New Data on ALK Inhibitors and CAR T-Cell Therapies


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The 2018 American Association for Cancer Research (AACR) Annual Meeting was abuzz with more than 22,000 attendees from around the world who came to Chicago to hear the latest in basic science and clinical trial results. Here we present summaries of a few of the highlights from the AACR meeting that you may have missed.

Crizotinib in Rare ALK-Positive Tumor

Crizotinib (Xalkori) achieved an objective response in 50% of patients with anaplastic lymphoma kinase (ALK)-positive inoperable inflammatory myofibroblastic tumors in the multicenter, nonrandomized phase II EORTC 90101 CREATE trial.1 Although this is a small trial, crizotinib met the prespecified criteria for success.

“The results presented here support the rationale for inhibiting ALK in patients with inflammatory myofibroblastic tumors. Crizotinib could be considered the standard of care for patients with locally advanced or metastatic ALK-positive inflammatory myofibroblastic tumors who do not qualify for surgery,” said lead author Patrick Schöffski, MD, MPH, of Leuwen Cancer Institute, Leuwen, Belgium.


Crizotinib could be considered the standard of care for patients with locally advanced or metastatic ALK-positive inflammatory myofibroblastic tumors who do not qualify for surgery.
— Patrick Schöffski, MD, MPH

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The role of crizotinib in ALK-negative disease remains to be determined, as inflammatory myofibroblastic tumor is a rare mesenchymal cancer occurring mainly in children and adolescents. Typically, these tumors are adjacent to vital structures and not amenable to surgical removal. Local recurrence can lead to death. Management options are limited for unresectable disease.

The phase II study enrolled 20 eligible patients aged 18 or older, 19 of whom were evaluable for the primary endpoint of objective response rate (12 were ALK-positive and 7 were ALK-negative). A total of 6 of 12 ALK-positive patients (50%) and 1 of 7 ALK-negative patients (14%) achieved an objective response (either a partial or confirmed response according to Response Evaluation Criteria in Solid Tumors [RECIST]).

The most common treatment-related adverse events were nausea (55%), fatigue (45%), blurred vision (45%), vomiting (35%), and diarrhea (35%). Five patients experienced a total of 8 serious adverse events (fever of unknown cause, heart attack with increased creatinine and possible sepsis, abdominal abscess with acute renal insufficiency, and prolonged QT interval).

Lorlatinib in Non–Small Cell Lung Cancer

Lorlatinib—an investigational third-generation ALK inhibitor—is an emerging therapeutic option for patients with ALK-positive advanced non–small cell lung cancer who fail to respond to earlier-generation ALK inhibitor therapy. Lorlatinib is an oral, reversible, potent, selective, central nervous system–penetrant inhibitor of ALK and ROS1.

“Lorlatinib was specifically designed to penetrate the blood-brain barrier. In the clinic, lorlatinib seems to have the broadest activity against mutations associated with resistance,” said lead author Alice T. Shaw, MD, PhD, of Harvard Medical School and Massachusetts General Hospital in Boston.


Lorlatinib is specifically designed to penetrate the blood-brain barrier. In the clinic, lorlatinib seems to have the broadest activity against mutations associated with resistance.
— Alice T. Shaw, MD, PhD

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Dr. Shaw presented the results of a phase II dose-expansion trial enrolling 275 patients with ALK- or ROS1-positive lung cancer that may have progressed on previous ALK tyrosine kinase inhibitor therapy.2 The primary objective was to assess the antitumor activity of lorlatinib and identify potential biomarkers based on molecular profiling of tumor tissue and circulating tumor DNA from peripheral blood samples obtained before and after treatment.

All of the dose-expansion cohorts experienced treatment-related adverse events (mostly grade 1 or 2), and most of the grade 3 and 4 adverse events were laboratory abnormalities. The drug was generally well tolerated, with 3% of patients discontinuing treatment due to adverse events.

Among patients previously treated with crizotinib, the objective response rate was 69%. The intracranial response rate was 58%. Median progression-free survival was not reached. “This suggests that most crizotinib-resistant tumors do remain vulnerable to further ALK inhibition,” she commented.

However, patients previously treated with second-generation ALK inhibitors (ie, ceritinib [Zykadia], alectinib [Alecensa], or brigatinib [Alunbrig]) were less responsive to the more potent lorlatinib. The best objective response rate was observed in crizotinib-resistant patients who had a detectable ALK mutation in tumor tissue DNA. Among patients in whom therapy with a second-generation ALK inhibitor failed, the presence of a detectable ALK mutation in tumor tissue DNA identified those most likely to have ALK-dependent resistance and most likely to respond to lorlatinib; these patients also had a striking improvement in progression-free survival compared with those without a detectable ALK resistance mutation in tumor tissue.

ALK G1202R was the most common point mutation associated with resistance to second-generation ALK inhibitors. Lorlatinib is highly effective against this “recalcitrant” mutation, Dr. Shaw noted.

“For crizotinib-resistant patients, objective  response rate was high regardless of ALK mutation status. In contrast, response rate was higher in second-generation ALK inhibitor–resistant patients who had ALK resistance mutations, and responses were more durable. The presence of ALK resistance mutations in patients relapsing on a second-generation ALK tyrosine kinase inhibitor may serve as a biomarker to identify patients more likely to respond to lorlatinib,” Dr. Shaw concluded.

Off-the-Shelf CAR T-Cell Products

Chimeric antigen receptor (CAR) T-cell therapy has achieved some remarkable results in B-cell lymphoma and leukemia, and two different CAR T-cell products are now approved by the U.S. Food and Drug Administration. Both products require the patient’s own immune cells, which are removed by apheresis and genetically engineered ex vivo to express an antigen-targeting receptor; then the product is reinfused into the patient.


These first-of-kind CAR19 T cells can be packaged, stored, and made readily available to treat a large number of patients.
— Bob Valamehr, PhD

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The manufacture of CAR T cells is a drawn-out process that is not reproducible. A new universal off-the-shelf CAR T-cell product promises to be widely applicable, renewable, and more efficient. Thus far, the product—FT819—has been studied under preclinical experimental conditions, but it is moving along in development.

“CAR T-cell therapy has shown remarkable results in certain cancer patients. However, today the therapy is highly personalized, time-consuming to produce, and consists of only enough cells for a single dose of treatment with variable quality,” said Bob Valamehr, PhD, Vice-President of Cancer Immunotherapy at Fate Therapeutics. “Additionally, today’s CAR T-cell therapies only target a single antigen, which can limit efficacy.”

Dr. Valamehr presented preclinical specificity, functionality, and efficacy proof-of-concept studies of FT819,3 which is manufactured using a renewable cell line made from healthy donor cells rather than using the cancer patient’s own cells. Using healthy donor cells, the investigators create a master induced pluripotent stem cell line capable of producing large quantities of universal CAR T cells that are not patient restricted.

“These first-of-kind CAR19 T cells can be packaged, stored, and made readily available to treat a large number of patients,” he said.

“We wanted to put desirable attributes into this off-the-shelf product,” Dr. Valamehr continued. FT819 is T-cell receptor–less; that is, the T-cell receptor has been eliminated from this product candidate, which is a critical step in avoiding graft-vs-host disease.

 


Starting with poor-quality T cells may be a key problem in manufacturing effective CAR T cells.
— David M. Barrett, MD, PhD

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FT819 targets CD19 and additionally has a CD16 Fc receptor, which can bind other proven cancer treatments, such as monoclonal antibody therapies, to target a broad spectrum of tumor--associated antigens and overcome antigen escape. “FT819 is pure for CD19 and CD16 expression,” he noted. “This product would be broadly applicable, reduce the cost of manufacturing, permit multiple dosing, and allow us to reach more patients in need.” The company is planning human clinical trials to fully assess the safety and efficacy of FT819.

Improving Outcomes With CAR T-Cell Therapy

A major reason why CAR T-cell therapy has lackluster results in some hematologic malignancies and solid tumors may lie with the starting material. “Starting with poor-quality T cells may be a key problem in manufacturing effective CAR T cells,” said David M. Barrett, MD, PhD, Assistant Professor of Pediatrics at Children’s Hospital of Philadelphia.

Dr. Barrett reported on research using peripheral-blood T cells from 157 pediatric cancer patients with malignancies that included acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma.4 The quality of the T cells was assessed at diagnosis and after each cycle of chemotherapy.

AACR HIGHLIGHTS

  • Crizotinib achieved an objective response in 50% of patients with ALK-positive inoperable inflammatory myofibroblastic tumors in the phase II CREATE trial.
  • In a phase II dose-expansion trial, lorlatinib exhibited antitumor activity in a variety of resistance-associated mutations in patients with ALK- or ROS1-positive lung cancer that progressed on previous ALK inhibitor therapy.
  • Preclinical data for FT819, a first-of-kind, dual-targeted off-the-shelf CAR T-cell product, suggest that it can be mass produced from a master induced pluripotent stem cell line and can be used in combination with monoclonal antibody therapy to mitigate antigen escape.
  • A study of peripheral-blood T cells from 157 pediatric patients with hematologic malignancies found good-quality T cells were obtained from more than 90% of ALL patients at diagnosis, whereas the quality of T cells collected from children with lymphomas was poor, which may have implications for the further development of CAR T-cell therapies.

With conventional CAR T-cell therapy, the starting material comes from the patient. “We have no control over their quality,” Dr. Barrett stated. “However, we do know what a high-quality CAR T cell looks like.”

Among those included in the study, good-quality T cells were obtained from more than 90% of ALL patients at diagnosis, and he said that may be related to why pediatric ALL is one of the great successes of CAR T-cell therapy. By contrast, the quality of T cells collected from children with lymphomas was quite poor. “We have only successfully treated two children with lymphoma,” Dr. Barrett said.

T cells collected from Wilms tumor patients appeared to be of better quality, with more than 50% of cells looking like they had good potential. But there is no CAR T-cell product for Wilms tumor yet, he said. T cells collected from patients with solid tumors had poor performance. When the investigators looked at T-cell quality after chemotherapy, they found that cumulative chemotherapy had a negative effect, impairing the quality.

A preliminary finding was that T cells utilizing the glutamine and fatty acid pathways as fuel sources were more likely to have good CAR T-cell potential, whereas those depending on glycolysis for fuel did not have good CAR T-cell potential. More work is being done to determine whether reversing pathways that depend on glycolysis will improve the quality of T cells. ■

DISCLOSURE: Drs. Schöffski, Shaw, and Barrett reported no conflicts of interest. Dr. Valamehr is an employee of Fate Therapeutics.

REFERENCES

1. Schoffski P, Sufliarsky J, Gelderblom H, et al: Prospective precision medicine trial of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumor with and without ALK alterations: EORTC phase II study 90101 “CREATE.” 2018 AACR Annual Meeting. Abstract CT045. Presented April 15, 2018.

2. Shaw AT, Martini JF, Besse B, et al: Efficacy of lorlatinib in patients with advanced ALK-positive non-small cell lung cancer and ALK kinase domain mutations. 2018 AACR Annual Meeting. Abstract CT044. Presented April 15, 2018.

3. Clarke RL, van der Stegen S, Lee T, et al. Generation of off-the-shelf TCR-less CAR-targeted cytotoxic T cells from renewable pluripotent cells for cancer immunotherapy. 2018 AACR Annual Meeting. Abstract LB-108. Presented April 16, 2018.

4. Das RK, Storm J, Barrett DM, et al: T cell dysfunction in pediatric cancer patients at diagnosis and after chemotherapy can limit chimeric antigen receptor potential. 2018 AACR Annual Meeting. Abstract 1631. Presented April 15, 2018.


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