Major advancements in immunotherapy are at the forefront of treatment for patients with acute lymphoblastic leukemia (ALL), according to Naval G. Daver, MD.

“[There are] 3 major backbone therapies right now in ALL in the immune area [and] there are more coming,” said Daver, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, during a presentation at the 2nd Annual Live Medical Crossfire

: Hematologic Malignancies meeting in New York.

Although immunotherapy shows promise, Daver advised that the use of tyrosine kinase inhibitors should still be considered, particularly for patients with Philadelphia chromosome—positive ALL.

Novel Agents Versus Standard-of-Care Chemotherapy

Inotuzumab ozogamicin (Besponsa) was approved by the FDA in August 2017 for the treatment of adults with relapsed or refractory B-cell precursor ALL. The antibody—drug conjugate is composed of a monoclonal antibody that targets CD22, which is expressed on leukemic blasts in more than 90% of patients with ALL, and is linked to a cytotoxic agent.

The phase III INO-VATE trial, which the approval was based on, compared inotuzumab ozogamicin with investigator’s choice of standard intensive chemotherapy.

 Of the 218 randomized patients included in the primary analysis, 80.7% of patients had a complete remission (CR) or complete remission with incomplete platelet recovery (CRi) in the inotuzumab ozogamicin arm (n = 109), with a median overall survival (OS) of 7.7 months. In contrast, only 29.4% achieved a CR/CRi in the chemotherapy arm (n = 109) with a median OS of 6.2 months. The 2-year OS for patients in the inotuzumab ozogamicin arm was more than doubled compared with those in the chemotherapy arm (22.8 vs 10.0 months; 

Among those who had a CR/CRi, 78.4% of patients in the inotuzumab ozogamicin group achieved minimum residual disease (MRD)—negativity, compared with 28.1% in the chemotherapy group (

“This trial shows you 2 things: 1) how bad chemotherapy does in the salvage population, and 2) this drug was much more effective,” Daver explained. “If you look at the tail of the curve, at 2 as well as 3 years, you are getting 15% to 20% more [patients] alive at those marks, which I think is important, because it [shows] a durability component beyond the median.”

The second novel agent in a head-to-head study with standard-of-care chemotherapy was blinatumomab (Blincyto), a bispecific monoclonal antibody constructed that enables CD3-positive T cells to recognize and eliminate CD19-positive acute ALL blasts. Most recently, the FDA granted an accelerated approval in March 2018 to blinatumomab for the treatment of adult and pediatric patients with B-cell precursor ALL who are in remission but are MRD-positive.

In the randomized phase III TOWER study, patients with Philadelphia chromosome—negative relapsed/refractory B-cell precursor ALL in the blinatumomab arm (n = 271) had a 34% CR rate with a median OS of 7.7 months, compared with a 16% CR rate in the standard chemotherapy arm (n = 134) with only a 4.0-month median OS.

Additionally, in the blinatumomab arm, there was no difference in OS or recurrence-free survival between those who received allogeneic hematopoietic stem cell transplant (allo-SCT) versus those who did not. Among those who achieved a CR, 76% of patients in the blinatumomab obtained MRD-negativity status, versus 48% who received standard chemotherapy.

“These people were MRD-positive, then got blinatumomab with the intent of making them MRD-negative. And in about 80% of patients, the drug successfully eradicated MRD and was also associated with a significant median OS benefit. And a number of patients were able to go to allo-SCT.”

A recent study has looked at the potential for combining novel agents in ALL with standard chemotherapy. In the single-arm, phase II trial, adults with relapsed/refractory Philadelphia chromosome—negative ALL (n = 59) achieved a CR rate of 59% when treated with inotuzumab ozogamicin plus low-intensity chemotherapy, referred to as mini-HCVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m

Among the 46 (78%) of patients who responded, the MRD-negativity rate was 82% and 26 (44%) went on to receive allo-SCT. Of note, veno-occlusive disease (VOD) occurred in 9 patients (15%). Similar combinations are being studied in elderly patients with ALL, which also show significant responses.

Although not yet approved for elderly patients, chimeric antigen receptor (CAR) T-cell therapy has generated excitement for treating pediatric and young adult patients. Tisagenlecleucel (Kymriah) was the first FDA approved CAR T-cell therapy in August 2017 for patients up to age 25 years with relapsed/refractory B-cell precursor ALL that is refractory or in second or later relapse, based on the results of the ELIANA trial.

Of the 75 patients who received a single infusion treatment on the phase II trial, 60% had a CR and all of these patients were MRD-negative, with 95% achieving MRD-negativity by day 28. The overall response rate was 81%.

Studies are now considering which patients will benefit most from CAR T-cell therapy. In a phase I single-institution study, Memorial Sloan Kettering Cancer Center (MSK) assessed the long-term follow-up for adults with relapsed/refractory B-cell precursor ALL (n = 53) who received an infusion of autologous T cells expressing 19-28z CAR, which were manufactured by MSK.

 With a median follow-up of 29 months (range, 1-65), patients with low disease burden who received the CD19-directed CAR T-cell therapy had a median OS of 20.1 months compared with 12.4 months among patients with a high disease burden.

Patients with high disease burden were also associated with a higher risk of severe cytokine release syndrome (

“The question really is who are the best patients for CAR T cells. This was something that was looked at by the Sloan Kettering group,” added Daver. “They did a number of analyses, but the one they found that really helped to separate our outcome with CAR T-cell therapy was the disease burden. When you pick people who have low disease burden, less than 5%, which is usually an MRD-positive group…you see the impact of the CAR T-cell [therapy] was very significant.”

Several concerns still exist, however, with giving CAR T-cell therapy. Nearly all patients (95%) on the ELIANA trial experienced an any-grade treatment-related adverse event (TRAE) with tisagenlecleucel, and nearly three-quarters of patients experienced grade 3/4 TRAEs. Additionally, 40% of patients experienced neurologic events within 8 weeks of infusion, with 13% of patients experiencing grade 3 neurological events that were managed with best supportive care.

Seventy-nine percent of patients experienced cytokine release syndrome (CRS), of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1022) and lasted for a median of 8 days (range, 1-36).

Another concern is the duration of time between treatment. “One of the things that we are thinking about is to reduce the logistics or duration [of] time many patients have to wait,” Daver said. Off-the-shelf’ CAR T cells can significantly shorten the duration and have been proven to be just as affective. He noted that this therapy should be administered only by the highly experienced. “This is not something that can be done in the community or even, I would say, the smaller academic centers. At this time, large academic centers are the ones that are able to do this.”

Kantarjian, HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozagamicin versus standard therapy for acute lymphoblastic leukemia. 

. 2016;375(8):740-753. doi: 10.1056/NEJMoa1509277.

Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimum residual disease in adults with B-cell precursor acute lymphoblastic leukemia. 

. 2018;131(5):1522-1531. doi: 10.1182/blood-2018-08-798322.

Jabbour E, Ravandi F, Kebriaei P, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: a phase II clinical trial. 

. 2018;4(2):230-234. doi: 10.1001/jammaoncol.2017.2380.

Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults in b-cell lymphoblastic leukemia. 

. 2018;378(5):439-448. doi: 10.1056/NEJMoa1709866

 Park JH, Riviere I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. 

. 2018;378(5):449-459. doi: 10.1056/NEJMoa1709919.

Articles

Major advancements in immunotherapy are at the forefront of treatment for patients with acute lymphoblastic leukemia.

Immunotherapy at the Forefront of ALL Treatment, Expert Says

Although not yet approved for patients with relapsed/refractory multiple myeloma, chimeric antigen receptor (CAR) T-cell therapies have shown great promise, in addition to the various immunotherapy treatment options already available, according to Sham Mailankody, MBBS. Immunotherapy with checkpoint inhibitors, however, has encountered a rockier road in multiple myeloma.

Favorable Outcomes With Triplet Combinations

During a presentation at the 2nd Annual Live Medical Crossfire: Hematologic Malignancies meeting presented in New York, NY, Mailankody, a medical oncologist/hematologist at Memorial Sloan Kettering Cancer Center, discussed current treatment options and shifting preferences, especially toward triplet combinations, as well as emerging immunotherapy treatment options.

Currently, several doublet and triplet treatment options are recommended by the National Comprehensive Cancer Network for patients with relapsed/refractory multiple myeloma. Recent data, however, show superior outcomes with triplet combinations.

The phase III TOURMALINE study, for example, showed improved PFS rates with a triplet combination of the proteasome inhibitor ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone compared with placebo, lenalidomide, and dexamethasone in patients with relapsed/refractory multiple myeloma.

Of the randomized 772 patients, the median PFS was 20.6 months in the ixazomib arm versus 14.7 months in the placebo arm (HR, 0.74; 95% CI, 0.587-0.939; 

 = .01). Additionally, the rate of serious adverse events was similar between both arms (47% vs 49%, respectively).

Likewise, the phase III CASTOR study randomized 498 patients with relapsed/refractory multiple myeloma to receive daratumumab (Darzalex), bortezomib (Velcade), and dexamethasone or bortezomib and dexamethasone alone.

 After a median follow-up period of 7.4 months, the median PFS was not yet reached for the daratumumab arm versus 7.2 months for the doublet combination (HR, 0.39; 95% CI, 0.28-0.53; 

 <.001). Higher rates of thrombocytopenia and neutropenia, however, were noted in the daratumumab group.

“Continuing with the theme…the 3 drugs here are better than the 2 drugs for PFS,” Mailankody said.

In the single-arm phase Ib EQUULEUS study, daratumumab plus pomalidomide (Pomalyst) and dexamethasone showed promise in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy (n = 103) with an ORR of 60%.

 Of the responders, 29% were MRD-negative.

Early Data Show Promise for CAR T-cell Therapies

Based on this trial, the FDA approved the combination for patients with relapsed/refractory who have received ≥2 prior lines of therapy including a proteasome inhibitor and lenalidomide.

In the CRB-401 phase I study of bb2121 CAR T-cell therapy, 21 adults with relapsed/refractory multiple myeloma received bb2121 in 4 cohorts in the dose-escalation portion of the trial.

 The overall response rate (ORR) in 18 evaluable patients receiving doses ≥150 x 10

 was 94%. Additionally, 56% (n = 10) of patients achieved a complete response. Of the responders, 9 out of the 10 were minimum residual disease (MRD)—negative.

Bb2121 is a second-generation CAR T-cell therapy, developed by bluebird bio, targeting B-cell maturation antigen (BCMA) to redirect T cells to recognize and kill malignant myeloma cells, Mailankody explained.

“[These data are from the 2017 ASH Annual Meeting], showing very high response rates for patients who were treated at ≥150 x 10

 mark, there is very little or no activity,” he added. From the preliminary findings, doses of 150 to 450 x 10

 CAR T cells were selected for an expansion phase.

Based on updated data presented at the 2018 ASCO Annual Meeting, evaluable patients had a median progression-free survival (PFS) of 11.8 months at active doses ≥150 x 10

 Of those who achieved MRD-negativity (n = 16), a median PFS of 17.7 months was seen.

“The mere fact that we are able to get 16 out of 43 patients to MRD-negative levels with a single CAR T-cell [treatment] in this setting is certainly quite remarkable,” Mailankody said. “The fact that we now have patients who are 1.5 to 2 years out without needing any additional treatment…is quite remarkable. I think it speaks to why there is so much enthusiasm and so many different trials from different companies that are ongoing in this space currently.”

Questioning Potential With Checkpoint Inhibitors

A global phase II trial of bb2121 called KarMMa has been initiated following the findings of CRB-401 (NCT03361748).

“As everyone in oncology is aware right now, we have checkpoint blockades, with the most prominent being PD-1 and PD-L1—targeted drugs, that can stimulate the immune system,” Mailankody said.

Recent trials have looked at PD-1 and PD-L1 checkpoint inhibitors in combination with immunomodulatory drugs, such as lenalidomide and pomalidomide. “As the name suggests, lenalidomide and pomalidomide have significant effects on the Tregs [regulatory T cells] suppression, natural killer and natural killer T-cell activation, and Th1 cytokine production. It would make rational sense to combine immunomodulatory drugs with checkpoint blockade for these reasons.”

Two phase III studies, however, were recently postponed due to deaths in patients utilizing the combination strategy.

In the KEYNOTE-183 trial, the combination of pembrolizumab (Keytruda), pomalidomide, and low-dose dexamethasone was being compared with pomalidomide and low-dose dexamethasone alone in 249 patients with relapsed/refractory multiple myeloma who have undergone at least 2 lines of prior treatment.

According to an FDA analysis, at a median follow-up of 8.1 months, there were 29 deaths in the pembrolizumab arm versus 21 deaths in the control arm. The hazard ratio for overall survival for the pembrolizumab group compared with the control arm was 1.61 (95% CI, 0.91-2.85), translating to a >50% increase in the relative risk of death.

There were 301 patients included in the safety and efficacy analysis of c comparing pembrolizumab, lenalidomide, and low-dose dexamethasone with lenalidomide and low-dose dexamethasone. At a median follow-up of 6.6 months, there were 19 deaths in the pembrolizumab group compared with 9 in the control arm (HR for OS, 2.06; 95% CI, 0.93-4.55). The relative risk of death in the pembrolizumab was more than double that of the control arm.

“Both of these studies were put on pause and are no longer requiring patients. Which has led to a re-evaluation of the role of checkpoint blockade in myeloma.”

Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. 

. 2016;374(17):1621-1634. doi: 10.1056/NEJMoa1516282.

Palumo A, Chanan-Khan a, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. 

. 2016;375(8):754-766. doi: 10.1056/NEJMoa1606038.

Berdeja JG, Lin Y, Raje N, et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, GA. Abstract 740.

Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. Presented at: ASCO 2018 Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 8007. meetinglibrary.asco.org/record/160693/abstract.

Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. 

. 2017;130(8):974-981. doi: 10.1182/blood-2017-05-785246.

FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA

 (pembrolizumab) in Patients with Multiple Myeloma. Posted August 31, 2017. www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed July 14, 2018.

Sham Mailankody, MBBS, discusses current treatment options and shifting preferences, especially toward triplet combinations, as well as emerging immunotherapy treatment options in multiple myeloma.

Immunotherapy Treatment Options Continue to Grow in Relapsed/Refractory Multiple Myeloma

With newer agents approved for patients with chronic lymphocytic leukemia (CLL), physicians are now challenged with how best to utilize them, according to a presentation by Anthony Mato, MD, MSCE, at the 2nd Annual Live Medical Crossfire: Hematologic Malignancies meeting presented in New York, NY.

"There have been several molecules that have been approved," said Mato, director of the CLL Program Leukemia Service, Memorial Sloan Kettering Cancer Center. "It is wonderful for providers and patients to have these opportunities, but new challenges have emerged on how to best sequence these therapies, combine these therapies, and how to manage patients who fail all of these therapies either sequentially or in combination."

Treatment for patients with CLL has significantly evolved from the historical standard of initial chemotherapy with chlorambucil. To date, chemoimmunotherapy regimens have been exploring the incorporation of monoclonal antibodies and targeted therapy, including Bruton tyrosine kinase (BTK) inhibitors and novel inhibitors of phosphoinositide 3-kinase (PI3K).

The BTK inhibitor ibrutinib (Imbruvica) in combination with standard frontline chemoimmunotherapy fludarabine/cyclophosphamide/rituximab was explored in a recent phase II study as a frontline treatment for patients with CLL who were young and fit.

 Of the 35 patients evaluable for efficacy, the overall response rate (ORR) was 100%. Furthermore, 57% of patients achieved a complete response with bone marrow minimal residual disease (MRD)-negativity and 83% achieved bone marrow MRD-negativity at best response.

In a similar population setting, ibrutinib was also combined with chemoimmunotherapy fludarabine, cyclophosphamide, and monoclonal antibody obinutuzumab (Gazyva) as frontline treatment.

 TP53 aberrations, however, were excluded from the study and all patients (n= 32) were IGHV-mutated. The phase II trial showed an objective response rate of 100%, similar to the previous trial, with 87% of patients achieving bone marrow MRD-negativity after 3 cycles of therapy.

"The take home from this evaluation was that early on in therapy, we see 100% ORR, we see a high proportion of patients who are MRD-negative or MRD-undetectable," said Mato. "So [these are] very active combinations."

Other combinations outside of chemoimmunotherapy are also undergoing evaluation. The phase III MURANO study included 389 patients with relapsed/refractory CLL who were randomized to rituximab plus either venetoclax (Venclexta) (n= 194) or bendamustine (n= 195).

With a 23 month-median follow up, median progression-free survival (PFS) was not reached in the venetoclax arm compared with 18.1 months (95% CI, 15.8-22.3) in the bendamustine arm (HR, 0.19; 95% CI, 0.13-0.28; 

 <.0001). Additionally, higher and more durable peripheral blood MRD-negativity rates were obtained with the use of venetoclax and rituximab (Rituxan). Based on these findings, venetoclax was granted a standard FDA approval for patients with CLL following at least 1 prior therapy.

Venetoclax has also proven to be effective in combination with ibrutinib. The phase II CAPTIVATE data demonstrated 100% ORR with the frontline combination.

 Of the 164 patients enrolled on the study, 77% of patients tested for MRD-negativity in the peripheral blood after 6 cycles of treatment.

A significant proportion of patients of patients with CLL are treated with ibrutinib in the first-line and relapse/refractory setting, noted Mato. For these patients, the reason for discontinuation greatly influences the choice for next therapy, however, data on sequencing following ibrutinib are limited.

A prospective phase II trial looked at venetoclax as monotherapy in patients with CLL who had discontinued either ibrutinib or idelalisib (Zydelig).

 For those who discontinued ibrutinib-based therapy (n = 91), the ORR was 60% (n = 59). Additionally, a durable PFS of 24.7 months was observed.

Additionally, data from a retrospective analysis looked at patients who had discontinued treatment with a BTK inhibitor or venetoclax.

 For patients who discontinued B-cell receptor kinase inhibitor (KI) treatment based on toxicity, those treated with an alternative KI showed superior PFS when compared with patients who discontinued treatment based on disease progression.

"The take home here was that reasons for discontinuation may be relevant. For patients who discontinued ibrutinib because of toxicity, they could be rescued with idelalisib, for example. For patients who discontinued ibrutinib in the setting of disease progression, an alternative KI didn't do so well. Those patients were probably best suited for venetoclax-based therapy."

Additional considerations need to be considered in the relapsed/refractory setting, added Mato, including repeated prognostic evaluation. "CLL is not a static disease, it is a disease of genetic instability. You can acquire abnormalities and those may influence treatment decision-making."

For patients treated with chemoimmunotherapy who develop relapsed/refractory disease, re-challenging chemoimmunotherapy is rarely advised based on limited efficacy and potential risks. Instead, preliminary data have shown promise with novel agents, such as ibrutinib, idelalisib, and venetoclax, after failure of frontline treatment.

Although monotherapy and combination therapy in the setting of frontline and relapse/refractory CLL are continuing to be evaluted, Mato noted during his presentation that comparative data are lacking. "If all of these drugs are available for me, how can I pick and choose one combination over another? Additionally, we have no data on sequencing, no comparison to sequential monotherapies, which I think is important," said Mato. "If I give everything upfront, is it any better than doing ibrutinib, idelalisib, and venetoclax sequentially? We have no relevant control tests with the exception of the data from the MURANO trial."

Davids MS, Kim HT, Brander DM, et al. A multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. In: Proceedings from the American Society of Hematology 59th Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA. Abstract 496.

Jain N, Thompson PA, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del (17p). 

Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. 

. 2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.

Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). 

Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. 

 2018;131(151):1704-1711. doi: 10.1182/blood-2017-06-788133.

Mato Ar, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. 

. 2017;28(5):1050-1056. doi:10.1093/annonc/mdx031.

With newer agents approved for patients with chronic lymphocytic leukemia, physicians are now challenged with how best to utilize them.

Despite New Treatments in CLL, Comparative Data and Guidance Slow to Emerge

The market for biosimilar introduction is “extremely unstable,” but the FDA is working to ease the launch of more affordable cancer medicines, both biosimilars and generics, with a strategy that includes an attempt to reduce anticompetitive behavior, according to Scott Gottlieb, MD, commissioner of the FDA.

Gottlieb discussed the competitive landscape for oncology agents and how it is affecting the introduction of new medicines in a keynote talk at the 2018 Community Oncology Conference that the Community Oncology Alliance held in National Harbor, Maryland, in April.

There are numerous approval and marketing challenges for makers of biosimilars who seek to challenge the dominance of branded drugs. Since September 2017, 2 biosimilars have received FDA approval specifically for treatment of cancer and 2 for conditions related to cancer. Gottlieb said that pace has been a pleasant surprise. “I always thought it was going to be a slower-developing area with more hurdles to get over, but we’re right on track,” he said.

Although the FDA has no regulatory power over the prices set by manufacturers, distributors, and retailers, Gottlieb said, the FDA’s commitment to encouraging biosimilar and generic competition in the cancer drug marketplace has the potential to lower costs and improve patient access to available cancer care.

“Drug treatment costs are only a fraction of total care oncology costs, but patients [with cancer] are disproportionately shouldering the cost of oncology medicines,” stated Gottlieb. “The perverse reality of the market today is that cancer treatment comes with its own financial toxicity.”

In tandem with his discussion on improving competition in the oncology drug marketplace, Gottlieb discussed new guidelines from the FDA on the development and review of next-generation sequencing (NGS) tests.

 These tests also should help to spur innovation and the introduction of life-extending oncologics, he said.

“The FDA recognizes the tremendous potential of NGS technology to guide and improve patient outcomes,” Gottlieb said. “And we’re developing a policy approach to keep the pace with fast-moving NGS technologies that give patients and clinicians confidence in these panels’ analytical and clinical validity.”

The first breakthrough-designated NGS-based diagnostic test, F1CDx (FoundationOne CDx), was approved in November 2017. The powerful diagnostic tool can detect mutations in 324 genes and 2 genomic signatures in any solid tumor type. In March, CMS followed up with a national coverage determination in favor of NGS panel testing, expanding coverage to FDA-approved tests for patients with relapsed, refractory, or stage III cancers in addition to stage IV cancers.

Large-panel NGS tests will make it “easier and less expensive to screen patients for tumor mutations with a single test and then efficiently match them with available clinical trials,” Gottlieb said. He predicted that the information gained through this process will illuminate pathways to more effective therapies and stimulate the development of new agents. “This will increase the productivity of drug development, as drugs can then be targeted at common biomarkers across numerous tumor types.”

Gottlieb said that the FDA is striving to make NGS guidelines and current and future regulations “as nimble and sophisticated as the science driving these technologies so that clinicians and patients have access to them as soon as possible, while still providing patients with the reasonable assurance of safety and effectiveness they expect.”

The first set of guidelines addresses the design, development, and analytical validation of NGS-based panels, which can be used when diagnosing individuals with suspected genetic diseases. “For oncology, germline cancer predisposition contributes to about 5% to 10% of observed cancers. For cancer predisposition syndromes, such as Lynch syndrome, interventions like colonoscopies may be able to improve expected survival by sharply decreasing the rates of colorectal cancer,” Gottlieb noted.

These recommendations also explain what the FDA would look for in a premarket submission to assess a prospective test’s analytical and clinical validity, as well as its accuracy in detecting the presence or absence of a particular genomic change, leading to what Gottlieb said would be consensus standards for future NGS-based tests.

The second set of guidelines recognizes the availability of public human genetic variant databases, which could help to confirm the clinical utility of in vitro diagnostic (IVD) tests, particularly during premarket review. These FDA-recognized databases could serve as sources of existing evidence for the claims, such as of the clinical significance of a germline or somatic mutation, that developers of IVD tests make in the review process.

An additional piece of draft guidance explains a process that oncology trial sponsors can use to establish the risk level associated with an investigational IVD to be used in a trial of an investigational cancer drug or biological product.

 According to the guidelines, investigational IVDs are categorized as a significant risk, nonsignificant risk, or exempt from review. If a device is determined to be a significant risk, meaning that it could pose a serious risk to the health or safety of a patient, an investigational device exemption may be needed. The level of risk may disqualify a study for streamlined submission.

“This guidance reduces burdens on sponsors and on FDA staff by outlining circumstances under which sponsors may be able to include information about an investigational IVD into the investigational new drug application submission to the FDA center responsible for the therapeutic product,” Gottlieb said.

With these new policies, the FDA hopes to provide test developers with a more efficient path to market by means of efficient and accurate testing. They will encourage the innovation and adaptation of tools that can increase the productivity research and patient care.

FDA finalizes guidances to accelerate the development of reliable, beneficial next generation sequencing-based tests [news release]. Silver Spring, MD: FDA; April 12, 2018. 2018. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm604462.htm. Accessed April 12, 2018.

Investigational in vitro diagnostics in oncology trials: streamlined submission process for study risk determination guidance for industry. FDA website. www.fda.gov/downloads/Drugs/GuidanceCompliance- RegulatoryInformation/Guidances/UCM604441.pdf. Published 2018. Accessed May 17, 2018.

The market for biosimilar introduction is “extremely unstable,” but the FDA is working to ease the launch of more affordable cancer medicines with a strategy that includes an attempt to reduce anticompetitive behavior. 

FDA Strategizes to Step Up Introduction of Lower-Cost Drugs and NGS

The unique biological characteristics of uveal melanoma have prompted the National Comprehensive Cancer Network (NCCN) to develop the first set of guidelines for the diagnosis and management of the rare but deadly cancer, according to Christopher A. Barker, MD.

The recommendations represent “the first pathway-based guidelines” for the malignancy, Barker said in presenting the highlights of the paradigm during the 2018 NCCN Annual Conference.

 He is the director of clinical investigation in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center and a member of the NCCN Melanoma Subcommittee.

The goals of treating uveal melanoma differ from those for cutaneous melanoma, Barker explained during an interview with 

. Local treatment for uveal melanoma consists of globe-preserving therapies or enucleation.

“Ocular or uveal melanoma is genetically and biologically a very distinct form of melanoma that has very little overlap with cutaneous melanoma,” Daniel G. Coit, MD, a surgical oncologist at Memorial Sloan Kettering and chair of the NCCN Uveal Melanoma Subcommittee, said in an interview. “What we have wanted to do for years is to codify the treatment [of patients with uveal melanoma] so that practitioners would have a consistent management algorithm.”

The guidelines highlight 2 forms of staging criteria to determine therapeutic choice: the Collaborative Ocular Melanoma Study (COMS) system and the American Joint Committee on Cancer (AJCC) staging manual. Both systems are based on the size of the primary tumor, including thickness and diameter, which has consistently been associated with outcome for patients with uveal melanoma, Barker said. The COMS system has 3 categories and AJCC’s has 4, which are further subdivided based on the anatomical extent of the tumor according to ciliary body and extrascleral involvement.

“The COMS was developed as part of the COMS trials. These landmark trials helped to establish the current standards of care and therefore are of considerable relevance to contemporary practice,” Barker said. “The AJCC system was developed more recently in an attempt to refine clinical predictions based on tumor features. Both systems are of value to clinicians, and for this reason, both were used in the development of the guidelines.”

A total of 1003 patients with choroidal melanoma were enrolled in the COMS large-tumor trial and randomized to receive standard enucleation or external radiation of the orbit and globe prior to enucleation. Patients were followed for 10 years to analyze potential predictors of treatment effectiveness and mortality. No significant difference was found between the 2 arms in terms of survival.

“The COMS trials showed 4 ocular melanomas that can be adequately treated with radiation therapy. That is the best level 1 evidence we have, that the prior practice of removing the eye is simply not necessary for many people with ocular melanoma,” Coit said. “There are obviously exceptions in the big cases, but for most people, radiotherapy has become a standard based on level 1 evidence.”

The guidelines, based on the results of the COMS studies, provide options for primary treatment according to the size of the primary tumor. For example, for patients with tumors that are <2.5 mm thick and 5 to 16 mm in the largest diameter, the guidelines recommend brachytherapy plaque, particle beam radiation, or laser ablation for patients who are not good candidates for radiation or surgery.

If the tumor is <18 mm thick and 2.5 to 10 mm in the largest diameter, suggested treatments include iodine-125 brachytherapy, particle beam radiation, and enucleation for specified patients.

Particle beam radiation therapy is preferred if a tumor of any thickness is >18 mm in the largest diameter, >10 mm thick with any diameter, or >8 mm thick with optic nerve involvement and any diameter. The guidelines recommend stereotactic radiosurgery as an acceptable alternative, or enucleation for certain patients.

If there is no evidence of gross residual disease in the eye orbit, observation is the first suggestion, but particle beam or photon beam radiation is a possibility. If evidence of gross residual disease is present after enucleation, however, the guidelines recommend biopsy of the extraocular tissue, if sufficient tissue is available. Intraoperative cryotherapy, orbital exenteration, and radiation therapy to the orbit with particle beam or photon beam radiation are viable options.

The guidelines divide patients into 3 categories of risk (low, medium, and high) of distant metastasis. The risk of metastasis after first-line therapy is due to several factors, including cell type—epithelioid or spindle cell, cytogenetics, gene expression, and genetic aberrations. A large number of alterations in cutaneous melanoma are predictive of response to treatment. Although there are fewer associated alterations in uveal melanoma, these are prognostic of outcomes. For example, patients with 

 mutations are considered at high risk of metastasis. In these cases, frequent surveillance imaging— every 3 to 6 months for 5 years, then every 6 to 12 months for up to 10 years&mdash;is suggested.

Once a patient develops distant metastatic disease, the guidelines’ foremost suggestion is to enroll in clinical trials. “As in many cancers, metastasis is one of the biggest issues for patients with uveal melanoma. There is a complete void of treatments available to prevent metastasis or to effectively treat metastasis when it occurs,” Barker said. Other options include liver-directed therapies— because recurrence in uveal melanoma typically occurs in the live&mdash;systemic therapy or radiotherapy for symptomatic disease, or palliative care.

Treatment for metastatic uveal melanoma is limited, mainly because the advancements made in cutaneous melanoma, such as targeted therapy and immunotherapy, do not easily translate, and randomized clinical trials are limited for such a rare disease, according to Coit. “Community oncologists should recognize that because conventional systemic treatments do not work very well for metastatic ocular melanoma, this is a disease where clinical trials are imperative,” he said. “When we get positive clinical trials in ocular melanoma, they will appear immediately in the guidelines.”

The NCCN guidelines for uveal melanoma were deliberated for several months by a wide-ranging panel of specialists, based on the best available evidence and opinion, Barker said.

Certain “gray areas” created some of the biggest challenges while assembling the guidelines, Coit said. For example, many panel members were divided on how best to manage lesions of the eye that are not obvious uveal melanomas and the risks associated with initiating treatment. “This is one of the rare tumors that is often treated without biopsy and just based on clinical appearance,” he said. “When to make the diagnosis of melanoma and when the patient crosses from an indeterminate lesion in the eye to melanoma—that is a huge controversy.”

Other debates centered on the role of biopsy in material genomic analysis, follow-up treatment for patients for recurrence, and the best way to guide community oncologists with a lack of available data.

Barker CA. New NCCN guidelines: uveal melanoma. Presented at: NCCN 23rd Annual Conference; March 22-24, 2018; Orlando, FL.

Hawkins BS; Collaborative Ocular Melanoma Study Group. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report number 24. 

. 2004;138(6):936-951. doi: 10.1016/j.ajo.2004.07.006.

The unique biological characteristics of uveal melanoma have prompted the National Comprehensive Cancer Network to develop the first set of guidelines for the diagnosis and management of the rare cancer. 

Samantha Hitchcock

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