Beyond Checkpoint Inhibitors: Novel Immunotherapy Combinations With Antitumor Activity

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THE 2018 Society for Immunotherapy of Cancer (SITC) Annual Meeting hosted a meeting of the minds of the world’s premier cancer immunologists. In addition to the cutting-edge laboratory science explored and presented at the meeting, numerous phase I clinical trials and a few phase II studies offered a peek at the next big thing: enhancement of the effects of immunotherapy through combination strategies.

Although checkpoint blockade overcomes many immune-suppressive mechanisms in the tumor microenvironment, most patients do not benefit from this strategy. It is believed that certain tumor microenvironments may also require other complementary immune agonists to fully overcome immune suppression and resistance. These investigations and other abstracts presented at the SITC meeting represent attempts to do that.

Harnessing the IL-2 Pathway

Adi Diab, MD

Adi Diab, MD

NKTR-214 WAS invented to harness the potent immune-stimulatory benefits of the interleukin-2 (IL-2) pathway, with minimal toxicity. Adi Diab, MD, of The University of Texas MD Anderson Cancer Center, Houston, presented an update of the first-line phase II PIVOT-02 trial in 41 patients with previously untreated metastatic melanoma who received NKTR-214 plus nivolumab (Opdivo).1

The objective response rate was 53%, and 24% of patients achieved complete responses. The disease control rate was 76%. After a median follow-up of 7.2 months, 85% of patients have ongoing responses, and the median duration of response has not been reached.

Grade 3 or 4 treatment-related adverse events were seen in 19.5% of patients. Side effects related to cytokine release, most of which were low-grade, decreased with subsequent treatment cycles, he reported.

“Clear activation of the IL-2 pathway was demonstrated by an increase in absolute lymphocyte count, with activated and proliferating CD4, CD8, and natural killer cells in the blood. The combination demonstrated T-cell infiltration and activation in the tumor microenvironment. The T-cell receptor repertoire analysis demonstrates the presence of newly trafficked clonal infiltrates after treatment with NKTR-214 plus nivolumab,” Dr. Diab said.

“The T-cell receptor repertoire analysis demonstrates the presence of newly trafficked clonal infiltrates after treatment with NKTR-214 plus nivolumab [in patients with melanoma].”
— Adi Diab, MD

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A randomized phase III first-line study in melanoma has been initiated and will enroll more than 700 patients.

Tyrosine Kinase Inhibitors

SITRAVATINIB IS a small-molecule inhibitor of a spectrum of related receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), KIT, and the TAM family. The drug was evaluated in the phase II MRTX-500 study in combination with nivolumab in 56 patients with nonsquamous non–small cell lung cancer (NSCLC) progression on or after treatment with chemoimmunotherapy. Results were presented by Kai He, MD, PhD, of The Ohio State University Comprehensive Cancer Center, Columbus.2

“A CD8-positive T–effector cell response was evident in patients [with NSCLC] achieving clinical benefit from [sitravatinib plus nivolumab].”
— Kai He, MD, PhD

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Of 56 patients, 11 had either a confirmed response or unconfirmed response and were still on study, and 45 showed some degree of tumor regression. The median duration of response was more than 9 months. “A nonsignificant trend between high programmed cell death ligand 1 (PD-L1) expression and clinical benefit was observed, with 47% of PD-L1–low patients having clinical benefit and 27% of PD-L1–high patients having no benefit,” he said. “There was no correlation between total mutation burden and clinical benefit. A CD8-positive T–effector cell response was evident in patients achieving clinical benefit from the combination.”

LAG-3 Therapies

LYMPHOCYTE-ACTIVATION gene 3 (LAG-3) is a cell-surface molecule that plays a role in downregulating the immune response. LAG-3 is widely expressed on tumor-infiltrating lymphocytes and cytotoxic T cells. High expression is associated with tumor-mediated immune suppression. MK-4280 is a humanized immunoglobulin G4 anti–LAG-3 antibody that prevents LAG-3 from binding to its major ligand. In a first-in-human multicenter phase I/II trial, MK-4280 was evaluated in combination with pembrolizumab (Keytruda) in 15 patients with metastatic solid tumors for whom standard treatment options had failed.3 Partial responses were observed in 27% of patients, and the disease control rate was 40%, reported Nehal Lakhani, MD, PhD, of START Midwest, Grand Rapids, Michigan, part of a global network of phase I clinical research sites.

Nehal Lakhani, MD, PhD

Nehal Lakhani, MD, PhD

Adnan Khattak, MD

Adnan Khattak, MD

Adnan Khattak, MD, of Fiona Stanley Hospital in Perth, Australia, presented data for the soluble LAG-3 fusion protein IMP321 (eftilagimod alpha) plus pembrolizumab in unresectable or metastatic melanoma.4 Eftilagimod alpha is an antigen-presenting cell activator and not a checkpoint inhibitor. Antigen-presenting cell activators boost and sustain CD8-positive T-cell responses and activate multiple immune cell subtypes. LAG-3 antibodies, on the other hand, are checkpoint inhibitors that increase cytotoxicity of the preexisting CD8-positive T-cell response.

In the phase I TACTI-mel trial, 18 patients received several cycles of pembrolizumab, followed by pembrolizumab plus eftilagimod for up to 6 months. The objective response rate was 33%, and the disease control rate was 66%. When response was calculated from the pre-pembrolizumab time point, according to immune-related response criteria, the response rate rose to 61%, he reported.

“The combination [of eftilagimod alpha plus pembrolizumab] showed encouraging clinical activity in patients [with melanoma and] suboptimal response to pembrolizumab monotherapy.”
— Adnan Khattak, MD

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“The combination showed encouraging clinical activity in patients with suboptimal response to pembrolizumab monotherapy,” Dr. Khattak said.

Anti-TIGIT Antibody

TIGIT IS an immunomodulatory receptor that may play a role in the suppression of T-cell production and activation. TIGIT is also involved in tumor cell immune evasion and the inhibition of antiviral immune responses. Anti-TIGIT antibodies are designed to target TIGIT in order to enhance the T-cell–mediated response.

In a multicenter phase I trial, the anti-TIGIT agent MK-7684 was paired with pembrolizumab in 34 patients with advanced solid tumors for whom standard treatment options had failed.5 The response rate was 19%, and the disease control rate was 47%.

Talia Golan, MD

Talia Golan, MD

Responses were also observed in patients who crossed over from the monotherapy MK-7684 arm to the combination, reported Talia Golan, MD, of Sheba Medical Center in Tel Hashomer, Israel.

Anti–TIM-3 Antibody

TIM-3 IS a marker of exhausted CD8-positive T cells. It is highly expressed on CD8 T cells in multiple tumors including melanoma and NSCLC.6 TIM-3 negatively regulates T-cell activation on CD8 T cells. Recent work suggests that TIM-3 also impacts T-cell activation indirectly by acting on other cells in the tumor microenvironment including dendritic cells.7 Preclinically, TIM-3 blockade has resulted in increased proliferation and cytokine production by CD8 T cells.

TSR-022 is a potent and selective anti–TIM-3 antibody that binds to native TIM-3 with high affinity and is being developed in the clinic along with TSR-042, an anti–PD-1 antibody. Preclinically, a combination of TSR-022 and TSR-042 increased the proliferation and production of IL-2 by human tumor–specific T cells. The TSR-022/TSR-042 combination is being investigated in patients with advanced solid tumors in the ongoing AMBER study.

Diwakar Davar, MD

Diwakar Davar, MD

Diwakar Davar, MD, of the University of Pittsburgh, presented results from the dose-expansion portion of the phase I/II AMBER study. In this portion of the trial, 39 patients with NSCLC, all of whom had received prior treatment with anti–PD-1/PD-L1 agents, received TSR-042 at 500 mg with TSR-022 at either 100 mg or 300 mg every 3 weeks.8 Of 33 evaluable patients with NSCLC, 20 received TSR-022 at 300 mg, and 11, at 100 mg. At the 300-mg dose, 3 of 20 patients achieved partial responses and 8 patients had stable disease. Of 12 patients with PD-L1 expression ≥ 1%, 4 had a partial response and 5 had stable disease, suggesting PD-L1 may be a biomarker for patient selection. The AMBER study is continuing to enroll patients with NSCLC and melanoma for treatment with TSR-022 at a 900-mg dose level.

Targeting B7

B7-H3 IS a member of the B7 family of molecules involved in immune regulation and is overexpressed on a wide variety of solid tumor types, especially melanoma and cancers of the head and neck, bladder, and lung. Its overexpression is associated with adverse outcomes, and its expression may inversely correlate with responsiveness to anti–PD-1 therapy.

Inhibition of certain members of the B7 family has been shown to have powerful antitumor effects in several solid tumor types. Enoblituzumab is a first-in-class antibody targeting B7-H3 and designed to enhance Fc-mediated activities, including antibody-dependent cellular cytotoxicity. The rationale for combining enoblituzumab with anti–PD-1 antibodies is to coordinate engagement of innate and adaptive immunity and therefore mediate greater tumor regression than with either single agent, said Charu Aggarwal, MD, MPH, of the University of Pennsylvania Abramson Cancer Center, Philadelphia.

Charu Aggarwal, MD, MPH

Charu Aggarwal, MD, MPH

The study reported by Dr. Aggarwal evaluated enoblituzumab plus pembrolizumab in a variety of solid tumors.9 Her presentation focused on outcomes in lung cancer and head and neck cancer cohorts.

Response rates were 33.3% in 21 patients with squamous cell head and neck cancer (post platinum chemotherapy) and 35.7% in 16 patients with NSCLC showing < 1% PD-L1 expression. In the lung cancer cohort with B7-H3 expression ≥ 10%, responses were seen in 45.4%. Disease control rates were 61.1% in the head and neck cancer cohort and 92.9% in the lung cancer cohort. These responses, especially in PD-L1–negative patients and immunotherapy-naive patients benchmarked favorably compared to historical experience showing response rates of 13% to 17% with anti–PD-1 therapy alone.

“[In patients who had previously received anti–PD-1/PD-L1 therapy], subsequent treatment with enoblituzumab plus pembrolizumab produced prolonged disease stabilization and objective radiographic responses in some patients,” she reported.

DISCLOSURE: Dr. Diab reported receiving fees for consulting/advisory roles for Nektar Therapeutics, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma; and has received research funding from Nektar Therapeutics, Bristol-Myers Squibb, Idera Pharmaceuticals, Jounce Therapeutics, and Apexigen. His study was sponsored by Nektar Therapeutics. Dr. He has received research funding and is an advisor/consultant for BMS, Merck, Novartis, Genentech, Mirati, GSK, Adaptimmune, Perthera, and GenePlus. Dr. Lakhani reported financial relationships with ALX Oncology, Amgen, ArQule, Ascentage, Apexian, Asana Biosciences, Formation Biologics, Beigene, Celgene, Constellation Pharma, CytomX, Daiichi Sankyo, Forty Seven, InhibRx, Incyte, MacroGenics, Loxo, Livzon Mabpharm, Merck, Northern Biologics, Pfizer, Regeneron, Symphogen, and TaiRx. His study was sponsored by Merck Sharp & Dohme. Dr. Khattak has received a travel grant for his presentation from Immutep. Dr. Golan is a consultant/advisor for AbbVie and AstraZeneca and has received honoraria from Bristol-Myers Squibb, MDS, Rafael Pharmaceuticals. Dr. Davar is a consultant/advisor for Incyte, Merck, Tesaro, and Iovance. His study was sponsored by Tesaro. Dr. Aggarwal is a consultant for Bristol-Myers Squibb, Celgene, Genentech-Roche, and AstraZeneca and has received institutional research funding from Merck, Incyte, MacroGenics, and MedImmune. Her study was sponsored by MacroGenics.


1. Diab A, Tykodi S, Curti B, et al: Immune monitoring after NKTR-214 plus nivolumab (PIVOT-02) in previously untreated patients with metastatic stage IV melanoma. 2018 SITC Annual Meeting. Abstract O4. Presented November 9, 2018.

2. He K, Leal A, Spira A, et al: Preliminary biomarker analysis of sitravatinib in combination with nivolumab in NSCLC patients progressing on prior checkpoint inhibitor. 2018 SITC Annual Meeting. Abstract P385. Presented November 10, 2018.

3. Lakhani N: The anti-LAG-3 antibody MK-4280 as monotherapy in combination with pembrolizumab for advanced solid tumors. 2018 SITC Annual Meeting. Abstract O26. Presented November 9, 2018.

4. Triebel F, Mueller C, Brignone C, et al: Results from a phase I dose escalation trial (TACTI-mel) with the soluble LAG-3 protein (IMP321, eftilagimod alpha) together with pembrolizumab in unresectable or metastatic melanoma. 2018 SITC Annual Meeting. Abstract O28. Presented November 9, 2018.

5. Golan T: Phase 1 dose-finding study of the anti-TIGIT antibody MK-7684 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. 2018 SITC Annual Meeting. Abstract O25. Presented November 9, 2018.

6. Anderson AC: Tim-3: An emerging target in the cancer immunotherapy landscape. Cancer Immunol Res 2:393-398, 2014.

7. de Mingo Pulido A, Gardner A, Hiebler S, et al: TIM-3 regulates CD103+ dendritic cell function and response to chemotherapy in breast cancer. Cancer Cell 33:60-74, 2018.

8. Davar D, Boasberg P, Eroglu Z, et al: A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in combination with TSR-042 (anti-PD-1) in patients with colorectal cancer and post-PD-1 NSCLC and melanoma. 2018 SITC Annual Meeting. Abstract O21. Presented November 9, 2018.

9. Aggarwal C, Joshua A, Ferris R, et al: A phase I, open-label dose-escalation study of enoblituzumab in combination with pembrolizumab in patients with select solid tumors. 2018 SITC Annual Meeting. Abstract O24. Presented November 11, 2018.

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