Anita Shaffer

Complete remissions with mosunetuzumab, a novel bispecific antibody, were achieved&nbsp;in greater than 20% of patients&nbsp;with highly refractory non-Hodgkin lymphomas (NHLs) who had been&nbsp;previously treated with chimeric antigen receptor (CAR) T-cell therapy, according to study results presented at the 2019 American Society of Hematology Annual Meeting.

&ldquo;Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf immunotherapy product that can be given to patients without having to genetically modify their T cells,&rdquo; lead investigator Stephen J. Schuster, MD, said in a statement.

The agent represents a promising therapy for patients whose disease has recurred after receiving CAR therapy or is progressing too rapidly to be treated with personalized gene therapy, said Schuster, director of the lymphoma program at Abramson Cancer Center at the University of Pennsylvania (UPenn) in Philadelphia.

The therapy exhibited a tolerable safety profile, with mostly low-grade occurrences of cytokine release syndrome (CRS) and neurological adverse events (AEs), said Schuster, who is also the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research at UPenn.

Mosunetuzumab is a humanized antibody that contains 2 antigen-recognition sites: CD3, a T-cell surface antigen, and CD20, a tumor-associated antigen exclusively expressed on B cells.

&ldquo;In binding to the T cells, it&rsquo;s capable of inducing T-cell activation and, when engaged with a B cell, it will cause a death of the target cell and eliminate those cells,&rdquo; Schuster said at a press briefing.

The 2 FDA-approved CAR therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), are CD19-directed genetically modified autologous T-cell immunotherapies. Although CAR agents represent a significant advance in treating refractory B-cell malignancies, Schuster said, two-thirds of patients with lymphomas do not respond.

He also said the process of producing and obtaining insurance approval for CAR therapy delays treatment by several weeks. &ldquo;A month or 2 months doesn&rsquo;t sound long but it&rsquo;s an eternity when you have a patient with a very fast-paced disease,&rdquo; he said.

&ldquo;To be able to use the cellular immunotherapeutic approach [with mosunetuzumab] rapidly in patients who need this approach because traditional immunochemotherapy is no longer working is, I think, a very important aspect,&rdquo; Schuster added. An off-the-shelf product that has alternative B-cell targets to CD19, which the approved CAR T cell products address, is necessary.&rdquo;

At the briefing, Schuster reported efficacy results for 191 evaluable patients treated with mosunetuzumab monotherapy during the ongoing phase I/Ib dose-escalation GO29781 study (NCT02500407) in late-line relapsed/refractory B-cell NHLs. The data are from Group B of the study, in which patients received mosunetuzumab intravenously with stepped-up dosing on days 1, 8, and 15 of cycle 1, and then as a fixed dose on day 1 of each subsequent 21-day cycle (maximum 17 cycles).

Among 124 patients with aggressive NHL, the objective response rate (ORR) was 37.1% (n = 46), including 19.4% (n = 24) with a CR, according to pooled data from participants who received mosunetuzumab at doses ranging from 2.8 mg to 40.5 mg. After a median follow-up of 6 months, 17 patients remain in CR.

In 67 participants with indolent NHL, the ORR was 62.7% (n = 42), including 43.3% (n = 29) with a CR, for dosing cohorts ranging from 2.8 mg to 13.5 mg. Twenty-four patients remain in CR up to 26 months after initial treatment.

Notably, patients who previously received CAR T-cell therapy also responded to mosunetuzumab. Among 18 evaluable patients in this cohort, the ORR was 38.9% (n = 7), including a 22.2% CR rate (n = 4). Investigators also observed an expansion of lymphocytes, including residual CAR T cells in 2 of 8 patients, and CRs with and without CAR T-cell expansions.

Schuster described a 58-year-old woman with relapsed/refractory follicular lymphoma (FL) who had 8 prior lines of systemic treatment that included CD19-directed CAR T-cell therapy. The patient achieved a CR after 3 cycles of mosunetuzumab therapy and remains in CR after more than 8 months.

&ldquo;This not an ongoing therapy forever,&rdquo; Schuster said. &ldquo;This is a therapy that patients receive until they&rsquo;re in remission and then it&rsquo;s discontinued. Three-quarters of the remission patients are off therapy.&rdquo;

In the population evaluable for safety, the study has enrolled 270 patients; the median age is 62.0 years (range, 19-96), and 61.2% had a baseline ECOG performance score of 1. The safety population comprises 66.7% with aggressive NHLs, including diffuse large B-cell lymphoma (DLBCL), transformed FL, mantle cell lymphoma, and 31.5% with FL and other indolent NHL types. The median number of prior system therapies was 3 (range, 1-14). In terms of prior therapies, 28.5% had received autologous stem cell transplantation and 71.9% were refractory to their last prior therapy.

Of 30 patients who had received prior CAR T-cell therapy, 22 (73.3%) were refractory to that therapy. This group had received a median 5 lines of prior systemic therapies (range, 3-14).

In the safety analysis, the incidence of all grades of CRS was 28.9% among all participants (N = 270) and 26.7% among those who previously received CAR therapy (n = 30). The majority of these events were of grade 1 or 2 severity, occurred mostly in cycle 1 of therapy, and had a median duration of 2 days (range, 1-59). There were 3 grade 3 CRS occurrences in the total population (1.1%) and 1 in the prior CAR cohort (3.3%). A total of 8 patients received tocilizumab (Actemra) as supportive care and most CRS events (96.6%) were resolved by the clinical cutoff date.

In all, neurological AEs were observed in 43.7% of patients in the total population and 43.3% in the CAR cohort. The most common neurological AEs included headache (15.6%), insomnia (9.3%), and dizziness (9.3%) and were of grades 1 and 2 severity. The incidence of grade 3 neurological AEs was 3.7% in the broad population and 10.0% in the CAR group.

&ldquo;The safety with regard to cytokine release syndrome and neurological adverse events are almost identical whether the patients have had prior CAR T-cell therapy or not,&rdquo; Schuster said. &ldquo;What&rsquo;s interesting is [that] these 2 adverse events are much more frequent during CAR T-cell therapy.&rdquo;

In addition to the refractory setting, Schuster sees potential for mosunetuzumab to be used either before or after CAR T-cell therapy. He noted that 3 of 4 patients in the GO29781 study responded to retreatment with mosunetuzumab, including 1 person who remains in CR.

&ldquo;It suggests that over time, there was some diminution of the immune response and then the ability to restimulate it,&rdquo; he said. &ldquo;It&rsquo;s not something that we&rsquo;ve seen with CAR T cells.&rdquo;

Additionally, Schuster said, treatment with mosunetuzumab does not preclude subsequent CAR treatment. &ldquo;This could be a bridging approach that doesn&rsquo;t require chemotherapy that actually stimulates and invigorates T cells and [that] then [can] be used to make a CAR T-cell product,&rdquo; he said.

Mosunetuzumab, which is being developed by Genentech, also is being studied in combination therapies. In addition to the monotherapy arm reported at the conference, the GO29781 trial will have an expansion phase in which patients receive mosunetuzumab in combination with the PD-L1 inhibitor atezolizumab (Tecentriq), according to the ClinicalTrials.gov website. The international trial aims to enroll 665 participants.

In another phase I study, mosunetuzumab is being evaluated in combination with polatuzumab vedotin-piiq (Polivy), CD79b-directed antibody-drug conjugate with and without bendamustine and rituximab (Rituxan) in patients with relapsed/refractory DLBCL and FL (NCT03671018).

Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-Cell (CAR-T) therapies, and is active in treatment through multiple lines. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 6. ash.confex.com/ash/2019/webprogram/Paper123742.html.

Mosunetuzumab. NCI Drug Dictionary. cancer.gov/publications/dictionaries/cancer-drug/def/774847. Accessed December 7, 2019.

Articles

Complete remissions were achieved in greater than 20% of patients&nbsp;with highly refractory non-Hodgkin lymphomas who had been&nbsp;previously been treated with chimeric antigen receptor T-cell therapy with&nbsp;Mosunetuzumab, a novel bispecific antibody,&nbsp;according to study results presented at the 2019 American Society of Hematology Annual Meeting.

Durable Complete Remissions Achieved in NHL Following CAR T

-mutant nonsmall cell lung cancer (NSCLC) has experienced significant improvements with the development of tyrosine kinase inhibitors (TKIs), but resistance mechanisms that promote disease recurrence have tampered the runaway success of these revolutionary agents, said&nbsp;Katerina A. Politi, PhD, during the 2019 ASCO Annual Meeting.

Much remains unknown about the nature and evolution of aberrations in

-mutant disease, Politi, associate professor of pathology at Yale School of Medicine, said to the audience. She noted that T790M is the most prevalent acquired

resistance mutation in patients who receive first- and second-generation TKIs. That picture is changing now that osimertinib (Tagrisso), which targets T790M, has moved into the frontline setting.

&ldquo;We&rsquo;re really in the initial stages of beginning to understand the mechanisms of resistance to third-generation tyrosine kinase inhibitors when these are used in the first-line setting and in the second-line setting,&rdquo; Politi said. &ldquo;Even with all these improvements in the treatment of

-mutant lung cancer, resistance is a major impediment to cures.&rdquo;

She said osimertinib represents an important step forward in the treatment paradigm. The drug was initially approved in 2015 for patients with metastatic T790M mutationpositive NSCLC. In April 2018, the FDA expanded its indication to include first-line therapy for patients with metastatic disease whose tumors harbor

exon 19 deletions or exon 21 L858R mutations.

The use of first- or second-generation TKIs in the frontline setting has resulted in progression-free survival (PFS) of 10 to 15 months and response rates of approximately 70%, Politi said. With frontline osimertinib, a third-generation TKI, the PFS has been extended to 19 months and the response rate has grown to approximately 80%.

Besides acquired T790M mutations, resistance mechanisms to TKI therapy include

pathway alterations, histologic transformation to small cell lung cancer or epithelialmesenchymal transition, and oncogenic fusions. With osimertinib therapy, new resistance mutations have been identified. These include C797X, L718Q, and G724S after both first- and second-line osimertinib; additional mutations in G796X and L792X have been found after second-line therapy.

However, Politi noted that knowledge about TKI resistance mutations is incomplete. &ldquo;One of the first things that we have to do is really identify all the mutations and mechanisms that are on-target mechanisms that can confer resistance to osimertinib,&rdquo; she said. &ldquo;We need to understand the relationship between the baseline

mutation and resistance mechanisms.&rdquo;

Politi described 2 central thrusts of ongoing research: countering on-target

-dependent mechanisms of resistance to TKIs and finding ways to attack TKI-resistant tumors without on-target

In the realm of known genetic targets, researchers are focusing on

amplification, which is found in 5% to 10% of tumors resistant to first- and second-generation TKIs and may be present in 15% to 20% of tumors resistant to third-generation TKIs.

One novel antibody that is showing early signs of efficacy in this arena is JNJ-61186372, a bispecific antibody that targets

receptors. Following Politi&rsquo;s presentation, Eric B. Haura, MD, reported the latest findings from an ongoing first-in-human phase I study (NCT02609776).

The study, which seeks to enroll 345 participants, is being conducted in 2 stages. Part 1, which sought to establish the appropriate dosage, recruited patients with metastatic or unresectable NSCLC who have progressed after receiving prior therapy or are ineligible for or unwilling to undergo other therapeutic options.

In Part 2, patients are required to have an

activating mutation. They are being channeled into 4 cohorts depending on whether they have received prior EGFR TKI therapy and on their mutations. Patients are receiving either 1050 mg or 1400 mg of JNJ-61186372 administered intravenously once a week during the first 28-day cycle and once every 2 weeks during subsequent cycles. JNJ-61186372 elicited a response rate in 30% of 108 participants with diverse primary and secondary

mutations who received the therapy in doses ranging from 700 mg to 1400 mg, said Haura, a senior member in the Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute. All responses were partial responses (PRs).

In 58 patients with progression after a third-generation TKI, the response rate was 28%, all PRs. This group comprised 8 patients with C797S mutations, 3 with

-based resistance. These patients had received a median of 2.5 prior lines of therapy (range, 1-6). The median duration of treatment was 3 months (range, 0.03-17) and 39% were still receiving therapy.

In terms of adverse events (AEs), infusion-related reactions were most common; occurring in 62% of participants. These reactions typically occurred on the first day of treatment exposure and then grew less frequent as therapy continued, Haura said. Only 1 of the infusion-related reactions was of grade 3 severity; the rest were less than grade 3.

Other treatment-related AEs included rash (56%), paronychia (26%), constipation (22%), dyspnea (19%), fatigue (19%), and nausea (18%). These were all less than grade 3 severity. Grade 3 AEs included 1 each for impetigo, myalgia, peripheral edema, pericardial effusion, and pustular rash. There was 1 patient with grade 4 elevated lipase.

With so many mechanisms of resistance to anti-EGFR TKI therapies in first- and second-line settings, a drug that targets

expression offers the potential to address multiple mutations, according to Pasi A. J&auml;nne, MD, PhD.

J&auml;nne presented early findings for U3-1402, an antibodydrug conjugate aimed at

-mutant NSCLC. The drug is comprised of an anti-HER3 antibody attached to a novel topoisomerase I inhibitor.

U3-1402 inhibited tumor growth in patient-derived xenograft models of

mutations that had grown resistant to EGFR-targeting therapy. It is now being tested in a phase I dose escalation and expansion study in patients with metastatic or unresectable

-mutant NSCLC who are T790M-negative after progressing on TKI therapy or who have progressed after osimertinib (NCT03260491).

So far, 23 patients have received &ge;1 dose of U3-1402, which is administered intravenously once every 3 weeks at doses ranging from 3.2 mg/kg to 6.4 mg/kg. Sixteen patients remain on treatment, while 7 have discontinued therapy, mostly because of progressive disease (n = 5).

At a median follow-up of 4.2 months, U3-1402 therapy resulted in tumor shrinkage for all 16 evaluable patients, including 4 who had a PR, said J&auml;nne, who is director of the Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science at Dana-Farber Cancer Institute. Additionally, 6 patients still receiving therapy have achieved clinical benefit through stable disease.

The most frequently reported AEs included nausea, which affected approximately 60% of participants, and fatigue, vomiting, and decreased appetite, each reported in about 40% of patients. Grade &ge;3 toxicities included nausea, hypokalemia, and decreased platelet count. For dose-limiting toxicities, there were 3 occurrences of grade 4 platelet count decrease at the 6.4-mg/kg dose. One patient experienced grade 3 febrile neutropenia and grade 4 platelet count decrease at the 5.6-mg/kg dose.

J&auml;nne said the trial is continuing with the 5.6-mg/kg cohort with a dose expansion planned for later this year. He said the strategy of targeting

may prove more practical than seeking to target individual mutations.

&ldquo;Developing therapies to combat all individual resistance mechanisms is likely impractical if not impossible. Similarly, in patients with multiple mechanisms of resistance,&rdquo; J&auml;nne said. &ldquo;An alternative strategy is to develop an approach that would be broadly active against all forms of resistance and be agnostic to the resistance mechanism itself.&rdquo;

Politi K. How can we overcome TKI resistance in

-mutant NSCLC? Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. meetinglibrary.asco.org/record/175039/slide.

Haura EB, Cho BC, Lee JS, et al. JNJ-61186372 (JNJ-372), an

-driven advanced non-small cell lung cancer (NSCLC). Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9009. meetinglibrary.asco.org/record/174459/abstract.

J&auml;nne PA, Yu HA, Johnson ML, et al. Safety and preliminary antitumor activity of U3-1402: a HER3-targeted antibody drug conjugate in EGFR TKI-resistant,

m NSCLC. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9010. meetinglibrary.asco.org/record/174523/abstract.

The treatment of&nbsp;<em>EGFR</em>-mutant non&ndash;small cell lung cancer has experienced significant improvements with the&nbsp;development of tyrosine kinase inhibitors, but resistance mechanisms that promote disease recurrence have tampered the runaway success of these revolutionary agents, said&nbsp;Katerina A. Politi, PhD, during the 2019 ASCO Annual Meeting. Early findings are presented for 2 novel agents aiming to potentially overcome resistance.&nbsp;

New Approaches Target Overcoming Resistance to TKIs in EGFR+ NSCLC

A new immune checkpoint called PVRIG has emerged as a ripe target for anticancer therapy in solid tumors and an antibody that blocks its ability to suppress an antitumor response is in development, according to original research presented in a late-breaking abstract at the at the Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting & Associated Programs.

Researchers have demonstrated in preclinical experiments that inhibiting PVRIG results in enhanced activation of tumor-infiltrating lymphocytes (TILs), primary CD4-positive T cells, and tumor-derived CD8+ T cells.

In humanized mouse models, there was a reduction in tumor growth and increased survival when anti-PVRIG antibodies were used in combination with PD-L1 pathway blockade. Tumor growth also was reduced in PVRIG knockout mice.

The goal of the research is to find a way to boost the efficacy of checkpoint blockade immunotherapy strategies, said John Hunter, PhD, site head and vice president of antibody research at Compugen USA, Inc., who presented the findings on behalf of the company.

&ldquo;Despite the outstanding advancements that were made in the last 6 years, we&rsquo;re still in the position where the majority of patients do not derive long-term benefit from these treatments, and this constitutes a very large unmet medical need,&rdquo; said Hunter.

The company plans to file an investigational new drug application with the FDA in 2017 for COM701, its lead antibody that targets PVRIG, said Hunter. The compound binds to PVRIG with high affinity (KD <1nM) and blocks the receptor from binding to its ligand, PVRL2.

Compugen identified PVRIG as a novel immune system target through the use of computational biology tools. The company, based in Israel with a US headquarters in South San Francisco, works with researchers at Johns Hopkins University, Bar-Ilan University, and Tel Aviv University.

Hunter said PVRIG&rsquo;s functional gene structure matched that of known checkpoint receptors such as PD-1 and CTLA-4. Additionally, the tumor expression characteristics of PVRIG were similar to those of T-cell receptor checkpoints.

PVRIG is an immunoglobulin (Ig) domain protein that can be expressed on the surface of tumor cells or on myeloid cells in the tumor microenvironment, Hunter said in an interview. Although researchers are still developing an understanding of the functioning of PVRIG, Hunter said it exerts negative regulatory effects on T-cell activation.

&ldquo;Likely, in a normal cell setting, it plays a role in keeping the immune response in check, similar to the other co-inhibitory checkpoints,&rdquo; said Hunter. &ldquo;There&rsquo;s differences among the known checkpoints in terms of where they operate and the exact mechanism of action. But in a broader sense, we do think that [PVRIG] serves in the normal immune system to make sure that the immune system does not become hyperstimulated.&rdquo;

In human cancer, increased expression of PVRIG would inhibit an antitumor response. Specifically, investigators found that expression of PVRIG was highest in CD8+ effector memory RA T cells, Hunter said. its expression also was found to be upregulated in human and mouse tumors.

In further characterizing the activity of PVRIG, researchers focused on its binding partner, PVRL2, by designing COM701 to target the interaction of the receptor and its ligand.

&ldquo;The antibody binds to a site on PVRIG that is required for the interaction with PVRL2, and, because it binds at a higher affinity than PVRL2, it blocks that binding site so that you can&rsquo;t get that interaction,&rdquo; explained Hunter. &ldquo;We think that that interaction is required for activating PVRIG and inducing the inhibition of T-cell response.&rdquo;

Moreover, this interaction is important because PVRL2 is known to be a binding counterpart to DNAM-1, a key element in the TIGIT immune checkpoint axis, Hunter said. Compugen found that combined blockade of PVRIG and TIGIT also enhanced TIL activation.

The company&rsquo;s experiments are in keeping with a current trend toward exploring combination checkpoint blockade approaches, Hunter noted. &ldquo;Obviously the existing immune checkpoints aren&rsquo;t effective in all patients and we think one of the underlying reasons is that there may be other checkpoints that have to be inhibited as well to reactivate the immune response,&rdquo; he said.

Hunter said Compugen&rsquo;s findings about PVRIG&rsquo;s mechanisms of action complement conclusions reached by University of Colorado researchers earlier this year.

Zhu et al described PVRIG (also called CD112R) as a poliovirus receptor (PVR)like protein that is a member of the B7/CD28 family.

DNAM-1 (also known as CD226) competes with PVRIG to bind to PVRL2 (also called CD112).

Disrupting the ability of PVRIG to interact with its ligand enhances T-cell response, Zhu and colleagues said.

Meanwhile, TIGIT is becoming an increasing focus of immuno-oncology research. In another poster presented at the SITC 31st Annual Meeting & Associated Programs, researchers from Genentech described efforts to inhibit expression of TIGIT in conjunction with PDL1 inhibition in mouse models as a means of enhancing CD8+ T-cell function.

The strategy resulted in significant tumor clearance, and Genentech has moved into phase I testing of an anti-TIGIT molecule.

MTIG7192A is a fully human monoclonal antibody that binds to TIGIT and prevents its interaction with PVR. The trial, which opened in June, will evaluate the safety and efficacy of MTIG7192A as a monotherapy and in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) in a 2-step study that aims to enroll 300 patients with locally advanced or metastatic tumors.

Levy O, Chan C, Cojocaru G, et al. Computational identification, functional characterization, and antibody blockade of a new immune checkpoint in the TIGIT family of interacting molecules. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract O3.

Zhu Y, Paniccia A, Schulick AC, et al. Identification of CD112R as a novel checkpoint for human T cells. J Exp Med. 2016;213(2):167-176. doi: 10.1084/jem.20150785.

Grogan J, Manieri N, Chiang E, et al. The immunoreceptor TIGIT regulates anti-tumor immunity. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract 214.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02794571. Accessed November 11, 2016.

A new immune checkpoint called PVRIG has emerged as a ripe target for anticancer therapy in solid tumors and an antibody that blocks its ability to suppress an antitumor response is in development.<br />
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Anita Shaffer | Authors

Articles

Durable Complete Remissions Achieved in NHL Following CAR T

New Approaches Target Overcoming Resistance to TKIs in EGFR+ NSCLC

Novel Immune Checkpoint Identified as Promising Target for Blockade Strategies