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Update on Clinical Trials of Novel Therapies


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Long-term follow-up data on axicabtagene ciloleucel (Yescarta) in lymphoma, potential partners for nivolumab (Opdivo) in solid tumors, and a targeted agent for RET-altered cancers were featured during the developmental therapeutics program at the 2018 ASCO Annual Meeting. At the Best of ASCO Chicago, these findings were described by Laura Williams Goff, MD, Associate Professor of Medicine and Associate Director of the Hematology and Oncology Fellowship Program, Vanderbilt University, Nashville.1

Axicabtagene Ciloleucel: ZUMA Update

ZUMA-1 is a pivotal phase ii study of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma. Investigators reporting on follow-up data for axicabtagene ciloleucel (the chimeric antigen receptor [CAR)] T-cell product with specificity for CD19) in 108 patients with refractory large B-cell lymphoma followed for a median of 15.4 months.2 In the update, 41% of patients with a partial response had converted to a complete response, showing that responses seemed to deepen and improve


The 3-month mark seemed to be where the tail of the curve plateaued. The response rate at 3 months seems to be a surrogate for long-term survival.
— Laura Williams Goff, MD

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over time. Responders at month 3 had an almost 80% chance of maintaining the response at 1 year. Progression-free survival was similar for patients achieving a partial or complete response at month 3, Dr. Goff noted.

“The 3-month mark seemed to be where the tail of the curve plateaued. The response rate at 3 months seems to be a surrogate for long-term survival,” she said.

Almost all patients had some degree of cytokine-release syndrome. Two-thirds had neurotoxicity, but these conditions were typically manageable.

The results raise the question of whether responders should be directed to transplant and whether partial responders could benefit from additional treatment at 3 months to boost them toward a complete response. “These data would suggest you can just ‘hang on’ with them at 3 months,” according to Dr. Goff.

Nivolumab Plus JTX-201

“We see tremendous responses to programmed cell death protein 1 (PD-1) inhibitors, but in only a small percentage of patients. The question is how we can increase these percentages,” she said. That is the aim of immunotherapy combinations.

Although the combination of ipilimumab (Yervoy) plus nivolumab increased response rates in multiple tumor types, the combination was associated with more toxicity. Also, recent trials in solid tumors returned disappointing results with pembrolizumab (Keytruda) plus the IDO1 inhibitor epicadostat (phase III ECHO-301-KEYNOTE-252 trial) and with the MEK inhibitor cobimetinib (Cotellic) plus atezolizumab (Tecentriq; phase III IMblaze370 trial), noted Dr. Goff.

“We’re looking for how to get more patients to respond to immunotherapy, what is the right combination, and how we can do that safely,” she added. Combinations of PD-1 inhibitors with first-in-class agents, she said, as reported at ASCO 2018, “are our next hope.”

JTX-2011 is a first-in-class inducible co-stimulator of a T-cell agonist that appears to shift the balance of T cells toward antitumor activity. An inducible co-stimulator of T cells can be upregulated by a variety of agents, and high expression seems to be associated with favorable outcomes. “The investigators felt this made it an ideal target for combination therapy,” shared Dr. Goff.

Both JTX-2011 and NKTR-214 will need to demonstrate that their outcomes are better than with nivolumab alone. Certainly, when we see response rates like 60% to 70%, we get excited.
— Laura Williams Goff, MD

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The phase I/II ICONIC trial evaluated JTX-2011 in heavily pretreated patients with several tumor types.3 Its single-agent activity was assessed in 40 patients in phase I, which was a population that was not enriched for inducible co-stimulator of T-cell expression. In this study, 10 patients (25%) achieved stable disease, which was durable in 2 patients. In phase II, which included tumor types known to be enriched for inducible co-stimulator of T-cell expression, 5 of 27 patients (18%) achieved stable disease, and 1 of 8 patients with gastric cancer had an ongoing response at 8.5 months.

Stronger activity was seen when JTX-2011 was combined with nivolumab in 31 patients in phase I and 75 patients in phase II, producing stable disease in 29% and 32%, respectively. Many responses were durable, mostly in patients with gastric, triple-negative breast, and lung cancers. The greatest disease control rate (58%) was reported in non–small cell lung cancer (NSCLC), whereas patients with head and neck cancer were the least likely to benefit. Induction of high-inducible co-stimulator of T-cell expression in CD4 T cells was associated with response.

Rates of grade 3 and 4 toxicities were low compared with other immunotherapy combinations, although treatment discontinuation rates were fairly high (58%–78%), for reasons that are not yet clear. JTX-2011 will next be studied in combination with ipilimumab, which preclinical data suggest could be a more synergistic partner.

Nivolumab Plus IL-2 Agonist

The other combination trial evaluated nivolumab plus NKTR-214, a CD122-biased agonist, in patients with advanced solid tumors. Single-agent NKTR-214 was associated with increased PD-1 expression on the T cells, providing a rationale for its use with checkpoint inhibitors. Treatment with NKTR-214 leads to the proliferation of CD8-positive T cells (ie, tumor-infiltrating lymphocytes).

In the large phase I/II dose-finding PIVOT trial, NKTR-214 was evaluated in immunotherapy-naive patients with melanoma, renal cell carcinoma, NSCLC, and urothelial cancer. Updated efficacy data from phase I and phase II cohorts that met prespecified efficacy endpoints were presented at ASCO 2018.4

Immunotherapy Clinical Trials

  • In the ZUMA-1 update, which evaluated axicabtagene ciloleucel in refractory large B-cell lymphoma, 41% of partial responses converted to complete responses. Patients who had a partial response at 3 months had an 80% chance of still responding at 1 year.
  • Nivolumab was paired with an ICOS agonist (JTX-2011) and an IL-2 agonist (NKTR-214) in two studies. In several solid tumors, the combinations led to greater responses than seen with nivolumab alone.
  • The combination of atezolizumab and bevacizumab produced a durable 61% response rate in heavily pretreated patients with hepatocecullar carcinoma.
  • LOXO-292, which targets RET-altered tumors, produced responses in 45% to 77% of patients previously treated with multikinase inhibitors.

In several immunotherapy-naive cohorts, high response rates could be achieved with the combination. In programmed cell death ligand 1 (PD-L1)–positive patients, response rates (complete and partial responses) were 62% in those with melanoma, 29% in those with renal cell carcinoma, and 60% in those with urothelial cancer. In PD-L1–negative patients, responses were seen in 42%, 53%, and 50%, respectively. Conversion from PD-L1–negative to –positive was associated with response. Toxicity was similar to that of nivolumab alone, and the typical side effects associated with IL-2 were rare.

“Both JTX-2011 and NKTR-214 will need to demonstrate that their outcomes are better than with nivolumab alone. Certainly, when we see response rates like 60% to 70%, we get excited,” Dr. Goff commented.

‘Intriguing’ Combination in Hepatocellular Carcinoma

Dr. Goff also expressed optimism for atezolizumab plus bevacizumab (Avastin) in hepatocellular carcinoma, based on an uncontrolled clinical trial presented as a poster at ASCO 2018.5 The combination therapy yielded a 61% response rate in treatment-naive patients and durability out to 15 months.

“I think it should have been an oral presentation,” she added. “It was intriguing.” The U.S. Food and Drug Administration [FDA] granted the regimen Priority Review designation.

LOXO-292: ‘Most Clinically Relevant’

Dr. Goff deemed the study of LOXO-292 to be “the most clinically relevant abstract in terms of how you can treat your patients immediately or at least allocate them now,” she said.6 LOXO-292 is a potent and selective RET inhibitor that was evaluated in LIBRETTO-001 in 82 patients with tumors that are RET-altered (ie, via fusion or mutation). The study included a group of heavily pretreated RET-altered patients with NSCLC, thyroid cancer, and pancreatic cancer.

BEST OF ASCO 2019

Bellevue, Washington:

  • July 19–20

Austin, Texas:

  • July 26–27

Baltimore, Maryland:

  • August 2–3

LOXO-292 demonstrated robust antitumor activity across RET-altered cancers, independent of prior therapy. The response rate was 77% in those with RET fusion–positive cancers (also with intracranial activity) and 45% in those with RET-mutant medullary thyroid cancer. One of the complete responses was in a patient with the hereditary “gatekeeper” V804M mutation, which typically confers resistance to multikinase inhibitors. The patient remains in response at 6 months, and 91% of patients altogether remain on treatment.

“I think this population joins microsatellite stability–high and tropomyosin receptor kinase fusions as pan-cancer alterations that are truly actionable. You will see these patients and should direct them to clinical trials in this space,” Dr. Goff said. 

The FDA recently granted Breakthrough Therapy designation to LOXO-292 for the treatment of certain patients with RET--altered NSCLC and thyroid cancer. ■

DISCLOSURE: Dr. Goff is a consultant/advisor to Lilly, Eisai, Bayer/Onyx, and NewLink Genetics; and has received research funding from Astellas Pharma, Pfizer, Onyx, Sun Pharma, Leap Therapeutics, Lilly, Bristol-Myers Squibb, Agios, ArQule, H3 Biomedicine, and Incyte.

REFERENCES

1. Goff LW: Melanoma/skin cancers and developmental therapeutics. Best of ASCO Chicago. Presented August 11, 2018.

2. Locke FL, Ghobadi A, Jacobson CA, et al: Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma. 2018 ASCO Annual Meeting. Abstract 3003. Presented June 2, 2018.

3. Yap TA, Burris HA, Kummar S, et al: ICONIC: Biologic and clinical activity of first in class ICOS agonist antibody JTX-2011 ± nivolumab in patients with advanced cancers. 2018 ASCO Annual Meeting. Abstract 3000. Presented June 2, 2018.

4. Diab A, Hurwitz ME, Cho DC, et al: NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. 2018 ASCO Annual Meeting. Abstract 3006. Presented June 2, 2018.

5. Stein S, Pishvaian MJ, Lee MS, et al: Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma. 2018 ASCO Annual Meeting. Abstract 4074. Presented June 3, 2018.

6. Drilon AE, Subbiah VS, Oxnard GR, et al: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. 2018 ASCO Annual Meeting. Abstract 102. Presented June 2, 2018.


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