Four patients with lung adenocarcinoma with

fusions demonstrated some degree of response or tumor stabilization when given afatinib (Gilotrif), according to a poster presentation at the 2019 World Conference on Lung Cancer meeting.

The findings suggest that the irreversible pan-ERBB inhibitor is a potential treatment in this rare mutation of lung adenocarcinoma.

&ldquo;These findings add to a growing body of evidence suggesting afatinib activity in

fusionpositive non&ndash;small cell lung cancer (NSCLC),&rdquo; Michael Duruisseaux, MD, of the Lyon Cancer Institute in France, and colleagues reported in a poster presentation during the meeting. &ldquo;Mutational testing of patients with solid tumors may help to identify potentially targetable genomic aberrations, such as NRG1 fusions. This may be particularly important in lung invasive mucinous adenocarcinoma, where

fusion prevalence is relatively high.&rdquo;

NRG1 is a growth factor containing an epi- dermal growth factorlike domain that binds to ERBB3 or ERBB4 to activate ERBB signaling pathways. Clinically actionable

gene fusions that may function as oncogenic drivers have been identified in multiple tumor types, including NSCLC, the investigators noted.

fusions have an estimated prevalence of about 0.2% in various solid tumors, but the prevalence in lung invasive mucinous adeno- carcinoma could be as high as 31%.

Afatinib may represent a viable therapeutic option for

-associated lung adenocarcinoma, Duruisseaux and colleagues continued. They described 4 new cases of

fusionpositive lung adenocarcinoma treated with afatinib.

A 70-year-old nonsmoking Caucasian woman had a diagnosis of pan-wild type, nonmucinous lung adenocarcinoma in 2004 and received 14 lines of therapy prior to afatinib, including chemotherapy and targeted agents. The patient initiated afatinib in February 2015, had a rapid initial response, and remained on treatment until March 2017, when she developed progressive disease.

fusion was identified in October 2017 by NanoString analysis, and the patient reinitiated afatinib at 30 mg daily, which led to regression of lung condensations. The patient discontinued afatinib after 3 months because of cough and fever, but reinitiated afatinib in April 2018. Treatment continued until August 2018, when disease progression occurred.

The second case involved a 66-year-old non- smoking Asian woman with low body weight. In June 2015, the patient had diagnosis of metastatic nonmucinous lung adenocarcinoma, with multiple lung and lymph node metastases. The patient had received 4 prior lines of therapy, including nivolumab (Opdivo) and docetaxel/ ramucirumab (Cyramza).

In December 2017, the patient received afatinib treatment at 40 mg daily after detection of a CD74-

fusion. After several dose adjustments because of diarrhea and malaise, the patient attained a partial response (PR), which was ongoing after 19 months of follow-up.

The third patient was a 68-year-old Caucasian man with a &ge;20 pack-year history of smoking. He had cinous invasive lung adenocarcinoma in January 2016. He received 2 prior lines of therapy: cisplatin/pemetrexed chemotherapy, which led to progressive disease as best response, and nivolumab, which resulted in a PR. The patient remained on the PD-1 inhibitor from September 2016 to March 2017, when the treatment was discontinued because of progressive disease associated with immune hepatitis.

fusion, the patient was given afatinib at 30 mg daily in August 2018 and attained stable disease for 4 months. At disease progression, that patient chose not to have further treatment.

A diagnosis of invasive mucinousade- nocarcinoma of the lung in August 2016 formed the basis for the fourth case, a 43-year-old non-smoking Caucasian woman. Her treatment history consisted of pemetrexed/cisplatin chemotherapy plus bevacizumab (Avastin), followed by bevacizumab/pemetrexed maintenance until July 2017. She then received nivolumab until September 2017, when RNA sequencing identified a CD74-

The patient initiated treatment with afatinib, which led to a major PR, and treatment is ongoing.

&ldquo;A prospective study of a larger cohort of patients with

fusionpositive NSCLC treated with afatinib is warranted to better evaluate its potential activity,&rdquo; the investigators concluded in their poster.

Duruisseaux M, Laskin JJ, Tolba K, et al. Targeting NRG1-fusions in lung adenocarcinoma: afatinib as a novel potential treatment strategy. Present- ed at: 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain; Abstract P1.14-25.

Articles

Clinical Articles

Four patients with lung adenocarcinoma with NRG1 fusions demonstrated some degree of response or tumor stabilization when given afatinib, according to a poster presentation at the 2019 World Conference on Lung Cancer meeting. The findings suggest that the irreversible pan-ERBB inhibitor is a potential treatment in this rare mutation of lung adenocarcinoma.

Patients With Rare Gene Fusion NRG1 Respond to Afatinib in NSCLC

Findings from an interim analysis of the National Lung Matrix Trial (NLMT; NCT02664935), a large, multiarm trial involving patients with nonsmall cell lung cancer (NSCLC), demonstrated both promising activity and shortcomings in predefined goals in a presentation at the 2019 World Conference on Lung Cancer. Cancer investigator Gary Middleton, MBBS, MD, a professor of medical oncology at the University of Birmingham in the United Kingdom, presented the findings, which involved 19 of 22 mutation-defined patient cohorts and 8 targeted therapies, several of which had promising activity.

For example, the tyrosine kinase inhibitor crizotinib (Xalkori) had a >99% probability of achieving a defined rate of durable clinical benefit (DCB) and objective response (OR) rate for patients with

exon 14 skipping. However, positive findings were not always identified, because many of the matchups in the NLMT appeared unlikely to reach predefined goals for DCB, OR, or progression-free survival (PFS).

Middleton suggested several explanations for the results and strategies to turn apparently poor targets into potentially good targets: &ldquo;One of the risks with the paradigm of precision medicine is that we focus on very high levels of single-agent activity in oncogene addiction,&rdquo; he said. &ldquo;We might be missing a trait, or we might be missing a useful target in our patients.&rdquo;

As an example, he cited palbociclib (Ibrance) and capivasertib, both chosen for NLMT, for estrogen receptorpositive breast cancer. As single agents, the drugs had very modest activity, but studies subsequently showed that the drugs became much more effective in combination with fulvestrant. &ldquo;Critically, there is no evidence at all that the putative biomarkers for palbociclib or capivasertib are actually useful,&rdquo; he said.

Tobacco-associated lung cancer poses a multiplicity of obstacles for therapeutic development: genetic instability, ongoing evolution, onco-gene predominancy, and numerous pathways to resistance.

&ldquo;That brings up the criticality of the preclinical models that we need,&rdquo; Middleton said. &ldquo;We need to make sure that the targets we are gunning for are tested in models that completely replicate the genomic complexity and chaos of tobacco-associated nonsmall cell lung cancer.&rdquo;

The observations and comments followed his presentation of initial findings from the ongoing NLMT. The trial currently has 22 mutation-defined cohorts within 4 pathways of genomic alteration treated with 1 of 7 targeted drugs: cell cycle progression (palbociclib), RAS activation (palbociclib, vistusertib, and selumetinib/ docetaxel), PI3K/PTEN/AKT/mTOR (vistusertib, capivasertib), and RTK signaling (FGFR inhibitor AZD4547, crizotinib, osimertinib [Tagrisso]).

Each cohort eventually will have 30 patients. The Bayesian adaptive design of the trial allows for interim analyses to predict outcomes when a cohort is fully accrued.

The principal outcomes of interest are OR and DCB (stable disease or better for &ge;24 weeks), except for the RAS activation category, which has endpoints of DCB and median PFS. The target estimates for OR and DCB are >30% for single-agent treatment and >40% for a combination, and the median PFS target is 3 months.

Investigators used Bayesian methodology to estimate true rates and medians and credible 95% confidence intervals. A treatment is considered a go for further evaluation if the posterior probability of exceeding a target estimate is >0.50.

For the cell cycle progression category, median PFS with palbociclib exceeded the 3-month target for tumors with

amplification. Predictive probability of success (PPoS) ranged from 0.69 to 0.98. Median PFS remained below the target for tumors with

amplification, which was associated with a PPoS of 0.23. The DCB target had yet to be reached for any of the 4 subgroups.

In the RAS activation category, the combination of selumetinib and docetaxel had a 50% DCB and PPoS of 0.89 for the subgroup with

mutation, as well as a median PFS of 5.6 months. Palbociclib for tumors with

mutation resulted in a median PFS of 5.4 months and a predicted probability >0.99, and it also had a DCB rate of 44%. Three other subgroups appeared unlikely to meet DCB or PFS targets.

In the PI3K/PTEN/AKT/mTOR category, the DCB rates for the 5 subgroups ranged from 9% to 21%, associated with PPoS of 0.06 to 0.34. The PPoS for the response target was <0.20 for all the subgroups.

The RTK signaling group had 4 subgroups with DCB rates that exceeded the targets, and 3 of the 4 exceeded response targets. Crizotinib for tumors with

exon 14 skipping alterations had DCB rates of 71% and 80%, respectively, and OR rates of 68%, both associated with PPoS >0.99. Osimertinib for

T790M mutation had a 94% DCB and an OR rate of 76%, with a PPoS >0.99. AZD4547 for

mutation had passed the DCB target (31%), which was associated with a PPoS of 0.54. Crizotinib for tumors with

amplification appeared unlikely to meet the DCB or response target.

In closing, Middleton showed the impact of smoking status and histology on the interim results. Light smokers (&le;10 pack years) and never smokers had response rates of 17% and 28%, respectively, compared with patients who had smoking histories of 10 to 30 pack years (7%) and >30 pack years (10%). Similarly, responses occurred substantially more often among non-squamous versus squamous tumors (16% vs 1%). He noted that 99% of the patients with squamous cell histology had been treated with palbociclib or capivasertib.

Middleton G, Popat S, Fletcher P, et al. National Lung Matrix Trial (NLMT): first results from an umbrella phase II trial in advanced non-small cell lung cancer (NSCLC). Presented at: International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.09.

Findings from an interim analysis of the National Lung Matrix Trial, a large, multiarm trial involving patients with non&ndash;small cell lung cancer, demonstrated both promising activity and shortcomings in predefined goals in a presentation at the 2019 World Conference on Lung Cancer.

Expert Reports Mixed Results in Interim Analysis for Multiarm NSCLC Trial

The advent of an era of targeted immunotherapy and CAR T-cell therapies for the treatment of adult patients with acute lymphoblastic leukemia (ALL) may reduce the need for hematopoietic stem cell transplant (HSCT) in certain cases.

&ldquo;The best patient to go forward with transplant is that patient who is MRD [minimal residual disease] negative. As you go beyond first remission, the likelihood of achieving MRD negativity goes down,&rdquo; said Partow Kebriaei, MD, professor in the Department of Stem Cell Transplantation in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, in an interview with

Kebriaei joined Michael Pulsipher, MD, professor of pediatrics at the Keck School of Medicine of the University of Southern California and section head of Blood and Marrow Transplantation at Children&rsquo;s Hospital Los Angeles, California, to present opposing views on the use of HSCT versus systemic therapies in certain patients with ALL at the Seventh Annual Society of Hematologic Oncology Meeting, held September 11 to 14, 2019, in Houston, Texas.

Arguing against the use of HSCT, Pulsipher noted that risk stratification by MRD status, a prognostic factor for response, is one way to better determine whether patients are candidates for targeted immunotherapeutics (low risk) or cellular therapies (high risk). Other upfront approaches to decrease the need for HSCT, such as combinations of immunotherapies with chemotherapy backbones and CAR T-cell therapies, are currently being explored.

Targeted Immunotherapeutics in Patients Ineligible for HSCT

Prior to the broad introduction of immunotherapies into the treatment paradigm of ALL, overall survival (OS) rates in adults 5 years after a first relapse were below 10%.3 The current rationale for treating ALL with immunotherapy is based on chemoresistance, treatment-related mortality due to factors such as bimodal disease incidence or advanced age, and improved response with the combined use of immunotherapies and chemotherapy.

Novel therapies approved in the past 5 years have dramatically improved response rates for patients with relapsed/refractory ALL. Examples include the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), the monoclonal antibody inotuzumab ozogamicin (Besponsa), and the first CAR T-cell therapies.

In older patients with ALL, standard intensive chemotherapy approaches often result in lower response and higher toxicity than in younger patients.5 Prompted by the lack of optimal frontline therapy options for patients who are not good candidates for transplant, Pulsipher outlined studies suggesting benefits of targeted immunotherapies in this population.

Blinatumomab is a bispecific anti-body construct that targets both CD3 of the T-cell receptor complex and CD19, an antigen highly expressed on the surface of B cells, including ALL blasts. By transiently linking these 2 cell types, blinatumomab triggers T-cell activation, followed by T-cellmediated lysis of malignant B cells.

Blinatumomab received accelerated approval in 2014 for the treatment of Philadelphia chromosomenegative (Ph-) relapsed/refractory B-cell precursor ALL, with subsequent trials confirming clinical benefit and leading to the 2017 expansion of the indication to include patients with Ph-positive disease.

In March 2018, the results of the BLAST trial led to the agent gaining accelerated approval for an additional indication: the treatment of patients with B-cell precursor ALL who are in first or second complete remission (CR) with MRD &ge;0.1% (ie, with leukemic cells representing at least 0.1% of bone marrow cells according to highly sensitive, nonmorphologically based tests).

In the phase II BLAST trial, patients &ge;18 years with B-cell precursor ALL in first or later hematologic CR with persistent or recurrent MRD &ge;0.1% following intensive chemotherapy were given blinatumomab with the option to undergo allogeneic HSCT. The primary endpoint was MRD response after 1 treatment cycle. Of 113 patients evaluable for response, 78% achieved a complete MRD response, with longer relapse-free survival and OS observed in these patients versus nonresponders.

Consistent with prior literature and standard practices, 67% of patients treated in BLAST were offered HSCT, and transplant-related mortality was comparable to that in previous reports. There were 48 patients who remained in CR at the time of publication, of whom 36 had received HSCT.

Interestingly, sustained remission was observed in a number of patients who did not receive transplant, confirming data from previous studies. This finding suggests that blinatumomab treatment may allow some patients, particularly those who are frail or elderly, to forgo harsher treatment strategies that include HSCT.

Inotuzumab ozogamicin is an antibodydrug conjugate (ADC) consisting of a derivative of the potent DNA-binding cytotoxic antibiotic calicheamicin linked to a humanized monoclonal IgG4 antibody directed against CD22, an endocytic receptor specific to B-cell malignancies.

Its mechanism of action involves binding to CD22 and releasing calicheamicin into tumor cells, which causes double-stranded DNA breaks and apoptosis.

Inotuzumab ozogamicin was approved for the treatment of adults with relapsed/refractory B-cell precursor ALL based on the INO-VATE trial, which compared the single agent versus standard chemotherapy.

Inotuzumab ozogamicin induced CR at a rate of 80.7% versus 29.4% (

<.001) in the control group. In addition, a higher percentage of patients in the inotuzumab ozogamicin group who achieved CR were also below the 0.01% threshold for MRD compared with the control group (78.4% vs 28.1%;

In an analysis of 135 patients &ge;60 years with newly diagnosed Ph- ALL, 2 treatment programs were compared: the standard, intensive regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD); and a low-intensity regimen of mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone (mini-Hyper- CVD) plus inotuzumab ozogamicin with or without blinatumomab (

).1 Higher response rates (98% vs 88%) and lower rates of early death (0% vs 8%) were seen with the ADC-mini- HCVD combination than with HCVAD. OS (63% vs 34%;

= .004) and event-free survival rates (64% vs 34%;

= .003) at 3 years also favored the combination. Few patients (&le;5%) in either cohort went on to receive HSCT.

&ldquo;In the absence of randomized, prospective clinical trials, these results suggest that the combination is a superior frontline approach for older patients with Ph-negative ALL,&rdquo; the study investigators concluded.

CAR T-Cell Therapies in Low-Burden Disease

Response rates of up to 90% have been reported in patients with B-cell ALL treated with CAR T-cell therapies,1 but many patients still proceed to transplant following remission.2 As these therapies become more prevalent, determining which patients can avoid allogeneic HSCT following response to therapy will be important for reducing transplant-related toxic effects.

In a study of 53 adult patients with relapsed B-cell ALL, treatment with 1928z CAR T cells (which target both CD19 and CD28) induced CR in 83%. Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival.

In the same cohort, 32 patients had MRD-negative CR, and some of these patients proceeded to allogeneic HSCT. Analyses of event-free survival and OS showed that there was no statistically significant benefit to transplant in these patients (

A recent review of clinical trials of CAR T-cell treatment for ALL included a discussion of the use of HSCT in patients who achieve MRD-negative status following CAR T-cell therapy. Referring to the above study and a second trial showing a high rate of CD19-negative escape among patients who relapsed after HSCT, lead author Juanjuan Zhao, MD, said &ldquo;this analysis argues that [allogeneic] HSCT may not effectively eliminate the CD19-negative ALL clones that evaded CAR T therapy. These observations suggest that additional graft-versus-leukemia effects may not be achieved by [allogeneic] HSCT following effective CAR T cell therapy.&rdquo;

Kebriaei discussed challenges revealed during trials of CAR T-cell therapies. Better CAR T-cell persistence, improved toxicity profile, and prevention of CD19-negative escape are currently the most pressing areas of investigation, she said.

Longer-term follow-up of these clinical trials has shown that CAR T cells generally persist for months, although long-term disease control has been observed only in patients who have proceeded to transplant. Kebriaei noted that persistence up to several years has been reported by investigators using CAR T cells with the 4-1BB costimulatory domain.

&ldquo;In general, if a patient had a remission, and morphologic is adequate, and they are fit to undergo transplant, [then they meet the criteria] to go forward with transplant. What is happening now is that we are taking patients who may be on their third, fourth, or fifth line of therapy who, in the past, would not have been expected to have a response. Now these patients are attaining response, and we will take them to transplant because it does not matter that they have a response after their fifth line of therapy,&rdquo; Kebriaei said.

Kebriaei P, Pulsipher M. Is transplant still necessary in the era of targeted cellular therapy for ALL? Presented at: Seventh Annual Society of Hematologic Oncology Annual Meeting; September 11-14, 2019; Houston, TX.

Kebriaei P. Debate: Transplant is still necessary in the era of targeted cellular therapy for ALL.

Fielding AK, Richards SM, Chopra R, et al; the Medical Research Council of the United Kingdom Adult ALL Working Party and the Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study.

. 2007;109(3):944-950. doi: 10.1182/blood-2006-05-018192.

Kebriaei P. Targeted immunotherapy for acute lymphoblastic leukemia. Presented at: Seventh Annual Society of Hematologic Oncology Annual Meeting; September 11-14, 2019; Houston, TX.

Jabbour EJ, Sasaki K, Ravandi F, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-HCVD) with or without blinatumomab versus standard intensive chemotherapy (HCVAD) as frontline therapy for older patients with Philadelphia chromosomenegative acute lymphoblastic leukemia: a propensity score analysis.

. 2019;125(15):2579-2586. doi: 10.1002/cncr.32139.

Goebeler ME. Knop S, Viardot A, et al. Bispecific T-Cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016;34(10):1104-11. doi: 10.1200/JCO.2014.59.1586.

FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosomepositive B cell. FDA website.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-blinatumomab-and-expands-indication-include-philadelphia-chromosome

. Published July 11, 2017. Accessed September 24, 2019.

FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. FDA website.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomab-blincyto-amgen-inc-treatment-adult-and-pediatric

. Published March 29, 2018. Accessed September 24, 2019.

G&ouml;kbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia.

. 2018;131(14):1522-1531. doi: 10.1182/blood-2017-08-798322.

Ricart AD. Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin.

. 2011;17(20):6417-6427. doi: 10.1158/1078-0432.CCR-11-0486.

FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL. FDA website.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inotuzumab-ozogamicin-relapsed-or-refractory-b-cell-precursor-all

. Published August 17, 2017. Accessed September 24, 2019.

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

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

Park JH, Rivi&egrave;re 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.

Zhao J, Song Y, Liu D. Clinical trials of dual-target CAR T cells, donor-derived CAR T cells, and universal CAR T cells for acute lymphoid leukemia.

. 2019;12(1):17. doi: 10.1186/s13045-019-0705-x.

The advent of an era of targeted immunotherapy and CAR T-cell therapies for the treatment of adult patients with acute lymphoblastic leukemia may reduce the need for hematopoietic stem cell transplant in certain cases.<br />
&nbsp;

Treating ALL With Cellular and Targeted Immunotherapies Reduces the Need for Transplant

Findings from part 1 of the phase II/III RESILIENT trial of irinotecan hydrochloride liposome (Onivyde) injection in second-line treatment of small cell lung cancer (SCLC) showed that for close to 50% of patients, disease control was maintained at 12 weeks. These data were presented at the 2019 World Conference on Lung Cancer.

The liposomal irinotecan induced an objective response rate (ORR) of 44% among 25 patients treated with the optimal dose of 70 mg/m2. The ORR comprised 11 partial responses (PRs). The rate of best overall response, which included all PRs as well as patients with stable disease, was 72%. The 12-week disease control rate, which included lasting PRs and instances of stable disease, was 48%. Sixty-eight percent of patients had some level of tumor shrinkage.

&ldquo;Immunotherapies and combination therapies have proven beneficial in the first-line setting, but despite these advances, many patients with SCLC rapidly relapse due to the aggressive nature of the disease,&rdquo; Luis G. Paz-Ares, MD, PhD, lead investigator and chief physician at Hospital Universitario 12 de Octubre in Madrid, Spain, said in a press release.

&ldquo;While the current standard of care in the second-line setting can extend survival, treatment toxicity has prevented some patients from receiving the full recommended dose. There is a clear need for more treatment options that may give more patients the chance to remain on therapy. It is positive that the RESILIENT trial will continue to investigate this,&rdquo; added Paz-Ares.

The 2-part, open-label phase II/III RESILIENT study is exploring single-agent liposomal irinotecan in patients with SCLC with disease progression following a frontline platinum-based regimen. Part 1 of the trial involves dose-finding and dose-escalation analyses, and in part 2, which has just started, patients are being randomized to compare the efficacy of liposomal irinotecan to topotecan (Hycamtin), the current standard of care. Key endpoints for part 2 are progression-free survival and overall survival.

Part 1 data from 30 patients with a median age of 60 years (range, 48-73) were presented at the WCLC. In the dose-finding phase, patients received liposomal irino- tecan every 2 weeks at 70 mg/m2 or 85 mg/m2. However, after 5 patients were enrolled to receive the 85 mg/m2 dose, investigators determined that the 85 mg/m2 dose was not tolerable because of dose-limiting toxicities they observed. During this phase, 12 patients received the 70 mg/m2 dose, which investigators deemed tolerable. This led to an additional 13 patients being treated at 70 mg/m2 in the dose-expansion phase (

Among the 25 patients who received the 70 mg/m2 dose, 40% (n = 10) were male, the median age was 59.8 years, and 88% had an ECOG performance status of 1. The median time since most recent disease progression was 3.2 weeks, 2 patients had locally advanced disease, and 23 patients had metastatic disease. Twelve patients had completed the study, 7 remained in the study, and 6 patients had died. Two patient deaths resulted from adverse events related to the study drug.

Grade &ge;3 treatment-emergent adverse events (TEAEs) occurred in 40% (n = 10) of patients treated at 70 mg/m2. The most common grade 3 gastrointestinal TEAE was diarrhea (n = 5). Grade &ge;3 hematologic TEAEs included neutropenia (n = 4), anemia (n = 2), and thrombocytopenia (n = 2). There was also one case of grade &ge;3 fatigue.

Liposomal irinotecan is a nanoliposomal encapsulation of irinotecan. The liposomal formulation allows the irinotecan to remain in circulation longer than standard irinotecan does. Additionally, this mechanism allows for higher drug uptake within tumor cells and greater conversion of irinotecan to its active form,

The FDA approved liposomal irinotecan in October 2015 for use in combination with 5-fluorouracil (5-FU) and leucovorin as a treatment for patients with meta- static pancreatic cancer following administration of a gemcitabine-based regimen.

&ldquo;Onivyde has been proven to help many metastatic pancreatic cancer patients whose disease has progressed following gemcitabine-based therapy to live longer,&rdquo; Yan Moore, MD, senior vice president and head of oncology therapeutic area at Ipsen, Paris, France, which develops liposomal irinotecan along with Servier, said in a press release. &ldquo;By applying this research to other hard-to-treat-cancers, like SCLC, we aim to evaluate the potential benefit investigational Onivyde may bring to patients who otherwise would have limit- ed treatment options.&rdquo;

Ipsen and Servier announce initial phase II/III clinical data evaluating investigational liposomal irinotecan (Onivyde) as a second-line treatment for small cell lung cancer (SCLC) at the International Associations for the Study of Lung Cancer 2019 world conference on lung cancer [news release]. Paris, France: Ipsen; September 8, 2019. bit.ly/2lPeuHL. Accessed September 9, 2019

Paz-Ares L, Spigel D, Chen Y, et al. Initial efficacy and safety results of irinotecan liposome injection (NAL-IRI) in patients with small cell lung cancer [Abstract OA03.03]. Presented at: International Association for the Study of Lung Cancer 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain.

Zhang H. Onivyde for the therapy of multiple solid tumors. Onco Targets Ther. 2016;9:3001-3007. doi: 10.2147/OTT.S105587.

Simon S. FDA approves Onivyde for advanced pancreatic cancer. American Cancer Society website. bit.ly/2vApadL. Published October 22, 2015. Accessed September 19, 2019.

Findings from part 1 of the phase II/III RESILIENT trial of irinotecan hydrochloride liposome injection in second-line treatment of small cell lung cancer showed that for close to 50% of patients, disease control was maintained at 12 weeks. These data were presented at the 2019 World Conference on Lung Cancer.

Patients With Small Cell Lung Cancer Experience Tumor Response With Liposomal Irinotecan

Advances in the development of targeted therapies and the identification of emerging biomarkers of response to treatment have led to an improved ability to predict and enhance responses to immunotherapeutic agents in nonsmall cell lung cancer (NSCLC).

Available agents that have contributed to this transformation in recent years include nivolumab (Opdivo) and pembrolizumab (Keytruda), albeit with mixed results. In the first randomized phase III trials to report a 5-year outcomes for a PD-1 inhibitor in the setting of previously treated advanced or metastatic NSCLC, CheckMate 017 and CheckMate 057, data demonstrated a 5-year pooled overall survival (OS) rate of 13.4% with nivolumab versus 2.6% with docetaxel and a 5-year pooled progression-free survival (PFS) rate of 8.0% and 0%, respectively. Following treatment with nivolumab, those patients who did not exhibit disease progression at 2 and 3 years exhibited a 60% and 78% chance, respectively, of remaining progression free at 5 years. Furthermore, 10% were no longer receiving nivolumab at 5 years, had not progressed, and had not received subsequent therapy.

Another landmark phase III trial, KEYNOTE-024, included patients with metastatic NSCLC and a PD-L1 tumor proportion score (TPS) of &ge;50% who received first-line treatment with pembrolizumab or platinum-based chemotherapy. After at least 3 years of follow-up, patients treated with pembrolizumab continued to exhibit significantly increased OS despite 65% of patients assigned to the chemotherapy arm being allowed to cross over to the pembrolizumab arm. Furthermore, pembrolizumab was associated with less toxicity than chemotherapy, with a manageable long-term safety profile. A durable clinical benefit was observed in patients who completed 35 cycles (2 years) of pembrolizumab, with most patients remaining alive at data cutoff.

Additional emerging biomarkers of treatment response and targetable tumor receptors are under investigation, and recent study results presented at 2019 World Conference on Lung Cancer held in Barcelona, Spain, spotlighted the most promising novel agents and strategies for therapy selection that are under development.

Originally identified in human leukemia as a transforming gene,

AXL, a receptor tyrosine kinase, has been suggested to be involved in cell cycle reentry, cell survival, and cell transformation.

AXL expression has also been shown to be involved in cancer invasion, with the potential for the use of protein expression analysis as a biologic marker of tumor progression in patients with lung cancer.

Bemcentinib is a first-in-class small molecule inhibitor of AXL kinase that has been shown to target the tumorimmune interface to dampen the aggressiveness of cancer cells in vitro and enhance chemotherapy efficacy in murine models.

In a phase II study of patients with advanced NSCLC and adenocarcinoma histology who were immunotherapy naïve and progressed on platinum-based chemotherapy in the first line, patients were given bemcentinib 200 mg daily plus pembrolizumab 200 mg every 3 weeks to assess safety and efficacy of the combination. Among 46 patients who received at least 1 dose of the combination, 58% of 33 evaluable patients were AXL positive. Among 38 patients evaluable for PD-L1 status, 8% had a TPS &ge;50% (strongly positive), 39% had a TPS of 1% to 49% (positive), and 53% were PD-L1 negative (

Among the 35 patients evaluable for response, 10 achieved partial response (PR), 12 had stable disease (SD), and 13 had progressive disease, for an objective response rate (ORR) of 29% and a clinical benefit rate (CBR) of 63%. Among the 15 AXL-positive patients, the ORR was 40% and the CBR was 67%, whereas the 13 AXL-negative patients hadanORRof15%andaCBRof54%.

Of the 2 patients with strongly-positive PD-L1 results, 1 had a PR and 1 had progressive disease, for an ORR and a CBR of 50% each. Among the 12 patients who were PD-L1 positive, 3 achieved a PR and 5 had progressive disease, resulting in an ORR of 25% and a CBR of 58%. Among the 15 PD-L1negative patients, 4 achieved a PR and 6 had progressive disease, resulting in an ORR of 27% and a CBR of 60%.

The median OS was 12.2 months (95% CI, 6.2not reached), and the 12-month OS rate was 54.2%.9 Among AXL-positive patients, the median PFS was 5.9 months compared with 3.3 months in AXL-negative patients. Adverse events (AEs) leading to treatment discontinuation included transaminitis, fatigue, asthenia, pneumonia, and aspartate aminotransferase increase.

Overall, the trial investigators concluded that these results suggest that the combination of bemcentinib and pembrolizumab is well tolerated and leads to promising clinical activity, particularly in patients with AXL-positive tumors with low or no PD-L1 expression.

The AXL-specific human immunoglobulin G1 antibody conjugated with monomethyl auristatin E (MMAE), enapotamab vedotin (ENA V)11 has demonstrated a primary mechanism of action based on MMAE-mediated killing of AXL-positive tumor cells and AXL-negative bystander tumor cells.

Results for patients with NSCLC without a known activating

alteration from a phase I/IIa dose-escalation/dose-expansion trial of ENA V were presented at the meeting and showed encouraging preliminary activity in those who had previously failed on immune checkpoint inhibitors and platinum based-chemotherapy.

&ldquo;This was a phase I study with a built-in expansion cohort for patients with advanced-stage NSCLC,&rdquo;

, professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, director of the Lung Cancer Program at Winship Cancer Institute of Emory University, both in Atlanta, Georgia, and lead author of the study, told

in an interview. &ldquo;After the recommended dose of ENA V was established, we proceeded to enroll patients with advanced-stage NSCLC that had progressed on prior standard therapies. The intent was to evaluate the efficacy of ENA V in this patient population.&rdquo;

Among 26 patients, the median treatment duration was 6 weeks (range, 2.0-24.7 weeks), and 25 patients discontinued treatment because of progressive disease (38%), adverse events (AEs; 38%), death (12%), or other (8%).

&ldquo;The safety profile is acceptable, with constipation, neuropathy, and fatigue as salient AEs,&rdquo; Ramalingam said.

The ORR was 19%, and the disease control rate was 50%, with a median time to onset of response of 11 weeks (95% CI, 5-15) and a median duration of response of 18.1 weeks.

Antiangiogenic Therapy Combined With Immunotherapy

&ldquo;This is a group of patients for whom there is an urgent need to develop novel treatment approaches. We view these as promising results, given that the patients enrolled had progressed on standard therapies,&rdquo; Ramalingam said. &ldquo;ENA V is associated with single-agent activity in advanced NSCLC.&rdquo;

Previous studies have demonstrated a synergistic effect of antiangiogenic therapy and immunotherapy. A recent phase I trial was the first designed to evaluate a chemotherapy-free regimen combining the PD-1 inhibitor sintilimab with the angiogenesis modulator anlotinib in treatment-naïve patients with advanced NSCLC.

Among 22 enrolled patients, 16 achieved a confirmed PR, for an ORR of 72.7% and a disease control rate of 100%. Responses were consistent by subgroup evaluation based on tumor PD-L1 expression and tumor mutational burden (TMB) status (

The 6-month PFS rate was 93.8%, and no unexpected toxicities were observed. Overall, these results suggest that the combination of sintilimab and anlotinib may be a potential first-line treatment option for patients with advanced NSCLC. The investigators of the trial concluded that based on these results, further confirmation in larger studies is warranted.

Mutations Associated With Immunotherapy Response

Within the nivolumab arm, investigators confirmed an association between

mutations and poor outcomes; however, molecular abnormalities were unable to predict outcomes for the nivolumab/ ipilimumab arm.

Recently, relevant clinical trials of immunotherapy agents have yielded studies evaluating the association between mutations and sensitivity or resistance to immunotherapy for better-informed treatment decision making.

In the open-label, randomized phase III MYSTIC study, 1118 immunotherapy- and chemotherapy-naïve patients with stage IV NSCLC were stratified by PD-L1 expression (<25% vs &ge;25%) and histology and randomized to receive durvalumab (Imfinzi), durvalumab plus tremelimumab, or platinum-based chemotherapy. Results of the trial were presented in late 2018 and showed that the primary endpoints of OS and PFS superiority with durvalumab/tremelimumab versus chemotherapy were not met, but further analyses into patient subgroups that may benefit from this regimen are ongoing.

Regardless of treatment, OS was shorter for patients with mutations in

compared with patients with wild-type disease. Patients with mutations in

exhibited improved OS and ORR following treatment with durvalumab plus tremelimumab compared with chemotherapy. Mutations in

were positively associated with blood TMB &ge;20 mutations per megabase, whereas mutations in

were positively associated with PD-L1 expression <25%. These results provide information on the impact of specific mutations on immunotherapy response, but further validation is needed.

In a retrospective study of patients with metastatic nonsquamous NSCLC,

genomic alterations were associated with shorter PFS with frontline chemoimmunotherapy or chemotherapy treatment. Furthermore,

genomic alterations were predictive of inferior clinical outcomes with chemoimmunotherapy in patients with PD-L1positive tumors.

Over 75% of patients with progressive disease as the best objective response to chemoimmunotherapy had

mutations. Patients with PD-L1positive disease with

mutations experienced shorter PFS and a lack of benefit from the addition of pembrolizumab to chemotherapy. These results suggest that patients with NSCLC and

mutations do not derive the same benefit with standard-of-care chemoimmunotherapy regimens and represent an unmet need for novel treatment strategies that contribute to effective antitumor immunity.

Despite heavy interest in its use for predicting outcomes for immunotherapy, TMB has become an elusive biomarker for assessing treatment response in NSCLC, with many investigators striving to incorporate its use into practice with mixed results.

In the phase III CheckMate 227 trial, patients with advanced NSCLC and high TMB exhibited prolonged PFS with nivolumab plus ipilimumab compared with chemotherapy, irrespective of PD-L1 expression.17 However, updated survival data as of October 2018 demonstrated superior results with nivolumab plus ipilimumab compared with chemotherapy, irrespective of TMB level.

It is important to remember that not all non-synonymous somatic mutations are equally immunogenic, Mari Mino-Kenudson, MD, director of pulmonary pathology at Massachusetts General Hospital in Boston, told an audience at the WCLC.

Because few somatic mutations ultimately prove immunogenic, the odds of T-cellmediated killing are increased by maximizing the number of different mutations as well as both their length (with frame-shift and nonsense preferable to missense mutations) and prevalence (with early-arising, widespread truncal mutations preferable to the later-arising, rarer branch mutations).

The nonsynonymous mutational burden has been associated with the clinical benefit of antiPD-1 therapy in patients with NSCLC.

The Lung-MAP substudy S1400I was a randomized phase III trial designed to assess nivolumab versus the combination of nivolumab plus ipilimumab as second-line therapy in patients with metastatic squamous cell lung cancer with no matching biomarker.

When PD-L1 or TMB was used as a biomarker, outcomes between nivolumab monotherapy and the combination of nivolumab/ipilimumab showed no statistically significant differences. However, exploratory analyses of the combination of PD-L1 and TMB suggest that for patients with 0% PD-L1 expression, TMB &ge;10 significantly improved outcomes with the immunotherapy combination versus nivolumab (HR, 0.39; 95% CI, 0.16-0.93;

= .004), whereas it was detrimental to patients with TMB <10 (HR, 2.52; 95% CI, 1.03-6.13;

Mino-Kenudson reviewed several issues that have been identified regarding the use of TMB for predicting response to immune checkpoint inhibitor therapy. Questions surround the choice of the best cutoff values for classification of high TMB; the use of whole-exome sequencing (WES) or next-generation sequencing (NGS); the bioinformatics process; and biological variables, including tumor cell content and intratumoral heterogeneity; within NGS, questions arise regarding the size of the panel and genetic region covered, the depth of coverage, and the gene selection biased |toward frequently mutated genes associated with cancer.

Mino-Kenudson further reviewed proposed recommendations for consistent assessment of TMB. Regarding sample processing, protocols should be standardized and interlaboratory variability should be minimized. Gene panels should be selected to screen for actionable mutations or biomarkers, and these panels should have larger genome coverage, ideally, of approximately 1 megabase or more. For standardization of workflow, panel-derived TMB values should be aligned to a WES analysisderived reference standard to ensure consistency, irrespective of the assay used. Bioinformatics algorithms used for mutation calling and filtering should be standardized. To calibrate outputs, reporting consistency should be ensured via development of templates for clinically meaningful reporting, and calibration of results from different studies should be allowed.

TMB efficiency is also attenuated based on the inclusion of adverse mutations, such as those in

. To combat this, the tumor mutation score was developed as an improved biomarker for response of immune checkpoint inhibitors in 240 patients with NSCLC treated with antiPD-1/ L1 therapy with or without anti&ndash;CTLA-4 from the MSK-IMPACT cohort. The tumor mutation score was defined as the number of genes with nonsynonymous somatic mutations. Significant associations with prolonged PFS and improved responses were observed with 12 genes and 11 genes, respectively. The tumor mutation score of 18 favorable genes (TMS18) was significantly correlated with overall TMB. Differences among patients with complete response, PR, SD, and progressive disease were more pronounced using TMS18 than TMB or PD-L1 expression. The combination of TMS18 and PD-L1 expression had a higher area under the curve for prediction of response; however, this difference was not significantly better than TMS18 alone.

Overall, these findings suggest that the selective TMS18 may be a better biomarker for response to immunotherapy than TMB in patients with NSCLC. Additionally, the combination of TMS18 and PD-L1 expression may contribute to improved efficiency for predicting response to immune checkpoint inhibitors; however, validation in larger cohorts is required.

These advances have contributed to an improved ability for predicting and enhancing responses to immunotherapeutic agents; however, additional questions remain regarding standardization of biomarker measurement and identification of optimal patient subgroups for treatment. Patient subgroups identified as having unmet needs will still require novel therapies and strategies for improved responses to therapy and overall patient outcomes.

Gettinger S, Borghaei H, Brahmer JR, et al. Five-year outcomes from the randomized, phase 3 trials CheckMate 017/057: nivolumab vs docetaxel in previously treated NSCLC. Presented at: International Association for the Study of Lung Cancer 2019 World Conference in Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA14.04.

Reck M, Rodr&iacute;guez-Abreu D, Robinson AG, et al. KEYNOTE-024 3-year survival update: pembrolizumab versus platinum-based chemotherapy for advanced NSCLC. Presented at: International Association for the Study of Lung Cancer 2019 World Conference in Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA14.01.

O'Donnell K, Harkes IC, Dougherty L, Wicks IP. Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: evidence for novel endothelial cell survival pathway.

. 1999;154(4):1171-1180. doi:10.1016/S0002-9440(10_65369-2.

O&rsquo;Bryan JP, Frye RA, Cogswell PC, et al. Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase.

. 1991;11:5016-5031. doi: 10.1128/mcb.11.10.5016.

Berclaz G, Altermatt HJ, Rohrbach V, Kieffer I, Dreher E, Andres AC. Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast.

. 2001;12(6):819-824. doi: 10.1023/a:1011126330233.

Lin WC, Li AF, Chi CW, et al. Tie-1 protein tyrosine kinase: a novel independent prognostic marker for gastric cancer.

Fujino N, Fujimori T, Maciewicz R, Hussell T. Axl receptor tyrosine kinase drives cell cycle re-entry and promotes symmetric cell division of airway basal cells in response to injury.

Advances in the development of targeted therapies and the identification of emerging biomarkers of response to treatment have led to an improved ability to predict and enhance responses to immunotherapeutic agents in non&ndash;small cell lung cancer.

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