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Investigators are studying LN-145, a novel immunotherapy developed from autologous tumor-infiltrating lymphocytes (TILs), as a potential new option for patients with unresectable or metastatic non–small cell lung cancer (NSCLC) after disease progression on a checkpoint inhibitor and chemotherapy. 

The IOV-LUN-202 trial (NCT04614103) is a phase 2 registrational study of LN-145 in patients without driver mutations. 

The therapy is a form of adoptive cell transfer in which TILs harvested from the patient’s tumor tissue are reinvigorated, expanded, and then infused into the patient.

“This therapy is clinically relevant, and we’ve seen some people benefit from this novel immunotherapy in related clinical trials,” said Kai He, MD, PhD, a medical oncologist at The Ohio State University Comprehensive Cancer Center—The James in Columbus, as well as an assistant professor of medicine in the Thoracic Oncology Program.

“If this clinical trial is successful, this therapy would provide a relevant way to sustain response; successful development will help the patient and, we hope, convert noncurable disease to a curable one eventually.”

Although PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have been incorporated into the first-line treatment paradigm as monotherapy or in combination with chemotherapy for patients with metastatic NSCLC without oncogenic mutations, most patients who receive ICIs will experience disease progression.

The combination of pembrolizumab (Keytruda), a PD-1 inhibitor, plus chemotherapy, which is among the preferred recommendations in the National Comprehensive Cancer Network guidelines,

 is a “popular regimen,” but the majority of patients relapse within 7 to 8 months, according to Benjamin C. Creelan, MD, a medical oncologist and clinical researcher in the Department of Thoracic Oncology at Moffitt Cancer Center in Tampa, Florida.

Checkpoint inhibitors may not work in some cancers because of the lack of T cells infiltrating the tumors, Creelan explained. “This trial is taking that exact population and trying an immune therapy again for them using TILs,” Creelan said. 

TIL therapy has shown signs of efficacy in metastatic NSCLC. In 2020, Creelan and colleagues presented findings from a phase 1 study (NCT03215810) in which TIL therapy resulted in an ORR of 25% in 20 patients with metastatic NSCLC who had disease progression after prior treatment with nivolumab (Opdivo).

In the IOV-LUN-202 trial, investigators are seeking to enroll 95 patients with unresectable or metastatic NSCLC who have progressed after a single line of treatment with ICI therapy plus chemotherapy with or without bevacizumab (Avastin) and whose tumors do not have an actionable driver mutation or translocation in genes such as 

To manufacture the TIL therapy, investigators will obtain a 1.5-cm sample of tumor tissue from each patient and send it to a manufacturing facility where the TILs will be reinvigorated and expanded. Prior to TIL infusion, patients will receive IV nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg x 2) plus f ludarabine (25 mg/m

 x 5), followed by a single infusion of autologous LN-145 (day 0) and up to 6 doses of IL-2 (600,000 IU/kg).

The IL-2 infusions are an important part of the therapy, Creelan said. “We know that the T cells that we culture still depend on those cytokines to carry out their activity when they are infused into the body,” Creelan said. “Giving patients a little extra boost afterward is believed to be important, but the amount of IL-2 and the length are up for discussion.”

The nonrandomized study will have 4 cohorts (

). Cohort 1 will enroll 40 patients whose tumors do not express PD-L1 prior to ICI therapy with a tumor proportion score (TPS) of less than 1%, whereas cohort 2 will enroll 40 patients with a TPS of 1% or greater before ICI therapy. Cohort 3, designed for 15 patients with a TPS of less than 1%, will use core biopsies for tumor acquisition for patients who are unable to safely undergo surgery.

Figure. LN-145 TIL Therapy in Metastatic NSCLC

Cohort 4 will comprise patients who have been previously treated with LN-145 in cohort 1, 2, or 3 and who may need retreatment with the TIL therapy.

“The vast majority of patients with stage IV lung cancer will progress, even on the state-of-the-art therapy,” He noted.

The primary end point in IOV-LUN-202 is ORR using RECIST 1.1 criteria, as assessed by the independent review committee (cohorts 1 and 2) or by the investigator (cohorts 3 and 4). Secondary end points include complete response (CR) rate, duration of response (DOR), disease control rate (DCR), progression-free survival, and OS.

Investigators are recruiting patients in 50 sites in the United States and Europe. The first site was activated in January 2021.

“This is highly sophisticated, hospital-based therapy, involving surgical and nonsurgical harvesting of the TILs, isolating the TILs, proliferating, and stimulating the cells. The patient will have lymphodepletion, the infusion of TIL, and then a short course of IL-2,” He said.

Iovance Biotherapeutics, Inc, the developer of LN-145, has optimized a manufacturing process originally pioneered by the National Cancer Institute. The company can deliver a cryopreserved TIL infusion product in 16 to 22 days.

Creelan said Moffitt Cancer Center is manufacturing the TIL therapy for the study. Meanwhile, Iovance is constructing a manufacturing facility in Philadelphia, Pennsylvania. Construction of the clean rooms was completed in late 2020, with commercial manufacturing on track to start in 2022, the company said.

Investigators also have been interested in pursuing TIL therapy for patients with NSCLC because of encouraging results in melanoma.

Most recently, at the American Association for Cancer Research Annual Meeting 2021, investigators presented findings from the phase 2 C-144-01 study (NCT02360579) involving a cohort of patients who were treated with a cryopreserved form of lifileucel (LN-144) that had been centrally manufactured in a 22-day process.

Cohort 2 enrolled 66 patients with unresectable or metastatic melanoma who had been treated with at least 1 prior therapy including an anti–PD-1 inhibitor and, for those with a 

 V600 mutation, a BRAF inhibitor or a combination of BRAF plus MEK inhibition. The median age of the patients was 55 years (range, 20-79) and the mean number of prior therapies in the cohort was 3.3.

After a median study follow-up of 28.1 months, the ORR among patients in the cohort was 36.4%, with 3 patients experiencing CRs and 21 exhibiting partial responses (PRs). The DCR, which includes patients with stable disease as well as responses, was 80.3%. The median DOR was not reached (range, 2.2-35.2+ months).

The adverse event (AE) profile was consistent with the advanced disease of the participants and the safety profile of the nonmyeloablative lymphodepletion and IL-2 regimens that participants also received, investigators noted.

The incidence of treatment-emergent AEs of grade 3 or 4 severity was 97.0%, most frequently thrombocytopenia, anemia, and febrile neutropenia. Two patients died, 1 from an intra-abdominal hemorrhage possibly related to TIL therapy and the second from acute respiratory failure not associated with TILs.

The TILs used to produce lifileucel for the study were procured from tumor tissue in numerous organ sites, showing that the therapy could be manufactured successfully regardless of the site of origin.

Investigators continue to study LN-145 in several other cancers. In head and neck squamous cell carcinoma (HNSCC), investigators are studying the immunotherapy in combination with pembrolizumab in patients with advanced recurrent or metastatic disease who have not been treated previously with ICIs. Interim results were presented in November 2020 at the 35th Anniversary Annual Meeting of the Society for Immunotherapy of Cancer.

In cohort 2A of the phase 2 IOV-COM-202 study (NCT03645928), the response rate was 44.4%, including 1 complete response and 3 partial responses, among 9 patients with HNSCC who received a one-time TIL administration plus pembrolizumab, for a DCR of 88.9%. Median DOR was not reached at 8.6 months of median study follow-up (range, 1.0+ to 10.9+ months).

The study is continuing to evaluate TIL therapy in 7 cohorts as monotherapy or in combination with pembrolizumab in patients with melanoma, HNSCC, or NSCLC, or in combination with nivolumab plus ipilimumab (Yervoy) in NSCLC.

The trial will test 3 types of TIL therapy: lifileucel (LN-144)/LN-145, produced on a 22-day manufacturing schedule; a third-generation version of LN-144, manufactured in 16 days; and LN-145-S1, a PD-1–selected TIL product.

Additionally, investigators are studying LN-145 as monotherapy and in combination with pembrolizumab in patients with metastatic cervical cancer in a phase 2 trial (NCT03108495).

Autologous LN-145 in patients with metastatic non‒small-cell lung cancer. ClinicalTrials.gov. Updated April 6, 2021. Accessed April 7, 2021. https://clinicaltrials.gov/ct2/show/NCT04614103

Massarelli E, Goldberg Z, Cacovean A, et al. Trial in progress: a phase 2, multicenter study of autologous tumor infiltrating lymphocytes (TIL, LN-145) cell therapy in patients with metastatic non-small cell lung cancer (IOV-LUN-202). Presented at: American Association for Cancer Research Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT246. https://www.abstractsonline.com/pp8/#!/9325/presentation/4856

Horvath L, Thienpont B, Zhao L, Wolf D, Pircher A. Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) ― novel approaches and future outlook. 

. 2020;19(1):141. doi:10.1186/s12943-020-01260-z.

NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 4.2021. Accessed April 14, 2021. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

Creelan B, Wang C, Teer J, et al. Durable complete responses to adoptive cell transfer using tumor infiltrating lymphocytes (TIL) in non-small cell lung cancer (NSCLC): a phase I trial. 

. 2020;80(suppl 16). doi:10.1158/1538-7445.AM2020-CT056

Iovance Biotherapeutics reports fourth quarter and full year 2020 financial results and corporate updates. News release. Iovance Biotherapeutics. February 25, 2021. Accessed April 7, 2021. https://ir.iovance.com/news-releases/news-release-details/iovance-biotherapeutics-reports-fourth-quarter-and-full-year-2

Chesney JA, Larkin JMG, Kirkwood JM, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up. Presented at: 2021 American Association for Cancer Research Annual Meeting; April 10-15, 2021; Virtual. Abstract CT008.

Iovance Biotherapeutics presents clinical data in head and neck cancer at Society for Immunotherapy of Cancer (SITC) 35th annual meeting. News release. Iovance Biotherapeutics. November 9, 2020. Accessed April 7, 2021. https://ir.iovance.com/news-releases/news-release-details/iovance-biotherapeutics-presents-clinical-data-head-and-neck

Gettinger S, Kluger H, Schoenfeld A, et al. A phase 2, multicenter study of autologous tumor infiltrating lymphocytes (TIL, LN 144/LN-145/LN-145-S1) in patients with solid tumors. Presented at: American Association for Cancer Research Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT235. https://cattendee.abstractsonline.com/meeting/9325/Presentation/4844

Articles

Investigators are studying LN-145, a  novel  immunotherapy  developed  from autologous  tumor-infiltrating  lymphocytes, as a potential new option for patients with unresectable or metastatic non–small cell lung cancer after disease progression on a checkpoint  inhibitor  and  chemotherapy.

TIL Immunotherapy Shows Promise   as Second-Line Treatment of NSCLC

In the United States, a geographic mismatch exists between the number of medical oncology and radiation providers and patients needing care, with more specialists clustered in urban and metropolitan areas. This imbalance happens, investigators said, because of the infrastructure needed to support high-quality oncology care. Larger geographic areas offer access to hospitals and universities, clinical trials, peers, and centers that furnish radiation services.

Addressing the gap in providers in rural areas is important because it affects patient care, experts say. Cancer incidence rates and deaths are higher in rural areas than in metropolitan areas.

 One analysis published in 2017 looked at 5-year cancer incidence and mortality rates between 2009 and 2013. Investigators found that in metropolitan counties, cancer incidence was 447 cases per 100,000 people, (range, 446-456 depending on county characteristics), whereas in rural counties, the incidence was 460 per 100,000 (range, 439-477).

Mortality rates were 166 per 100,000 in metropolitan counties (range, 164-173) and 182 per 100,000 in rural counties (range, 174-185). The difference was statistically significant for both benchmarks (P < .001).

“Access to oncology services is impacted by the low density of oncologists in the rural settings,” Smita Bhatia, MD, MPH, director of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham (UAB) School of Medicine, said in an interview with OncologyLive

She is also vice chair for outcomes in the Department of Pediatrics and associate director for outcomes research of the UAB Comprehensive Cancer Center, and associate director of the Center for Outcomes and Effectiveness Research and Education.

“We know that if patients with cancer who are undergoing treatment aren’t carefully monitored, they may have [adverse] effects or an exacerbation of symptoms, or other things that could go wrong. Then when the situation really deteriorates, they may go to emergency departments,” Susan Dentzer, senior policy fellow for Robert J. Margolis Center for Health Policy at Duke University in Durham, North Carolina, said in an interview.

In 2019, 64% of US counties had no oncology care providers whose primary practice site was within that county, and 12% had no oncologists in the adjacent counties, according to a recent analysis in 

Investigators in this study looked at the geographic distribution of oncologists and oncology pharmacists registered in the 2019 National Provider Identifier database and found wide discrepancies in the number of oncologists across geographic regions.

More than 65% of oncologists were based in 4 of 9 US Census Bureau divisions; areas with the fewest oncologists were located in the West North Central and West South Central divisions (

). Of note, a lower availability of cancer care providers was negatively associated with higher cancer rates (correlation, -0.085; 

Another analysis conducted by the American Society of Clinical Oncology (ASCO) showed that just 403 of the 1698 US hematology and medical oncology practices listed in the CMS Physician Compare database have sites in rural areas.

Almost 9 in 10 radiation oncologists work in urban or suburban communities (47% and 41%, respectively). The proportion of those practicing in rural areas declined from 16% in 2012 to 13% in 2017, according to the American Society for Radiation Oncology (ASTRO).

Meanwhile, the percentage of the US population living in rural areas varies from 15% to 19%, depending on the definition used. The US Census Bureau, for example, doesn’t actually define “rural.” It classifies Urbanized Areas as those with 50,000 or more people and Urban Clusters as those with 2500 to fewer than 50,000 people.

In the 2010 Census, 59.5 million people, 19.3% of the population, were considered to be living in rural areas, and more than 95% of US land area is still classified as rural.

The Office of Management and Budget (OMB) considers all areas outside of a metropolitan statistical area as rural. In 2010, non-metropol-itan counties contained 46.2 million people, approximately 15% of the total population and covered 72% of the land area of the country.

The Federal Office of Rural Health Policy uses the OMB classification but uses an addi-tional measure that attempts to allow for better identification of rural areas. By this measure, 57 million people, approximately 18% of the population, and 84% of the nation’s land area are considered rural.

ASCO and ASTRO have implemented initia-tives to focus on oncology care in rural areas. In 2019, both organizations launched efforts to address the needs of oncology care providers in rural areas and better support oncologists regarding provider education and training, telehealth, and research3 (

Bhatia, who is on ASCO’s cancer care task force, said the organization has developed recommendations for addressing oncology care and supporting rural oncologists; these are in manuscript form and will be published soon. One recommendation, she said, is to increase education, training, and mentoring opportunities for those practicing in rural areas, as well as develop the workforce development and build capacity.

Continuing education for physi-cians and staff has always been an issue in rural areas, said David Beyer, MD, medical director of radi-ation oncology at Cancer Centers of Northern Arizona Healthcare in Sedona. “The COVID-19 pandemic has forced us to exper-iment. A lot of CME [continuing medical education] last year was virtual, and it may be that we discovered quite by accident the models that might work in the future.”

The ASCO task force also recom-mended the following: harnessing the growing quality improvement and practice health programs to improve cancer care delivery in rural settings; collecting and analyzing additional data to better understand the current state, needs, and challenges of the rural cancer care workforce in both oncology and nononcology; and promoting research of the design and implementation of cancer care delivery models in the rural setting, Bhatia said in an interview.

Building up the oncology work force in rural areas will require making changes to training programs, said Geraldine M. Jacobson, MD, MPH, MBA, FACR, FASTRO, a radiation oncologist, professor and chair of the Department of Radiation Oncology at West Virginia University Cancer School of Medicine in Morgantown, West Virginia.

One way to do this would be to invest in a national program that supports physicians who want to practice in rural communities. “We need to get people from rural areas into our medical pipeline who will practice in rural areas and that includes maintaining our smaller training programs,” she said in an interview. “Money follows money and technology follows technology. If we want a different outcome, we have to do something different.”

Capacity building and increasing the density of oncology providers and ancillary support staff is important, but that won’t entirely address the rural care issues, Dentzer said.

A different model of care for patients is needed, where they are supported in their homes with telehealth services from clinicians and visits from advanced practice providers. Even in less populous states such as New Mexico, oncologists generally practice in urban or suburban areas, and it’s unlikely they will move to outlying areas, she noted.

“The business model for them [to operate in rural areas] would be unsustainable for the most part. It’s just not going to happen. We focus too much on getting patients and specialists in the same room. The question becomes how to get patients and specialists’ knowledge in the same room. And we’ve found we can put people together via technologies and via telehealth. It’s not about people transfer; it’s about knowledge transfer.”

Dentzer pointed to Project ECHO, the now-global effort that originated at the University of New Mexico School of Medicine as an example.

Project ECHO—which stands for Extension for Community Healthcare Outcomes—began in 2003 as a model to help specialists at the University of New Mexico in Albuquerque support primary care doctors and other clinicians in outlying areas of the state in treating treat patients with hepatitis C. Project ECHO has since grown to include global initiatives in many disease areas, including HIV, tuberculosis, rheumatology, maternal health, and opioid use disorders, as well as oncology.

Oncology organizations are beginning to launch similar efforts. One is ASTRO’s Peerto-Peer Match, which was released in June 2020. The online platform facilitates relationships and connects ASTRO members for peer review of patient cases. It allows clinicians to search for those with similar expertise to assist in evaluating treatment plans.

Peer-to-Peer Match helps to address a challenge radiation professionals in rural areas face, Beyer said. “This program is essentially a ‘Match.com’ for radiation oncologists in rural settings who want to review plans with somebody else, someone who has a similar practice style, a similar practice size, similar technical capabilities.”

Rural oncology patients can also be served by “hospital-at-home” programs, Dentzer said. An example of one such program is Huntsman at Home offered by Huntsman Cancer Institute at the University of Utah in Salt Lake City.

The institute launched Huntsman at Home in 2018 to support patients and caregivers and manage acute and post-surgical care, as well as end-of-life care. It uses nurse practitioners and registered nurses, working with oncology teams, to deliver acute level care at home.

An evaluation of the program’s utilization outcomes was presented at the 2020 ASCO Virtual Scientific Program. Investigators found evidence that the Huntsman at Home program can improve value by reducing hospitalizations, emergency department visits, and costs.

Investigators focused on patients at hospital discharge who needed continued acute level care. They found that for the first 14 months of the program, 19.5% of patients in Huntsman at Home (n = 169) had 1 or more unplanned hospitalizations compared with 35.4% of patients in a similar group outside the 20-mile radius of the hospitals (n = 198).

Additionally, 14.2% of Huntsman at Home patients had 1 or more emergency department visits vs 23.2% for the comparison group. Mean costs were also lower in the Huntsman at Home group ($10,238) vs the usual care group ($21,363).

“This was an initial test of the concept in oncology, and it shows that extending acute level cancer care into the home and communities of cancer patients utilizing a hospital-at-home model can significantly improve patient experience and outcomes,” said Kathi Mooney, PhD, RN, who presented the results. Mooney is a distinguished professor at the University of Utah College of Nursing and coleader of the Cancer Control and Population Sciences Program at the Huntsman Cancer Institute.

Currently, the program is available to patients within a 20-mile radius of the hospital in Salt Lake City. Hospital administrators are also working to increase Huntsman at Home’s reach, extending care to several rural counties in the state. In July 2020, Huntsman Cancer Institute received a $4.5 million gift from the Huntsman family to expand the program to rural Utah.

The institute is in the planning process for expanding the program to Carbon, Grand, and Emery counties, working with the communities identified for the rural expansion and the Huntsman Cancer Institute clinical teams, according to a Huntsman spokesperson. These counties were selected following evaluation of Utah’s cancer burden and conversations with community organizations and elected officials in these areas.

Blake KD, Moss JL, Gaysynsky A, Srinivasan S, Croyle RT. Making the case for investment in rural cancer control: an analysis of rural cancer incidence, mortality, and future trends. Cancer Epidemiol Biomarkers Prev. 2017;26(7):992-997. doi:10.1158/1055-9965.EPI-17-0092

Shih YCT, Kim B, Halpern MT. State of physician and pharmacist oncology workforce in the United States in 2019. JCO Oncol Pract. 2021;17(1); e1-e10. doi:10.1200/OP.20.00600

Key trends in tracking supply of and demand for oncologists. American Society of Clinical Oncology. August 2020. Accessed March 25, 2021. https://bit.ly/2RwnopZ

Radiation oncology workforce study indicates potential threat to rural cancer care access. News release. Newswise. April 4, 2019. Accessed March 25, 2021. https://bit.ly/3sp3azg

Defining rural population. Health Resources and Services Administration. Updated January 2021. Accessed March 25, 2021. http://bit.ly/3fbKUFN

ASCO announces new task force to address rural cancer care gap. News release. American Society of Clinical Oncology. April 10, 2019. Accessed March 25, 2021. http://bit.ly/3d5Gbmy

Project ECHO. University of New Mexico. Accessed March 25, 2021. https://hsc.unm.edu/echo/

Beyer D. Introducing Peer-to-Peer Match, a new platform for radiation oncologists. ASTRO blog. June 2, 2020. Accessed March 25, 2021. https://bit.ly/39fIvGq

Huntsman Cancer Institute researchers demonstrate better outcomes, lower cost in first-ever oncology hospital at-home evaluation. Huntsman Cancer Institute. May 29, 2020. Accessed March 25, 2021. http://bit.ly/2PBeQ3E

Mooney K, Titchener K, Haaland B, et al. The oncology hospital at home: health care utilization outcomes from the Huntsman at Home trial. J Clin Oncol. 2020;38(suppl 15):7000. doi:10.1200/JCO.2020.38.15_suppl.7000

Huntsman Cancer Institute announces next major expansion: cancer care coming to patient home in rural Utah. Huntsman Cancer Institute. July 15, 2020. Accessed March 25, 2021. http://bit.ly/3m2kOqr

Feature

In the United States, a geographic mismatch exists between the number of medical oncology and radiation providers and patients needing care, with more specialists clustered in urban and metropolitan areas.  

Shortage of Cancer Care Providers in Rural Areas Affects Patient Outcomes

Frequently dysregulared in cancer cells, the PI3K pathway has long been a high-priority therapeutic target in oncology.

 However, initial efforts with pan–class I PI3K inhibitors were hampered by disappointing efficacy and substantial toxicity.

The shift to isoform-specific inhibitors yielded more success, with several PI3Kδ inhibitors and the first PI3Kα inhibitor, alpelisib (Piqray), now approved by the FDA.

 The most recent addition to the armamentarium, umbralisib (Ukoniq), is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). With umbralisib approved by the FDA in February for the treatment of relapsed/refractory marginal zone lymphoma (MZL) and follicular lymphoma (FL),7 TG Therapeutics, Inc has also filed for approval of the agent combined with the company’s anti-CD20 antibody, ublituximab, to treat patients with chronic lymphocytic leukemia (CLL) based on topline data from the UNITY-CLL trial.

A host of other PI3K inhibitors designed to further improve the safety and efficacy of this drug class are being evaluated in clinical trials (TABLE). Meanwhile, indications for PI3K inhibitors could soon expand beyond B-cell malignancies and breast cancer, with promising signals from the development of the PI3Kγ inhibitor eganelisib (IPI-549) in combination with nivolumab (Opdivo) for the treatment of patients with metastatic urothelial carcinoma.

Although initial efforts to develop inhibitors targeting all of the class I PI3K isoforms were largely abandoned,2,3 copanlisib (Aliqopa) has emerged as a notable exception. In 2017, the FDA approved the kinase inhibitor for the treatment of adult patients with relapsed/ refractory FL in the third-line setting.

 Although copanlisib is described as a panclass I PI3K inhibitor, it most potently inhibits PI3Kα and PI3Kδ.

Several other pan–class I PI3K inhibitors are still in development. Buparlisib (BKM120) has been studied extensively in several tumor types, including breast cancer, culminating in the phase 3 BELLE-3 trial (NCT01633060). In BELLE-3, the combination of buparlisib plus fulvestrant (Faslodex) demonstrated improved progression-free survival (PFS) compared with placebo plus fulvestrant, but at the expense of substantial toxicity that precluded further development in this setting.

Worldwide development and commercialization rights for buparlisib were transferred from Novartis to the Chinese firm Adlai Nortye in July 2018.

 Buparlisib demonstrated promise in combination with paclitaxel for the treatment of platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in the phase 2 BERIL-1 study (NCT01852292),16 and Adlai Nortye has initiated the phase 3 BURAN trial (NCT04338399) of this combination in patients with HNSCC that progressed after prior platinum-based chemotherapy with or without prior PD-1/PD-L1 inhibitor treatment.

Other early efforts focused on dual inhibitors of PI3K (pan–class I) and its downstream target mTOR; these drugs largely suffered a fate similar to that of pan–class I inhibitors.17 Several continue to be evaluated in clinical trials, however; notable among them is the oral PI3K/mTOR inhibitor paxalisib (GDC0084). Most current clinical trials of this agent, which penetrates the blood-brain barrier, are in brain cancer; PI3K pathway upregulation has been demonstrated in 85% of glioblastoma cases.

Paxalisib is being evaluated in patients with newly diagnosed glioblastoma and unmethylated MGMT promoter status in an ongoing phase 2 trial (NCT03522298). Results of an interim analysis showed a median PFS of 8.4 months and overall survival of 17.5 months among 24 patients treated at the maximum-tolerated dose of 60 mg. The most common toxicities were rash, stomatitis, hyperglycemia, fatigue, nausea, and decreased appetite.

Attention in the field has largely gravitated toward isoform-specific inhibitors in the hopes of reducing off-target toxicity. Expression of the PI3Kδ and PI3Kγ isoforms is enriched in hematopoietic cells,

 leading to the pursuit of PI3Kδ/γ–specific inhibitors in patients with hematologic malignancies.

This quest culminated in the first FDA approval of a PI3K inhibitor in 2014. Idelalisib (Zydelig), an oral PI3Kδ inhibitor, was approved for the treatment of patients with relapsed/refractory small lymphocytic lymphoma (SLL) and FL and in combination with the CD20-targeting antibody rituximab (Rituxan) for the treatment of patients with relapsed/refractory CLL.

 Then, in 2018, the FDA approved the oral PI3Kδ/γ inhibitor duvelisib (Copiktra) for the treatment of adult patients with relapsed/refractory CLL, SLL, or FL.

Most recently in this category, umbralisib was approved for the treatment of adult patients with relapsed/ refractory MZL who have received at least 1 prior CD20 antibody–based regimen and those with relapsed/refractory FL previously treated with at least 3 lines of systemic therapy.

Umbralisib has a novel chemical structure, which is designed to reduce the potential for hepatotoxicity but also results in potent inhibition of CK1ε in addition to PI3Kδ. Combined inhibition of these 2 kinases has shown synergistic activity preclinically, with enhanced killing of lymphoma cells.

FDA approval was based on the MZL and FL single-arm cohorts of the UNITY-NHL trial (NCT02793583). Patients with relapsed/ refractory MZL (n = 69), FL (n = 117), or SLL (n = 22) were treated with 800-mg once-daily umbralisib. Objective response rates (ORRs) were 49.3%, 45.3%, and 50.0% in patients with MZL, FL, and SLL, respectively, with complete responses (CRs) in 16%, 5%, and 5%.

The most common any-grade adverse events (AEs) included diarrhea, nausea, and fatigue, and grade 3/4 AEs included neutropenia, diarrhea, and alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevations.

Topline data from the ongoing UNITY-CLL trial (NCT02612311) were recently presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition in December 2020. In this study, umbralisib in combination with the CD20-targeted anti-body ublituximab is compared against a combination of obinutuzumab (Gazyva) plus chlorambucil in patients with treatment-naïve or relapsed/refractory CLL.

At a median follow-up of 36.7 months, the median PFS was 31.9 months (95% CI, 28.2-35.8 months) in the umbralisib/ublituximab arm vs 17.9 months (95% CI, 16.1-22.6 months) in the comparator arm (HR, 0.55; 95% CI, 0.41-0.72; P < .0001). ORR was also significantly higher in the umbralisib/ublituximab arm compared with the obinutuzumab/chlorambucil arm (

 < .001), with numerical superiority in both treatment-naïve and previously treated patients. Responses were durable, with 62% of umbralisib/ublituximab responses maintained at 2 years.

The most common grade 3/4 AEs included neutropenia and diarrhea.9 In December 2020, TG Therapeutics initiated a rolling submission of a biologics license application to the FDA seeking approval of this combination in patients with CLL.

Among other PI3Kδ inhibitors in development, parsaclisib has more than 19,000-fold selectivity for PI3Kδ over other class I isoforms. Similar to umbralisib, it has a novel structure designed to reduce hepatotoxicity.

Preliminary results were presented at 2020 ASH. Patients with relapsed/refractory FL, MZL, and mantle cell lymphoma (MCL) were treated, respectively, in the CITADEL-203 (NCT03126019), CITADEL-204 (NCT03144674), and CITADEL-205 (NCT03235544) studies with parsaclisib at 20 mg once daily for 8 weeks, followed by either 20 mg once weekly or 2.5 mg once daily. As of January 2020, 106 patients with FL (22 with weekly dosing, 84 with daily dosing), 99 patients with MZL (28 weekly, 71 daily), and 151 patients with MCL (43 weekly, 108 daily) had received treatment.

Patients with MZL had received 1 or more prior therapies, including a CD20-targeted antibody, but had not been treated with a Bruton tyrosine kinase (BTK) inhibitor, whereas those with MCL were stratified according to prior receipt of a BTK inhibitor, such as ibrutinib (Imbruvica). ORRs were 69.8% and 54.3% in patients with FL and MZL, respectively, and 28.3% and 66.3% in patients with MZL who were previously treated with ibrutinib (n = 47) vs those who were not (n = 104).

Meanwhile, MEI Pharma, Inc is developing the oral PI3Kδ inhibitor zandelisib (ME-401). In the phase 3 COASTAL study (NCT04745832), patients with indolent non-Hodgkin lymphoma are treated with zandelisib in combination with rituximab. Zandelisib was awarded fast track designation for the treatment of adult patients with relapsed/refractory FL in March 2020.

The PIK3CA gene, which encodes the p110α catalytic subunit of the PI3Kα isoform, is among the most commonly mutated genes in human cancer,

 including approximately 40% of patients with hormone receptor–positive, HER2-negative breast cancer, and has been shown to be a driver of resistance to endocrine therapy, the cornerstone of treatment in this cancer type.

In May 2019, alpelisib became the first FDA-approved PI3Kα inhibitor. The agent is approved in combination with fulvestrant for the treatment of patients with hormone receptor–positive, HER2-negative, PIK3CAmutant advanced or metastatic breast cancer following progression on or after endocrine therapy.6 Approval was based on results from the phase 3 SOLAR-1 trial (NCT02437318), in which the combination prolonged PFS compared with placebo plus fulvestrant (median PFS, 11.0 months vs 5.7 months; HR, 0.65; 95% CI, 0.50-0.85; P < .001). The most common grade 3/4 AEs were hyperglycemia and rash; both were more common in the alpelisib arm.

 Alpelisib is approved only for patients with PIK3CA-mutant tumors, as determined by 1 of 3 FDA-approved companion diagnostic tests: Qiagen’s therascreen PIK3CA RGQ PCR Kit, a real-time, qualitative, single-gene polymerase chain reaction test that detects 11 mutations in the PIK3CA gene, and Foundation Medicine’s FoundationOne CDx and FoundationOne Liquid CDx, which are comprehensive genomic profiling tests that use next-generation sequencing to assess multiple genes, including PIK3CA. Qiagen’s test can be performed on both tissue and plasma, and the 2 FoundationOne tests are for tissue and plasma testing, respectively.

In recent years, CDK inhibitors have become a new part of standard care in hormone receptor–positive, HER2-negative breast cancer. Thus, the ongoing phase 2 BYLieve trial (NCT03056755) is evaluating alpelisib in combination with fulvestrant in patients whose most recent prior treatment was a CDK4/6 inhibitor plus an aromatase inhibitor (cohort A; n = 127) or alpelisib plus letrozole in those last treated with a CDK4/6 inhibitor and fulvestrant (cohort B; n = 126). The primary end point was met in both cohorts, with 50.4% (95% CI, 41.2%-59.6%) and 46.1% (95% CI, 36.8%-55.6%), respectively, of patients alive without disease progression at 6 months. The safety profile was manageable.

A number of other PI3Kα inhibitors are in development, including serabelisib (TAK117; Takeda Pharmaceutical licensed in 2019 to Petra Pharma Corporation

). Results from the dose-escalation portion of a phase 1b trial (NCT03154294) of serabelisib in combination with the TORC1/2 inhibitor sapanisertib (TAK228) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer demonstrated an ORR of 46% in 13 evaluable patients, with 2 patients achieving CRs.

Efforts also are underway to develop drugs specifically targeting mutant forms of PI3Kα to reduce the potential for off-target toxicity. Genentech’s inavolisib (GDC-0077) is a novel oral PI3Kα inhibitor that also degrades the mutant form of the protein.37 Among 20 patients treated with escalating doses of inavolisib monotherapy in an ongoing phase 1 trial (NCT03006172) in patients with advanced PIK3CA-mutant solid tumors, the clinical benefit rate was 45%, with partial responses in 5 patients. Grade 3 and higher treatment-related AEs included hyperglycemia, lymphopenia, fatigue, nausea, weight loss, and asthenia.

Eganelisib is another notable agent in clinical development that could expand the approved uses of this drug class in the near future. An oral PI3Kγ inhibitor, eganelisib is being evaluated in combination with nivolumab in patients with metastatic urothelial carcinoma in the ongoing phase 2 MARIO-275 trial (NCT03980041).

Preliminary data showed that, among 33 patients who received nivolumab plus eganelisib, the ORR was 30.3%, compared with 25.0% in 16 patients who received nivolumab plus placebo, and the median PFS was 9.1 vs 8.0 weeks, respectively. In this patient population, low or negative tumor PD-L1 expression is generally associated with a poor response to immune checkpoint inhibitor monotherapy. The investigators noted that the eganelisib combination gave a particularly strong efficacy boost to patients with PD-L1–negative tumors, with an ORR of 26% vs 14% in the nivolumab-alone arm and a disease control rate of 57% vs 14%. Eganelisib was well tolerated at a dose of 30 mg once daily.10 The combination has been granted fast track designation in this setting.

Eganelisib has also received a fast track designation in combination with an immune checkpoint inhibitor and chemotherapy for frontline treatment of triple-negative breast cancer.39 The combination of eganelisib, atezolizumab (Tecentriq), and nab-paclitaxel (Abraxane) is being evaluated in the ongoing phase 2 MARIO-3 trial (NCT03961698).

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ElsaLys Biotech announces submission of biologics license application to FDA for Leukotac (inolimomab) for the treatment of graft-versus-host disease in adult patients. News release. ElsaLys Biotech; July 23, 2020. Accessed February 26, 2021. 

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Frequently dysregulated in cancer cells, the PI3K pathway has long been a high-priority therapeutic target in oncology. However, initial efforts with pan–class I PI3K inhibitors were hampered by disappointing efficacy and substantial toxicity.

Vol. 22/No. 09 | Oncology Live®

TIL Immunotherapy Shows Promise as Second-Line Treatment of NSCLC

Shortage of Cancer Care Providers in Rural Areas Affects Patient Outcomes

Strategies for Targeting PI3K Proliferate

Tivozanib Boosts RCC Treatment Portfolio

Finding the Golden Ticket in Cholangiocarcinoma: Entering the Era of Precision Medicine

Clinical Trial Diversity Efforts Gain Steam

COVID-19 Has Diverse Effects on Cancer Care

Trilaciclib Tackles Myelosuppression in SCLC