combinations 

. Meanwhile, at least 2 dozen other trials are ongoing in China and Europe, according to clinicaltrials.gov.

CAR T cells are a form of adoptive cell therapy in which the effector cells of the immune system are transplanted into a patient to boost the antitumor immune response. The T cells are genetically engineered outside the body to express a CAR that is designed to target a TAA. CARs are artificial T-cell receptors (TCRs) made of the single-chain variable fragment from an anti- body, which confers antigen specificity, fused to an intracellular portion composed of the CD3ζ chain of the TCR and 1 or more costimulatory domains, which trigger T-cell activation. In this way, an antibody-like sensitivity is essentially grafted onto a T cell.

BCR indicates B-cell receptor; CAR, chimeric antigen receptor; CCR4, CC chemokine receptor 4. CAR-modified T cells targeting CD19 and CD22 transmembrane proteins on a malignant B cell. T-cell activation leads to apoptosis of the cancer cell.

Last year marked the first FDA approvals of this type of immunotherapy. These approvals and much of the research conducted to date have focused on targeting the TAA CD19—an ideal target for the treatment of leukemia and lymphoma thanks to its restriction to B cells and its frequent expression in B-cell malignancies.

Tisagenlecleucel gained the FDA’s approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. The decision was based on findings from the single-arm, phase II ELIANA trial, in which the overall response rate (ORR) was 81%, including complete remission (CR) in 60% of patients.

 The drug subsequently was approved for treating adults with relapsed or refractory (r/r) B-cell lymphoma after 2 or more lines of systemic therapy.

In October 2017, axi-cel was approved for treating patients with r/r large B-cell lymphoma after 2 or more lines of systemic therapy. The phase II ZUMA-1 trial demonstrated an ORR of 82%, with CR in 54% of patients 23 years and older (median age, 58 years; range, 23-76) with refractory large B-cell lymphomas.

CD19 has also proved an effective target in other forms of immunotherapy. In 2014, the FDA approved blinatumomab (Blincyto) for treating adult patients with r/r Philadelphia chromosome—negative precursor B-cell ALL. Blinatumomab is a new type of antibody format: a bispecific T-cell engager that binds to CD19 on B-lineage cells and CD3 expressed on T cells. In a single-arm, multicenter, open-label study of 189 patients, 43% of patients achieved CR or CR with partial hematologic recovery of peripheral blood counts within 2 cycles of blinatumomab.

Although CD19-targeted CAR therapies have undoubtedly produced dramatic and unprecedented responses in patients with B-cell malignancies, some patients do not respond, and among those who do respond, a significant proportion relapse. Because these therapies have been introduced only in the past several years, understanding of their durability is still evolving. Relapse rates of 10% to 20% have been observed in pediatric and adult patients with B-cell ALL who were treated with CARs, although rates in other studies have been higher.

 Some experts have observed differences in relapse rates and patterns, depending on the cancer type.

As a result, research efforts have begun to focus on understanding the driving forces behind this resistance.

Although the field is still in its infancy, 2 major types of resistance have been uncovered: CD19-positive and CD19-negative relapse. In the first scenario, the tumor retains CD19 expression and resistance has been linked to poor T-cell activity or persistence, allowing tumors to thrive in the presence of CD19-targeted therapies.

In the second scenario, the recurring tumor is a different phenotype from the original pretreatment tumor, having apparently lost expression of the CD19 antigen. A number of possible mechanisms explaining how this occurs have been proposed. These involve genetic or epigenetic alterations (deletions, mutations, or alternative splicing of the mRNA) that result in the outright loss of the CD19 gene or in the expression of a CD19 gene that lacks the epitope recognized by CAR T cells.

Alternatively, CD19 loss has been reported to occur via a process known as lineage switching. B cells are highly plastic, and their development is greatly influenced by other developing cells and by cues from the surrounding microenvironment. Acute leukemias that are initially classified as lymphoid at diagnosis can show the opposite myeloid lineage at relapse. This mecha- nism of resistance is frequently associated with the co-occurrence of MLL gene rearrangements.

Studies conducted to date suggest that CD19 antigen loss is a major form of resistance associated with CD19-targeted CAR T-cell therapy. This is also observed, albeit likely at a lesser frequency, with other types of CD19-targeted therapy. In a study of CD19-targeted CAR T cells in 59 pediatric patients with r/r B-cell ALL, 93% of patients achieved CR.

Table. CD22-Directed CAR T-Cell Trials in the United States

ALL indicates acute lymphoblastic leukemia; B-ALL, B-cell acute lymphoblastic leukemia; CAR, chimeric antigen receptor; DLBCL, diffuse large B-cell lymphoma; EGFRt, truncated form of the human epidermal growth factor; FL, follicular lymphoma; NCI, National Cancer Institute; NHL, non-Hodgkin lymphoma; r/r, relapsed or refractory; TCR, T-cell receptor.

Twenty patients subsequently relapsed after CR, and 13 of these patients (65%) had CD19-negative disease at relapse.

 Two separate studies of adult patients with B-cell ALL were conducted at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York, and Fred Hutchinson Cancer Research Center in Seattle, Washington. In the MSK study, among 87% of responders, the rate of CD19-negative relapse was 14%.

The Seattle research group reported that 2 of the 29 evaluable patients experienced CD19-negative relapse after first achieving CR, including 1 case of lineage switch.

Thus, CD19-negative relapses have been reported across different patient populations treated with different CAR constructs. In addition, evidence suggests that CD19 loss could occur in other types of B-cell malignancy beyond ALL following treatment with CD19-targeted CAR T-cell therapy, including patients with chronic lymphocytic leukemia and diffuse large B-cell lymphoma.

To date, the frequency of CD19 antigen loss appears to be highest in patients with ALL; however, it is not yet clear whether this reflects the greater clinical experience with this type of malignancy or genuine differences in disease biology.

In patients who relapsed after blinatumomab treatment, several studies have examined the frequency of CD19 negativity. In 16 of 20 patients with adult B-cell ALL who achieved CR with blinatumomab, there were 2 CD19-negative relapses. All 4 relapses occurred in patients who did not undergo stem cell transplantation, of which 2 were CD19 negative and 2 were extramedullary relapses.

 In a separate study, in adult patients with B-cell ALL, there were 10 relapses, and 3 of them were CD19 negative.

Most recently, the outcomes of 68 adult patients with r/r B-cell ALL after treatment with blinatumomab were evaluated. Overall, only 8% of patients lost CD19 expression, although the authors pointed out the short duration of exposure to blinatumomab of patients in this trial. The lower selective pressure could have influenced the frequency of CD19 negativity.

However, if the results of these studies are borne out in larger trials following longer exposure to blinatumomab, then a substantial proportion of patients who relapse after blinatumomab treatment may still be eligible for CD19-targeted CAR T-cell therapy.

The current understanding of CD19 antigen loss is limited, but investigators are homing in on this area to learn how and when it occurs and the potential risk factors for this type of relapse. Emerging evidence suggests that preexisting CD19-negative clones may be present prior to treatment and that they are selected for during CD19-targeted treatment.

CD19 antigen loss also has implications for monitoring disease progression in patients with B-cell ALL. Minimal residual disease and disease progression are often evaluated by quantifying the presence of CD19-positive cells using flow cytometry. However, if the loss of CD19 drives progression, these cells are not captured by conventional flow cytometry. In cases of CD19- negative relapse, it will be necessary to move away from exclusively relying on CD19 to monitor disease progression. Results from several studies have suggested CD22 as among potential alterna- tives or additional markers in this respect.

Regardless of the underlying mechanism, the prognosis for patients with r/r disease after CD19-targeted therapy is poor. This has prompted investigators to seek out alternative targets for CAR T cells and other immunotherapies for the treatment of B-cell malignancies.

CD22 has already demonstrated its value as a therapeutic target in patients with B-cell malignan- cies. Inotuzumab ozogamicin is an antibody—drug conjugate (ADC) in which a CD22 monoclonal antibody is linked to a cytotoxin from the calicheamicin class. The drug received regulatory approval in 2017 for the treatment of patients with r/r ALL irrespective of their Philadelphia chromosome status.

The approval was based on the results of the phase III INOVATE ALL trial in which inotuzumab ozogamicin was compared with chemotherapy in 326 patients. CR was observed in 35.8% of patients treated with the ADC, and the median duration of remission (DOR) was 4.6 months compared with a 17.4% CR rate and a 3.1-month median DOR in those treated with chemotherapy. The most common adverse events experienced by patients treated with inotuzumab ozogamicin included thrombocyto- penia, neutropenia, infection, anemia, and fatigue.

In September 2018, the FDA approved moxetumomab pasudotox-tdfk for treating adults with r/r hairy cell leukemia (HCL) who have received at least 2 prior systemic therapies, including treatment with a purine nucleoside analogue. The drug is a first-in-class CD22-directed cytotoxin composed of a murine immunoglobulin variable domain genetically fused to a Pseudomonas exotoxin that inhibits protein synthesis.

The approval was based on findings from a single-arm study that included 80 patients with HCL in which moxetumomab pasudotox induced an ORR of 75%, including a CR lasting for over 180 days (durable CR) for 30% of patients. The agent was approved with a boxed warning regarding the potential for grade 3/4 capillary leak syndrome and hemolytic uremic syndrome, which occurred at the rate of 3.8% each in the safety population.

Because the development of CARs directed at CD22 is in the preclinical and early stages, few reports of efficacy have been published.

Earlier this year, investigators at the National Cancer Institute reported findings from a first- in-human trial of CD22-targeting CAR T cells. The results of the small, dose-escalation study, published in Nature Medicine, suggested that this type of CAR T-cell therapy may have comparable efficacy to that of CARs targeting CD19 in patients with B-cell ALL.

Safety and efficacy were evaluated in 21 pediatric and adult patients, with a median age of 19 years, with r/r B-cell ALL, all of whom had undergone at least 1 prior hematopoietic cell transplantation. Most patients had also previously received CD19-targeted therapy.

Patients were treated with either 3 x 105 cells/ kg, 1 x 106 cells/kg, or 3 x 106 cells/kg. Sixteen patients experienced cytokine release syndrome (CRS); however, this was most commonly grade 1 or 2. Dose-limiting toxicities occurred in 1 patient at the first dose level. The recommended phase II dose was established at 1 x 106 cells/kg. The CR rate was 73% among patients receiving this dose and 57% across all dose levels, with a median DOR of 6 months. This study was the first to demonstrate the potential of CD22-targeted CAR T cells in their own right in patients with CD19 CAR—nai&#776;ve tumors and—most excitingly&mdash;in overcoming resistance to CD19-targeted therapies. CD19 negativity was observed in 10 patients in the study, 9 of whom had undergone CAR T-cell therapy and 1 of whom had been treated with blinatumomab.

In another study, CD22-targeted T cells were specifically tested as salvage therapy in 15 pediatric patients with B-cell ALL who relapsed after or were refractory to CD19-targeted CAR T-cell therapy. In the open-label, single-center, single-arm study, CAR T cells were administered at a dose of 8.2 x 10.05 cells/kg in patients who had not undergone stem cell transplantation and 0.9 x 10.05 cells/kg in those who had.

The results were presented at the 23rd Congress of the European Hematology Association in Stockholm, Sweden, in June. Thirty days after infusion, the CR rate was 80% and there was also 1 partial response. CD22-targeted CARs were well tolerated, with only mild cases of CRS.

Studies of CD22-targeted CARs have demonstrated that some patients also relapsed after treatment and that loss of CD22 expression is a mechanism of relapse; for example, 7 of 8 patients who relapsed in the first-in-human trial demonstrated dimin- ished CD22 expression.

This has prompted questions about how CD22 targeted CAR T-cell therapies should best be used. Should they be used as salvage therapy in patients who have relapsed on CD19-targeted therapy, or should they be used simultaneously with CD19-targeted therapy to prevent the development of resistant variants and reduce the risk of treatment failure? Ongoing clinical trials are testing a variety of scenarios, including sequential treatment with CD19-targeted therapy followed by CD22-targeted therapy, mixed infusions of CAR T cells targeting both antigens at the same time, and bispecific and even trispecific CAR constructs.

In a presentation at the 2018 ASCO Annual Meeting, investigators from Baylor College of Medicine detailed the development of 2 trivalent CAR T-cell products that target CD19 and CD22 in addition to CD20. In the first, dubbed a TriCAR, CAR T cells express 3 different CAR constructs, while in the second, called a sideCAR, T cells express a single CAR targeting CD19 and a second bispe- cific CAR targeting CD20 and CD22. Preclinical data demonstrated that both types of CAR T cells were more effective at killing cancer cells than CD19-targeted CAR T cells alone, at lower effector cell-to-target cell ratios.

Although CD19 has proved to be an attractive and effective target for chimeric antigen receptor T-cell therapies in hematologic malignancies, a significant subset of patients treated with this groundbreaking form of immunotherapy eventually relapse.

CD22 Emerges as CAR T-Cell Therapy Target

The presence of Lynch syndrome (LS) correlates with microsatellite-instability (MSI) status and DNA mismatch-repair deficiency (dMMR) across a variety of tumor types, according to a prospective study of 15,045 tumor samples that were analyzed with MSK-IMPACT next-generation sequencing and MSI testing. Tumors with MSI-high (MSI-H) and MSI-indeterminate (MSI-I) scores were most commonly associated with small bowel, endometrial, colorectal, and gastric cancers, according to the findings. A high proportion of MSI-H and MSI-I tumors exhibited dMMR signatures. The results also suggest that LS-associated cancers may be more heterogeneous than previously thought.

For the study, investigators employed the multiplex panel test MSK-IMPACT, which was authorized for tumor profiling by the FDA last year. The multiplex panel incorporates MSI assessment using a bioinformatics tool called an MSI sensor. The tool generates a report that designates a score of ≥10 as MSI-H, a score between 3 and 10 as MSI-I, and scores <3 as microsatellite stable (MSS).

Lead author Alicia Latham Schwark, MD, a medical genetics fellow at Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues demonstrated that among the noncolorectal/nonendometrial tumor samples, which spanned more than 50 cancer types, 50% of patients (33/66) with LS had either MSI-H or MSI-I tumors that were not previously associated with the syndrome. Findings were reported during the 2018 American Society of Clinical Oncology Annual Meeting, held June 1-5 in Chicago, Illinois.

The presence of MSI indicates a defect in the DNA mismatch repair system. It has been established that this finding is characteristic of LS-associated cancers, primarily colorectal and endometrial. Testing for MSI is routinely performed in all colorectal and endometrial cancers as an initial screening for LS. However, the prevalence of LS in other cancers has not been documented.

The study had 2 objectives: to determine the overall LS prevalence in all patients who underwent MSK-IMPACT testing, according to tumor MSI status, and to characterize germline findings into causative versus incidental through immunohistochemical (IHC) concordance rates and tumor mutational signatures across MSS, MSI-I, and MSI-H groups.

Five mismatch repair genes were assessed: 

 (single nucleotide variations and deletion [del]/duplication), and

(del only). In patients with LS with MSI-H and MSI-I tumors, IHC staining for MMR protein expression was performed. Breast cancer made up the largest group (16%) of tumor types, followed by lung cancer (13%). Overall, colorectal and endometrial cancer tumors made up 5% and 3.5% of the group, respectively. Because of its gene type, LS is often hard to detect when it is not associated with cancer, Schwark said. When tumors are categorized by MSI status, the distributions change, Schwark said.

“Small bowel cancer had the highest rate of MSI-H tumors at 25%. This was followed by endometrial, colorectal, and gastric cancers, which were previously associated with LS. When including the indeterminate prevalence, adrenocortical had the highest rate at over 40%.” Across the 3 groups, the prevalence of LS in patients with MSI-H tumors was 16.3%, the MSI-I group had a 1.9% LS prevalence, and the prevalence of LS in patients in the MSS group was 0.3% (

“This 0.3% is in line with current general population prevalence estimates,” Schwark said. “Looking at the MSI-H cohort, 43% of patients with LS had cancers other than colorectal and endometrial.”

When reviewing the distribution of germline mismatched repair mutations by gene and MSI status, the investigators found that the majority of germline mutations in the MSI-H and MSI-I groups were

. The majority of mutations in the MSS group were MSH6 and PMS2 (

“This is notable, as it has been previously demonstrated that 

 are lower penetrance genes that are found more commonly in the general population, suggesting that these may be incidental findings,” Schwark said.

Tumor mutational signatures identified patients with LS. Overall, 88% of high and indeterminate tumors from patients with LS exhibited dMMR tumor signatures, while 89% of MSS tumors from patients with LS did not.

Patients with LS who had MSI high or indeterminate tumors had tumors that were likely caused by LS. In the case of MSS tumors, LS was probably not the cause, Schwark said.

Figure. Distribution of MSI Status Across Tumor Types

Schwark added that about 45% of patients with LS who had either MSI-H or MSI-I noncolorectal or nonendometrial tumors did not meet clinical criteria for genetic testing. This suggests that these types of tumors, regardless of cancer type, should prompt LS testing.

The researchers concluded that overall prevalence of LS varied significantly across the cohorts, although MSI-H tumors showed significantly greater prevalence of LS. Half of the patients with LS, with either MSI-H or MSI-I tumors, had cancers other than colorectal or endometrial. Concordant IHC indicated that their cancer was caused by their LS. The overall concordance rate for IHC and MSI-H/I, which includes not-previously LS-associated tumor types was 98% (56/57). Moreover, patients with other cancers were less likely to meet clinical testing criteria.

Schwark AL, Srinivasan P, Kemel Y, et al. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. Presented at: 2018 ASCO Annual Meeting, June 4, 2018. J Clin Oncol. 2018;36 (suppl; abstr LBA1509).

The presence of Lynch syndrome correlates with microsatellite-instability status and DNA mismatch-repair deficiency across a variety of tumor types.

Testing Reveals Extent of Lynch Syndrome

A policy change that allows step therapy provisions in Medicare Advantage insurance plans is setting off alarm bells among oncology leaders, who have joined medical associations from across the country in objecting to the revision. The controversy has been mounting since the Centers for Medicare and Medicaid Services (CMS) announced in August that step therapy would be permitted for drugs covered under Medicare Part B.

Step therapy, a form of prior authorization, will enable Medicare Advantage plans, starting January 1, 2019, to require that preferred drugs be prescribed first and used until they prove ineffective before physicians can try other, potentially higher-cost agents. The policy reverses a prohibition on step therapy for Medicare Advantage plans established in 2012.

Anticancer drugs currently covered under Part B include infused drugs, such as chemotherapy, chimeric antigen receptor T-cell therapies, and, in some cases, other types of immunotherapy. Additionally, oral anticancer drugs that are also available as injectables are covered by Part B.

As it stands now, oncology experts do not expect the Medicare Advantage step therapy provision to have a large impact on treatment protocols because anticancer agents can rarely be substituted for one another. However, that’s not the case with supportive care drugs, said Stephen S. Grubbs, MD, vice president of clinical affairs for the American Society of Clinical Oncology (ASCO).

Based on prior experience with private payer policies, “It’s rare for step therapy to force changes in tumor treatment, but it often forces us to change supportive medications we prescribe patients with cancer for problems such as peripheral neuropathy. You start with a less expensive medication that often fails and work your way up to a more effective drug, which delays the benefit of therapy. And there are times when step therapy requirements do prevent you from getting your patients the right drug at the right dose at the right time. That’s just not acceptable, and that is why ASCO opposes this decision by CMS.”

In September, ASCO joined more than 90 state and national professional societies in urging CMS to reconsider its decision in a letter that the American Medical Association circulated.

 The letter also was signed by the American Society of Hematology, the American Society for Radiation Oncology, the Society of Gynecologic Oncology, and the American Urological Association. The Community Oncology Alliance (COA) also is opposing the policy.

ASCO and the other physician groups have urged CMS to reverse the step therapy decision on grounds that such requirements could end up denying a significant number of patients with cancer timely access to medications their doctors deem best suited for them, based on assessments of each patient’s unique circumstances. “While a particular drug or therapy might be generally considered appropriate for a condition, the presence of comorbidities, potential drug-drug interactions, or patient intolerances, for example, may necessitate the selection of an alternative drug as the first course of treatment,” the AMA letter states.

In explaining the rationale for the revised policy, CMS said that it will incentivize drug manufacturers and distributors to negotiate drug prices with Medicare Advantage plans much as they do for private payers that employ step therapy. The agency projects a median value of $1 billion in potential savings. In addition, CMS said, more than 50% of the savings achieved through step plans must be returned to Medicare beneficiaries in the form of gift cards or other noncash transfers.

The changes “should not result in increased costs to enrollees,” CMS said in its memo. Although the new step therapy guidelines compel plans to share at least half of any savings with patients, the competitive market for Medicare Advantage plans in many areas might pressure them to pass more savings to enrollees via lower premiums. Moreover, CMS officials said, regulatory safeguards would prevent access problems for patients. Patients and their doctors will have the ability to challenge step therapy decisions and policies, and reviews of those challenges must be completed swiftly, CMS said. Plans will have 14 days to address regular requests and 72 hours to adjudicate expedited requests.

CMS has encouraged Medicare Advantage plans to use their Part D protocols as templates for determining when it is appropriate to use step therapy for drugs in Part B. Part D drugs include self-administered prescription drugs, such as immunosuppressants and anticancer oral drugs. As part of the policy change, CMS emphasizes that physicians can be required to use lower-cost Part D drugs before being allowed to try a Part B drugs, which are often more expensive.

This ability to shift patients from Part B to Part D drugs, according to CMS, is a highlight of the new policy because it will give Medicare Advantage plans far more power than they currently have to direct patients to the best treatment, regardless of where it’s administered, and to win lower prices by getting more drug makers to compete against one other. However, to some observers, the ability to move patients back and forth among Part B drugs and Part D drugs suggests that CMS will allow a much more aggressive form of step therapy than merely preferring some drugs in a particular class over other drugs in that same class.

For its part, CMS stresses that “Medicare Advantage plans may apply step therapy to control the utilization of services in a manner that does not create an undue access barrier for beneficiaries.”

 This also precludes using prior authorization as a requirement for emergency services, CMS said. “Step therapy or other utilization management policies may not be used as an unreasonable means to deny coverage of medically necessary services or to eliminate access to a Part B covered benefit.”

However, many questions are left open to interpretation. It’s not clear, for example, whether aggressive cancers count as emergencies that would override step therapy protocols. Another unanswered question is if newer drugs proved superior to earlier agents would merit priority in a step therapy lineup.

“In conversations we’ve had with Health and Human Services Secretary Alex Azar and his staff, they have said they don’t expect this decision to have much effect on anti-cancer drugs. The main intent of the order is to save money by letting plans choose the order in which patients try similar medications with similar efficacy and toxicity. But their perception was that there just weren’t that many intraclass substitutions to be made in oncology,” Grubbs said. The assumption is that less-potent drugs would not be allowed in cancer treatment the way they are in less-urgent conditions, such as high blood pressure. “There might be a place for this in conditions like high cholesterol, where there’s little consequence to making some patients wait a few months for the expensive treatments they need while you figure out which patients do just fine on the cheap medications that have been around for decades. But any sort of delay tends to have dangerous consequences for patients with cancer,” COA Executive Director Ted Okon said in an interview.

“There is no place in cancer care for middlemen from insurance companies or pharmacy benefit managers [PBMs] to make these life-altering decisions, and we already know from our experience with private insurance about the dangers of policies forcing patients to use the cheapest treatments rather than the best treatments for them,” he added.

CMS’ decision on step therapy comes at a time when Medicare Advantage policies have become increasingly prevalent among the growing population of Americans 65 years and older, the group most at risk of a cancer diagnosis. Medicare Advantage plans covered 19 million Medicare beneficiaries in 2017, 33% of the total, up from 9.7 million, or 22% of the total, in 2008.

FIGURE. MANY STATES HAVE ENACTED STEP THERAPY LAWS TO PROTECT PATIENTS

Step therapy is used by payers to ensure that preferred medicines receive priority and health spending is kept under control.

Collectively, Medicare Advantage plans spend about $12 billion a year on Part B drugs, according to CMS officials. Private payer step plans have achieved savings of 15% to 20% on Part B drug expenditures, and CMS is hoping to achieve similar results by implementing the approach in Medicare Advantage plans.

Indeed, CMS’ move toward step therapy mirrors the trend in private sector insur- ance, where the use of step therapy provisions among employers has grown rapidly during the past decade, from 27% in 2005 to 73% in 2013.5 In 2019, 64% of employers cited “establishing aggressive utilization management” including prior authorization, step therapy, and quantity limits for biologics and other specialty drugs, as strategies for tackling the rising costs of health benefits.

The growth of step therapy plans in the private insurance market has generated a back- lash among patients and advocates nationwide, with critics often describing the plans as “fail first” requirements. In response to complaints, state legislatures have considered laws regu- lating the use of step therapy; such laws have been enacted in at least 18 states and bills are pending in 8 others (FIGURE).

The new CMS rules do not override step therapy laws that incorporate patient protec- tions limiting the use of such protocols. The policy change also forbids plans from using step therapy requirements to stop paying for treatments that patients are using when the new policies take effect. Step therapy require- ments can apply only to treatments that begin after the new rules are adopted. Further, plans that wish to implement step therapy for Part B drugs in 2019 must notify patients in their Annual Notice of Change and their Evidence of Coverage documents prior to the annual election period.

Additionally, CMS’ plan includes a patient engagement element that requires Medicare Advantage plans to provide avenues for their involvement in decisions affecting their care. Plans that implement step therapy must also offer patients the opportunity to partici- pate in “drug management care coordination activities,” a term that CMS defines, “at a minimum,” to include:

•Having interactive medication review and associated consultations for enrollees to discuss all current medications and perform medication reconciliation and follow-up when necessary;

• Providing educational materials and information to enrollees about drugs within the drug management care coordination program; and

• Implementing medication adherence strategies to help enrollees with their medication regimen.

The dispute over the step therapy provision is unfolding against a backdrop of frustration among oncology specialists and other physicians over the burden that prior authorization rules and drug utilization management strategies place on patients and practices. In ASCO survey findings published in July 2018, 58% of respondents from nearly 400 oncology practices identified payer practices as the top source of strain, led by prior authorization (78%) and coverage denials and appeals (62%).

Okon noted that news organizations have recently published reports containing anecdotal evidence that formulary restrictions hurt clinical outcomes. He singled out an 8-month investigation from the Columbus Dispatch as a particularly eye-opening look into the consequences of giving power to PBMs.

However, there appears to be a paucity of peer-reviewed research into how step therapy approaches affect outcomes in the cancer arena; neither Grubbs nor Okon knew of any research that ties step therapy to inferior outcomes in patients with cancer. Overall, much of the literature on step therapy is gener- ated by industries most directly affected by such policies: pharmaceutical companies, payers, and PBMs.

A 2010 review of 15 studies that examined the effects of step management policies found few concrete benefits and many areas of concern. “Although formulary restrictions may decrease drug costs, several studies have demonstrated that total healthcare costs remained the same or increased,” Rashad I. Carlton, PharmD, and colleagues reported in a study funded by Novartis.

Similarly, a 2017 literature review, written by Novartis pharmacists, found that step therapy and other formulary restrictions were posi- tively associated with pharmacy cost outcomes but negatively associated with medication adherence, clinical outcomes, patient-reported treatment satisfaction outcomes, healthcare resource utilization for outpatient visits and hospitalization, and medical costs.

Brenda R. Motheral, PhD, RPh, MBA, a PBM specialist, painted a more favorable picture in a 2011 review of step therapy studies in 5 therapeutic classes: antidepressants, anti-hypertensives, antipsychotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs).

 Her findings show that the drug savings and clinical impact of step therapy for antipsychotics was unclear, but that significant savings could be achieved for NSAIDs and PPIs without increasing the use of other medical services. At the same time, Motheral pointed to the need for further research for other therapy classes in which step therapy is used, notably independently funded evaluations “to help reduce the potential for study bias.”

Beyond the debate about the practical impact of step therapy provisions, some observers have focused on the ethical considerations of requiring patients to fail a first-step drug before moving on to another medication.

“More than other utilization management tools such as formulary tiering, step therapy raises important ethical concerns regarding the proper balance between cost control and the ability of patients and clinicians to tailor care to the needs of the individual patient,” bioethicists Rahul K. Nayak and Steven D. Pearson, MD, MSc, FRCP, wrote in a 2014 article in Health Affairs.

 Nayak is now an MD candidate at Harvard Medical School and Pearson is president of the Institute for Clinical and Economic Review and a visiting scientist in the Department of Bioethics at the National Institutes of Health. For patients with cancer, they noted, these issues are particularly acute “largely because the possible risks of failure of the first-step therapy are more clinically meaningful to patients and in some cases may represent irretrievable harms.”

Nayak and Pearson proposed 8 ethical criteria that should be incorporated into step therapy policies that require patients to take a less-expensive drug before covering a more expensive medicine:

• Weigh cost savings against long-term outcomes.

• Ensure that first-step drugs are clinically appropriate.

CMS believes that its mandated safeguards will eliminate any negative outcomes that have been associated with some step therapy plans, but agency officials say that patients who remain skeptical should be able to buy coverage that does not include step therapy requirements.

According to an analysis by the Henry J. Kaiser Family Foundation, the average Medicare beneficiary has access to 21 Medicare Advantage plans this year. Such numbers make it possible that most Americans will be able to choose among several plans that do and several plans that do not implement step therapy for Part B benefits. But such competition is not universal. Residents of 44 counties currently have access to only 1 Medicare Advantage plan. Barring new competition in those markets, patients would have to accept the incumbent’s decision or enroll in standard Medicare.

Medicare Advantage plans collectively spend about $12 billion a year on Part B drugs.

 If plans representing half of all patients implement step therapy programs and achieve an average savings of $1 billion per year, that would still be a small fraction of the estimated $535 billion that will be spent on prescription medications in the United States this year.

“The change to allow step therapy for Part B benefits probably won’t be an earth-shattering move when considered on its own, but it’s just one of a number of moves that [the Trump] administration is making to address the problem of drug pricing,” said Rachel E. Sachs, JD, MPH, an associate professor at the Washington University School of Law who studies how patent law and health law affect innovation and costs. “For example, the FDA is making a real push to get generics and biosimilars onto the market to increase price competition, and CMS has just issued another memo that gives plans more flexibility with the Part D formularies.

 Add everything together and you may see some real downward pressure on prices. But it’s still too early to tell.”

Sachs believes it’s also much too early to make reliable predictions about how many plans will implement step therapy for Part B benefits, how many patients will enroll in such plans, and who will benefit most from the savings. “You can make a plausible argument that the overwhelming majority of plans will implement Part B step therapy, and you can make a plausible argument that very few plans will do so, and you can make a plausible argument that it will vary from place to place such that nearly all of the plans in some plan regions adopt this and virtually none of the plans in other plan regions adopt this,” Sachs said. “As to the question of how any savings will be divided between plans and patients, CMS is obviously working to direct it to patients, but market forces will ultimately determine where the money goes, and that could vary greatly from place to place."

Verma S. Prior authorization and step therapy for part B drugs in Medicare advantage. CMS website. cms.gov/Medicare/Health-Plans/HealthPlansGenInfo/Downloads/MA_Step_Therapy_HPMS_Memo_8_7_2018.pdf. Published August 7, 2018. Accessed September 21, 2018.

Re: memo of August 7th regarding prior authorization and step therapy for Part B drugs in Medicare Advantage [letter]. American Medical Association. https://searchlf.ama-assn.org/undefined/documentDownload?uri=%2Funstructured%2Fbinary%2Fletter%2FLETTERS%2F2018-9-10-Signed-on-Letter-to-Verma-re-Step-Therapy.pdf. Published September 7, 2018. Accessed October 3, 2018.

Jacobson G, Damico A, Neuman T, Gold M. Medicare Advantage 2017 spotlight: enrollment market update. Henry J Kaiser Family Foundation. kff.org/medicare/issue-brief/medicare-advantage-2017-spotlight-enrollment-market-update/. Published June 6, 2017. Accessed September 25, 2018.

Joszt L. CMS will allow Medicare advantage plans to use step therapy to negotiate drug prices. American Journal of Managed Care® website. ajmc.com/newsroom/cms-will-allow-medicare-advantage-plans-to-use-step-therapy-to-negotiate-drug-prices. Updated August 8, 2018. Accessed September 21, 2018.

Manikhas A, Pennella EJ, Bondarenko I, et al. Biosimilar MYL-1401O monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 HERITAGE trial. 

Chung A, MacEwan J, Goldman DR. Does a ‘one-size-fits-all’ formulary policy make sense? Health Affairs Blog. healthaffairs.org/do/10.1377/hblog20160602.055116/full/. Published June 2, 2016. Accessed October 3, 2018.

Miller S. For 2019, employers adjust health benefits as costs near $15,000 per employee. Society for Human Resource Management. shrm.org/resourcesandtools/hr-topics/benefits/pages/employers-adjust-health-benefits-for-2019.aspx. Published August 13, 2018. Accessed October 3, 2018.

Statewide Prescription Drug Database | 2015-Present. National Conference of State Legislature website. ncsl.org/research/health/prescription-drug-statenet-database.aspx. Updated September 18, 2018. Accessed October 3, 2018.

Step therapy legislation. American Academy of Dermatology. aad.org/advocacy/state-policy/step-therapy-legislation. Accessed October 3, 2018.

Kirkwood MK, Hanley A, Bruinooge SS, et al. The state of oncology practice in America, 2018: results of the ASCO Practice Census Survey. 

. 2018;14(7):e412-e420. doi: 10.1200/JOP.18.00149.

Side effects: an ongoing investigation on the rising costs of prescription drugs. 

. gatehousenews.com/sideeffects/. Accessed September 21, 2018.

Carlton RI, Bramley TJ, Nightengale B, Conner TM, Zacker C. Review of outcomes associated with formulary restrictions: focus on step therapy. American Journal of Pharmacy Benefits® website. ajpb.com/journals/ajpb/2010/vol2_no1/review-of-outcomes-associated-with-formulary-restrictions-focus-on-step-therapy. Published April 6, 2010. Accessed September 21, 2018.

Park Y, Raza S, George A, Agrawal R, Ko J. The effect of formulary restrictions on patient and payer outcomes: a systematic literature review. 

. 2017;23(8):893-901. doi: 10.18553/jmcp.2017.23.8.893.

Motheral BR. Pharmaceutical step-therapy interventions: a critical review of the literature. 

. 2011;17(2):143-55. doi: 10.18553/jmcp.2011.17.2.143.

Nayak RK, Pearson SD. The ethics of 'fail first': guidelines and practical scenarios for step therapy coverage policies. Health Aff (Millwood). 2014;33(10):1779-85. doi: 10.1377/hlthaff.2014.0516.

Jacobson G, Damico A, Neuman T. Medicare Advantage 2018 data spotlight: first look. Kaiser Family Foundation website. kff.org/medicare/issue-brief/medicare-advantage-2018-data-spotlight-first-look/. Published October 13, 2017. Accessed September 21, 2018.

A look at drug spending in the U.S. The Pew Charitable Trusts website. pewtrusts.org/en/research-and-analysis/fact-sheets/2018/02/a-look-at-drug-spending-in-the-us. Updated August 28, 2018. Accessed September 21, 2018.

Indication-based formulary design beginning in contract year (CY) 2020. CMS website. Published cms.gov/newsroom/fact-sheets/indication-based-formulary-design-beginning-contract-year-cy-2020. August 29, 2018. Accessed September 21, 2018.

A policy change that allows step therapy provisions in Medicare Advantage insurance plans is setting off alarm bells among oncology leaders, who have joined medical associations from across the country in objecting to the revision.

Step Therapy Policy Alarms Cancer Leaders

One of the hallmarks of tumorigenesis is the ability of cancer cells to suppress, or circumvent, the host immune system.

 Advances in strategies to overcome tumor cell evasion of immune detection have led to a rapid pace of preclinical and clinical development in the field of cancer immunotherapy. Most notably, in recent years T-cell checkpoint inhibitors have demonstrated therapeutic efficacy in multiple cancer types. This class of immunotherapy modulates tumor tolerance among T cells by antagonizing specific inhibitory receptor—ligand interactions, thereby enhancing T-cell activation.

A frequent observation from clinical studies of T-cell checkpoint inhibitors is that even in the context of metastatic disease, a small subgroup of patients who respond to treatment have complete and durable regression of disease. This raises the possibility that augmenting response rates to checkpoint blockade or other such immunotherapies may result in a dramatic impact on survival of patients with advanced-stage malignancy. Nevertheless, durable tumor response remains elusive for the overwhelming majority of patients with metastatic cancers, and immunotherapies are not typically effective in patients with immunologically “cold” tumors, characterized by low levels of T-cell infiltrate and few mutation-created neoantigens.

One potential approach to improving the response to cancer immunotherapies is to combine such treatments with radiotherapy (RT). Radiation may interact with the tumor immune microenvironment at a targeted site through various mechanisms, including: (1) temporary local eradication of radiation-sensitive immune lineages including suppressor and effector lymphocytes; (2) local release of inflammatory cytokines and damage-associated molecular patterns, resulting in local effects on endothelial cell expression of adhesion receptors, immune cell trafficking, and immune cell activation; (3) immunogenic tumor cell death and release of tumor-specific antigens; and (4) induction of phenotypic changes in the expression of immune susceptibility markers on tumor cells surviving radiation.

 Because of these effects, radiation may enhance antigen cross-presentation and diversification of antitumor T-cell responses.

Figure. Historical Convergence of Radiotherapy and Immunotherapy Advancements

By modulating tumor immune tolerance and functional immunogenicity at a targeted site, external beam radiation therapy may serve as a method of in situ tumor vaccination, a therapeutic strategy that is intended to convert a patient’s own tumor into a nidus for presentation of tumor-specific antigens that will stimulate and diversify an antitumor T-cell response.

 The capacity of external beam radiation alone to elicit a systemic antitumor immune response is well documented (eg, abscopal effect) but quite rare.

 In the context of targeted immunotherapies such as checkpoint inhibitors, however, multiple preclinical studies have demonstrated that localized radiation therapy can consistently enhance a systemic antitumor immune response.

 Results from retrospective clinical studies indicate the safety of such combinations.

 This highlights decades of improvements in the physical targeting of radiation therapy and the molecular targeting of immunotherapies, which have rendered these treatments increasingly amenable to combined modality approaches (

). However, prospective clinical studies reported to date have not demonstrated response rates greater than anticipated with checkpoint blockade alone.

 More than 100 ongoing clinical studies are now investigating combinations of radiation therapy with immune checkpoint inhibition in various clinical contexts. This unprecedented extent of clinical investigation reflects both the promise and enthusiasm for such approaches, as well as a degree of uncertainty about the circumstances, disease sites, radiation dose and fractionation, timing and sequencing, and clinical settings that may portend greatest benefit for immuno-RT combinations.

As we await the emergence of clinical data that might demonstrate a cooperative interaction between radiation and immunotherapies, next-generation approaches to augment such interactions are already entering early-phase clinical investigation. For example, based on promising preclinical data showing an enhanced in situ vaccine effect with the combination of external beam radiation and intratumoral injection of a tumor-specific immunocytokine (tumor-specific antibody fused to immune-stimulatory IL-2 cytokine),

 our melanoma research team at the University of Wisconsin is advancing a unique phase I/II clinical trial. This study (UW16134) will test the safety of intratumoral injection of APN301 (hu14.18—IL-2) immunocytokine (Apeiron Biologics) alone and together with local radiation therapy and systemic administration of single- or dual-agent checkpoint blockade (Bristol-Myers Squibb). The study will enroll patients with metastatic melanoma and is led by members of our melanoma clinical research team, including Paul Sondel, MD, PhD; Mark Albertini, MD; and Zachary Morris, MD, PhD. At the same time, this team is advancing preclinical investigations of novel strategies that may overcome potential limitations of in situ vaccine approaches.

 Notably, this includes collaborative studies—led by Jamey Weichert, PhD; Mario Otto, MD, PhD; and Bryan Bednarz, PhD&mdash;investigating the use of moleculartargeted radionuclide therapies (Archeus Ltd) that may enable delivery of immunomodulatory RT to all tumor sites in the setting of metastatic or multifocal disease. Our colleague Ravi Patel, MD, PhD, was scheduled to present early and very promising results of these studies in October 2018 at the American Society for Radiation Oncology Annual Meeting in San Antonio, Texas.

As the immuno-oncology revolution transforms clinical practice, tremendous opportunities continue to arise for leveraging combined modality approaches to improve antitumor immune response and patient outcomes. Ultimately, the successful development of such approaches and their incorporation into standard practice will depend on the advancement of well-conceived clinical studies founded on rigorous preclinical investigation. We look forward to partaking in this effort.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. 

. 2011;144(5):646-674. doi: 10.1016/j.cell/2011.02.013.

Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combining radiotherapy and immunotherapy: a revived partnership. 

. 2005;63(3):655-666. doi: 10.1016/j.ijrobp.2005.06.032.

Sharabi AB, Nirschl CJ, Kochel CM, et al. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. 

. 2015;3(4):345-355. doi: 10.1158/2326-6066.CIR-14-0196.

Twyman-Saint VC, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. 

. 2015;520(7547):373-377. doi: 10.1038/nature14292.

Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. 

One potential approach to improving the response to cancer immunotherapies is to combine such treatments with radiotherapy.

Vol. 19/No. 20 | Oncology Live®

NCCN Issues Guidelines for Management of Rare Gestational Cancers

CD22 Emerges as CAR T-Cell Therapy Target

Testing Reveals Extent of Lynch Syndrome

Step Therapy Policy Alarms Cancer Leaders

Combinations With RT May Improve Immunotherapy Response

Specialization Trend Is Changing the Oncology Landscape

Promising Agents Could Alter the Treatment Paradigm in Metastatic TNBC

Genetic Revolution Should Not Overlook Privacy Concerns