Meir Rinde

Research on chimeric antigen receptor (CAR) T-cell therapies has exploded since the first such treatment received approval in 2017. Hundreds of trials are under way, 3 therapies for hematologic malignancies are on the market, and 2 new products may receive FDA approval in the next several months, including a BCMA–directed therapy that is poised to help transform treatment of multiple myeloma (MM).

In the near term, the approved therapies will gradually gain more indications and move to earlier treatment stages, experts say. On a parallel track, an off-the-shelf allogeneic product that is less costly and time-consuming to produce could be approved within a few years, greatly expanding the number of patients benefit-ing from CAR T cells. Other new categories of cellular therapies, such as tumor-infiltrating lymphocytes (TILs) that treat solid tumors, are also moving through the development pipeline.

The recent surge in research has been accompanied by a diversification of development and manufacturing pathways for these 

complex, personalized immunotherapies. Big pharmaceutical companies, start-ups, medical centers, and government labs alike are producing CAR T cells. Decentralized point-of-care processing and improved “cell engineering in a box” technologies may eventually speed up production and bring cellular therapies to more sites closer to patients.

“There’s a lot of innovation happening and a lot investment, and it’s really exciting. Before there were a few labs, and now we have a whole set of industries,” CAR T-cell pioneer Carl H. June, MD, said in an interview with 

. A 2015 Giants of Cancer Care® award winner, June is the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and director of the Parker Institute for Cancer Immunotherapy, both at the University of Pennsylvania in Philadelphia.

The number of clinical trials evaluating CAR T-cell therapies has increased dramatically since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials.gov website. In June 2020, the site listed 671 trials, comprising 357 registered in China, 256 in the United States, and 58 in other countries (

Table. A Snapshot of the CAR T-Cell Therapy Landscape

So far, the FDA has approved 3 CAR T-cell treatments, all directed at CD19. The first was tisagenlecleucel (tisa-cel; Kymriah), initially approved in August 2017 for refractory or relapsed B-cell acute lymphoblastic leuke-mia (R/R ALL) in patients up to 25 years old and later expanded to include adults with R/R large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (FL). The approvals are based on research June and colleagues conducted.

In October 2017, axicabtagene ciloleu-cel (axi-cel; Yescarta) gained approval for adults with R/R DLBCL, primary mediastinal B-cell lymphoma, and transformed FL. In July 2020, brexucabtagene autoleucel (brexu-cel; Tecartus) joined the roster with an accelerated approval for adults with R/R mantle cell lymphoma; continued approval may be contingent on a confirmatory trial.

Another CD19-directed therapy for R/R large B-cell lymphoma, lisocabtagene maraleucel (liso-cel; JCAR017), was under FDA review at press time.

 The application is based on the phase 1 TRANSCEND-NHL-001 study (NCT02631044),

 whose results showed an objective response rate (ORR) of 73% (95% CI, 66.8%-78.0%), including a complete response (CR) rate of 53% (95% CI, 46.8%-59.4%) among 256 evaluable patients.6 Median duration of response (DOR) was not reached (NR; 95% CI, 8.6-NR) with 12.0 months of median follow-up. Median progression-free survival was 6.8 months (95% CI, 3.3-14.1), and the median overall survival was 21.1 months (95% CI, 13.3-NR).

Safety analysis showed 79% of patients in the safety population (n = 269) had grade 3 or higher treatment-emergent adverse effects (TEAEs), primarily cytopenias (neutropenia, 60%; anemia, 37%; thrombocytopenia, 27%). Cytokine release syndrome (CRS) and neurological events occurred in 42% and 30% of patients, respectively. These effects included grade 3 or higher CRS in 2% of patients and neurological events in 10%.

Differences in trial design and patient cohorts make comparisons with other CAR T-cell therapies difficult, but liso-cel appears to have an impressive toxicity profile and good durability, said Andre H. Goy, MD. Goy is physician in chief at Hackensack Meridian Health Oncology Care Transformation Service, chairman and chief physician officer at John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, academic chairman oncology at Hackensack Meridian School of Medicine at Seton Hall University, and professor of medicine at Georgetown University in Washington, DC.

“Liso-cel’s impact is going to be significant because if it’s confirmed to be less toxic, as it looks like, and assuming there are no issues with the manufacturing process, this could definitely be a competitor. No question about that,” Goy, a leading investigator of brexu-cel

 and other CAR therapies, said in an interview.

Also in late-stage development is idecabtagene vicleucel (ide-cel, bb2121), with an FDA decision expected by March 27, 2021. The biologics license application seeks approval for the BCMA-directed CAR therapy for the treatment of adult patients with MM who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

The application is supported by data from the phase 2 KarMMA trial (NCT03361748) in heavily pretreated patients (N = 128) with refractory MM.

 Treatment with ide-cel resulted in an ORR of 73% (95% CI, 65.8%81.1%; P < .0001), meeting the trial’s primary end point, according to findings presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program. The CR/stringent CR rate was 33% (95% CI, 24.7%-40.9%; P < .0001), the median DOR was 10.7 months (95% CI, 9.0-11.3), and median progression-free survival was 8.8 months (95% CI, 5.6-11.6).

Grade 3 or higher CRS occurred in 5.5% of patients, and 1 death occurred because of a CRS event. Grade 3 neurotoxicity events occurred in 3.1% of patients. No grade 4 or 5 events were reported. Grade 3 or worse CRS or neurotoxicity events were reported in 6% or less of patients at the target dose of 450 x 106 CAR T cells. Any-grade CRS and neurotoxicity events occurred in 84% and 18% of patients, respectively.

Therapies targeting BCMA are expected to have a significant impact on the treatment landscape in MM. The transmembrane glycoprotein is expressed at high levels on MM cells and on plasma cells but not on other normal tissue, making it a promising target.

 In August 2020, the FDA approved the first therapy targeting BCMA, the antibody-drug conjugate belantamab mafodotin-blmf (Blenrep), for patients with R/R MM who have received at least 4 prior therapies.

Approval of ide-cel or another similar CAR T-cell therapy would be a “huge event” because it would fulfill a major unmet medical need and show that CARs work with targets other than CD19, according to June. “What the field definitely needs is curative therapy so patients aren’t on chronic treatment. It’s really exciting that that’s going to happen,” he said.

June added that he anticipates many trials 

will look at whether CAR treatments could replace stem cell transplants for patients with MM and, eventually, whether CARs can be used as frontline therapy for the disease.

Studies are already under way on using other CARs earlier in treatment paradigms. The phase 3 ZUMA-7 trial (NCT03391466) is evaluating axi-cel versus standard-of-care secondline therapy for patients with R/R DLBCL, and the phase 2 ZUMA-12 trial (NCT03761056) is studying the therapy as a frontline treatment for high-risk large B-cell lymphoma. The phase 2 TRANSCEND-PILOT-017006 trial (NCT03483103) is testing liso-cel as a second-line therapy for patients with aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for stem cell transplant. “A lot of studies are investigating the best timing for CAR T,” Goy said. “We’re looking at shifting [CARs] to a better, earlier use because we know that although patients respond even if they have failed multiple lines of therapy, if they have [a large burden of] disease and are kind of beat up by the prior treatment or lymphoma, they don’t do as well.”

Renier J. Brentjens, MD, PhD, a leading CAR T-cell investigator, also sees opportunities to move the therapies forward. “In the arena of, for example, DLBCL, where there are a significant number of durable remissions, I would not be surprised if [a CAR T-cell therapy] becomes kind of a second-line drug as opposed to the drug of last resort,” said Brentjens, director of the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York, New York.

Investigators are also conducting trials of CD19-directed CAR T-cell therapies against new indications, such as B-cell ALL in adults and low-grade lymphomas such as FLs and chronic lymphocytic lymphoma. Kite Pharma has filed a supplemental biologics license application with the FDA to expand axi-cel’s indications by adding R/R FL and marginal zone lymphoma following 2 or more systemic therapies, based on data from the phase 2 ZUMA-5 trial (NCT03105336).

are also studying existing CARs in combination with checkpoint inhibitors and other immunotherapy drugs.

Beyond liso-cel and ide-cel, dozens of enhanced CARs directed at CD19 and BCMA have shown promise and a few could be commercialized within 2 or 3 years. One is JNJ-4528, which is directed against 2 distinct BCMA epitopes. It was originally developed in China (where it is called ciltacabtagene autoleucel) and is now being developed through a collaboration between Legend Biotech and Janssen Biotech. The agent has shown positive results for patients with R/R MM in phase 1 and 2 trials and been granted breakthrough therapy designation in the United States and China, as well as PRIME status from the European Medicines Agency.

A number of novel CARs with different targets and formulations are in trials, but when they might become widely available is unclear. These include innovations such as bispecific or dual CAR T-cell therapies targeting CD19-CD22 or BCMA-CD3, “armored CARs” that secrete cytokines, and CARs aimed at solid tumors.

The next major CAR development may instead be an allogeneic, off-the-shelf product that uses donor T cells.

Goy said allogeneic products are among the most promising of the next wave of CAR treatments. “They’re off-the-shelf by definition, and very fit T cells. It’s very early but so far the responses have been very impressive, based on small numbers of patients, and not very toxic. That will be potentially very important,” he said.

June called an allogeneic CAR a potential “game changer” because it can be manufactured in large batches and delivered to patients anywhere for immediate infusion, at a significantly lower cost than that of current CAR therapies. He said these therapies could arrive in as soon as 3 years.

“Once allogeneic cell [therapies] come out, they’ll be everywhere and have much deeper penetration into smaller centers, more rural areas where people have no access to CAR T cells right now. All the small practices can just order them. That will be the tipping 

point. Right now it will stay at the major centers for these autologous cells,” June said.

Among the more advanced allogeneic therapies are UCART19 and ALLO-501, anti-CD19 CARs that Allogene and partner firms are developing. The 2 agents are structurally identical but use different manufacturing processes and are paired with different lymphodepletion regimens.

In pooled data from 2 phase 1 studies (CALM; NCT02746952 and PALL; NCT02808442), 82% (14 of 17) of patients with R/R B-ALL who received UCART19 and a lymphodepletion regimen containing fludarabine, cyclophosphamide, and alemtuzumab achieved CR or CR with incomplete hematologic recovery.

In the phase 1ALPHA study (NCT03939026), ALLO-501 was administered after a lymphodepletion regimen of fludarabine, cyclophosphamide, and anti-CD52 the monoclonal antibody ALLO-647 to patients with previously treated R/R large B-cell lymphoma or FL. The ORR was 63% (95% CI, 38%-84%), including a CR of 37% (95% CI, 16%-62%) in 19 evaluable patients.

The companies developing UCART19/ ALLO-501 have several allogeneic candidates, including an anti-BCMA MM therapy (ALLO-715). Meanwhile, Cellectis is trialing UCART123, a CD123-targeted therapy for R/R acute myeloid leukemia, in the phase 1 AMELI-01 study (NCT03190278).

Other allogeneic CAR T-cell therapies in trials include 3 from Precision BioSciences: a CD19-directed product (PBCAR0191) being studied for no-Hodgkin lymphoma (NHL) and ALL; a CD20-targeted therapy (PBCAR20A) for NHL, chronic lymphocytic leukemia, and small lymphocytic lymphoma; and an anti-BCMA therapy for MM (PBCAR269A).

 Caribou Biosciences’ CB-010, an anti-CD19 therapy for R/R B-cell NHL, is slated to launch the phase 1 ANTLER trial soon.

Off-the-shelf CAR therapies will eventually coexist with the personalized autologous therapies, predicted Jason Bock, PhD, vice president of the Therapeutics Discovery division and head of biologics product development at The University of Texas MD Anderson Cancer Center in Houston. “It will be dramatically more accessible, dramatically less costly, and probably a little bit less 

efficacious. There will be a lot of investment in technology to figure out how to try to bridge that gap. What you’ll lose in terms of pure potency, you’ll probably gain in terms of consistency,” he said.

Bock and others said they look forward to someday seeing CARs for solid tumors, but investigators face several biological hurdles, and marketable products are at least 5 years away. However, other types of adoptive cell therapies for solid tumors will likely become available much sooner. Iovance Biotherapeutics expects to file an application during 2021 for lifileucel, a TIL therapy for metastatic melanoma that is also being studied in cervical cancer.

As development of CARs and related therapies has mushroomed, research and manufacturing have moved from a small number of academic-industry partnerships into a variety of venues. Commercial T-cell products are manufactured at large pharmaceutical company hubs, and therapies for trials are being produced at those sites, at specialized contract labs, and at several major medical centers, such as Memorial Sloan Kettering, Dana-Farber Cancer Institute, MD Anderson, Stanford Medicine, and Moffitt Cancer Center.

Bock said MD Anderson recently added to its production capacity by purchasing a 60,000-square-ft cellular therapy manufacturing facility at Texas Medical Center in Houston. It will allow the organization to move therapies from the lab to the clinic quickly while assuring full access to data and firm control of the manufacturing process, which can significantly affect the quality of the product, he said.

“We wanted to be able to produce the product in such a way that if we had breakthrough products, and we didn’t have time to tech-transfer to a commercial facility, we wouldn’t have a delay in getting that product to patients. This facility can act as a launch facility,” Bock said in an interview. The facility could also potentially supply some niche products on an ongoing basis, such as a future cellular therapy for a rare tumor, he added.

Some physicians and patient advocates have argued that CAR T-cell products should be made at medical centers across the country rather than by industry because the centers can deliver the cells more quickly to their critically ill patients and at lower cost.19 Bock said he does not expect that to happen because of the complexity and tight federal regulation of cellular manufacturing processes. MD Anderson’s new facility will not be used for long-term manufacturing of commercialized CAR products, which is better left to pharmaceutical companies that are experts in large-scale production, distribution, and marketing, he said.

However, Bock and others said they can envision a time when fully enclosed, automated “cell engineering in a box” systems are perfected and installed at medical centers, allowing point-of-care CAR T-cell production. Technicians would essentially insert patient cells, viral vectors, and other supplies in one end and wait for a bag of engineered cells to come out the other for infusion. Investigators have experimented with such systems, using the Miltenyi CliniMACS Prodigy device to produce CAR T-cells and treating patients with hematological malignancies.

Brentjens said there may not yet be enough published data to conclude that automated systems are feasible, and he does not know what training would be required of hospital staff. He also noted that the hospital would still have to purchase viral vectors from a pharmaceutical company to make the process work.

“It’s like cake mix. You can either buy a fully made cake, or in that paradigm you’re buying the cake mix and you’re cooking up the cake yourself,” he said. “But obviously, the cake mix costs a lot less than the cake.”

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Articles

Hundreds of trials are under way, 3 CAR T-cell therapies for hematologic malignancies are on the market, and 2 new products may receive FDA approval in the next several months, including a BCMA–directed therapy that is poised to help transform treatment of multiple myeloma. 

CAR T-Cell Research Surges

Less than 3 years after the first checkpoint blockade immunotherapies were introduced for non—small cell lung cancer (NSCLC), the treatment paradigm is poised for dramatic changes in frontline care for patients with metastatic disease.

The FDA has granted priority reviews for 2 applications for first-line regimens for patients with metastatic nonsquamous disease: pembrolizumab (Keytruda) in combination with standard chemotherapy and atezolizumab (Tecentriq) plus bevacizumab (Avastin), carboplatin, and paclitaxel. Adding to the interest are recent study results for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with squamous or nonsquamous histology with high tumor mutational burden (TMB), an emerging biomarker.

The flurry of research developments is noteworthy even amid the rapid advancements in the lung cancer field that have occurred in less than a decade. The emerging combinations, if approved, would expand the use of the PD-1 immune checkpoint inhibitors pembrolizumab and nivolumab and the PD-L1 inhibitor atezolizumab, which already have lung cancer indications. Ipilimumab, which targets the CTLA-4 checkpoint, currently is approved only in melanoma settings.

Table. Key Findings in Frontline Lung Cancer Studies

The potential for expanding the use of these agents in NSCLC was showcased at this year’s American Association for Cancer Research (AACR) Annual Meeting in April (Table). Additional results for atezolizumab were reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in June. The study findings pave the way for greater opportunities to personalize care for patients, according to several experts who put the findings into perspective in interviews with 

In the KEYNOTE-189 trial, investigators found that pembrolizumab with pemetrexed (Alimta) and either cisplatin or carboplatin showed a much greater benefit than chemotherapy alone, reducing the risk of death by over 50% in patients with nonsquamous NSCLC without

At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1%-56.2%) in the control group (HR, 0.49; 95% CI, 0.38-0.64; 

The HR of 0.49, indicating the reduced risk of death in the pembrolizumab arm, is “absolutely astounding,” said Corey J. Langer, MD, director of thoracic oncology at the Hospital of the University of Pennsylvania Abramson Cancer Center in Philadelphia. In patients with a PD-L1 expression score of 50% or greater (% of tumor cells with membranous staining), the HR was even lower at 0.42. “In more than 30 years of being a clinical researcher I have never seen results like that in thoracic oncology. I’ve just never seen that profound a benefit, ever,” he said. “In my mind this really makes that triplet regimen, if not the standard care, certainly a strong standard care.”

Langer was the lead investigator on the KEYNOTE-021 cohort G trial, which showed significant increases in objective response rate (ORR) and progression-free survival (PFS) with the pembrolizumab triplet, and he said his practice has been using the treatment since it received FDA accelerated approval a year ago.

 The new results, which now form the basis of the application for permanent approval in this setting, cement the change and may compel skeptics to use the combination, he said.

Jessica R. Bauman, MD, a thoracic oncologist at Fox Chase Cancer Center in Philadelphia, said she held off changing her practice after the small KEYNOTE- 021 study (N = 123) came out but is now starting to administer the triplet therapy. She said KEYNOTE-189 (N = 616) shows there is “clear synergy” of immunotherapy with chemotherapy, with “vast improvement” at all endpoints including ORR and PFS, as well as benefit to patients in all PD-L1 expression level groups. She said physicians must now consider when to use the triplet for patients with high-PD-L1—expression and when to stick with pembrolizumab monotherapy. The latter which has been a standard frontline treatment for patients without 

 translocations since the KEYNOTE-024 trial results were published in 2016.

“Interestingly, the response rate in that earlier trial was about 45% for patients with 50% or greater PD-L1 expression, and the response rate in the current trial in that population was 61.4%. So it does raise the question, is the chemotherapy adding that much more benefit in this population in particular? It’s certainly adding at least a little bit more toxicity, considering single-agent pembrolizumab is so well tolerated. For that population specifically, we may still consider pembrolizumab alone. But more data will be helpful, as well as longer term follow-up,” Bauman said. It is hard to compare response rates across studies but the difference merits further investigation, she added.

Although the ORR for patients with high-PD-L1 expression differs between the 2 trials, the PFS rates were similar. In practice, the choice between pembrolizumab alone and the triplet will depend on patient preference and other factors, said Ticiana A. Leal, MD, a clinical assistant professor of medicine at the University of Wisconsin Carbone Cancer Center in Madison.

“For a patient with bulky disease who needs a more rapid response, you could consider using the triplet combination to get more tumor shrinkage, which potentially could provide them better symptom relief and disease control. Whereas perhaps with somebody who has cardiac or other important comorbidities, and who has more risk of [adverse] effects, including infection and neutropenia that are associated with chemotherapy, you might want to consider the pembrolizumab monotherapy,” Leal said. Patients who choose frontline monotherapy can still receive chemotherapy later if necessary, she said.

The triplet study excluded patients with 

mutations, for whom targeted therapy remains the standard of care. However, if a patient with high PD-L1 expression has a high metastatic burden and is very symptomatic, Langer said he may give them pembrolizumab monotherapy or the triplet right away rather than waiting weeks for results of a next-generation sequencing panel for oncogenic drivers. “We’re sometimes caught in this dilemma: If someone’s 80% PD-L1, a former smoker, maybe not a heavy smoker, and there’s a chance they might be 

-positive, then do you wait or do you act? I don’t think we have good answers for that,” he said. Bauman said she has also seen patients who needed immediate treatment, but she noted that single-marker tests are available that provide 

A number of other trials exploring the use of pembrolizumab in lung cancer have been recently completed or are under way. The phase III KEYNOTE-042 trial found that single-agent treatment with the PD-1 inhibitor improved OS versus chemotherapy as a frontline treatment for patients with squamous or nonsquamous NSCLC and PD-L1 expression of 1% or greater.

At the AACR conference, Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, mentioned the current INSIGNA study of patients with 1% or greater PD-L1, which includes 3 arms: pembrolizumab triplet induction followed by pembrolizumab-pemetrexed maintenance, pembrolizumab monotherapy as first-line therapy followed by second-line treatment with the triplet, and pembrolizumab monotherapy s first-line therapy followed by second-line treatment with pemetrexed-carboplatin.

“Trials like this are what we need. We now need to use trials to figure out how to bring this into practice with biomarker results,” Herbst said. He noted researchers must focus on combining pembrolizumab with antiangiogenic agents and other drugs, resistance, and using the PD-1 inhibitor as adjuvant and neoadjuvant therapy in squamous cancer, small cell lung cancer, and in oncogene-driven tumors. “We’re doing well, and we can do even better if we personalize this therapy,” Herbst said.

The latest first-line atezolizumab findings show survival improvements across a broad range of subgroups. In the IMpower150 study, investigators are evaluating the addition of atezolizumab to chemotherapy and bevacizumab in patients with chemotherapy-naïve advanced nonsquamous NSCLC. The chemotherapy doublet used in the study, carboplatin and paclitaxel, already is approved in combination with bevacizumab, which attacks angiogenesis by inhibiting VEGF, for the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC.

Findings from the study showed that the 4-drug regimen resulted in a significant OS improvement for patients in the intention-to-treat (ITT) population with wild-type tumors (n = 696), the coprimary endpoint of the study.6 Patients who received the atezolizumab-containing combination had a median OS of 19.2 months compared with 14.7 months with bevacizumab and chemotherapy (HR, 0.78; 95% CI, 0.64, 0.96; 

Additionally, the median OS benefit for the atezolizumab regimen compared with chemotherapy plus bevacizumab translated across key subgroups: 

translocations (not reached vs 17.7 months; HR, 054); liver metastases at baseline (13.2 vs 9.1 months; HR, 0.54); PD-L1—high expression (22.5 vs 16.4 months; HR.,0.77); and high expression of a T-effector gene signature (25.0 vs 16.7 months; HR, 0.83).

The survival findings, reported at ASCO, are the latest positive results that have been released for IMpower150. Previously released data indicate that the atezolizumab-containing regimen translated to a 38% reduction in the risk of progression or death (HR, 0.62; 95% CI, 0.52-0.74; 

“These data suggest that atezolizumab plus bevacizumab plus chemotherapy provides a new treatment option for these key patient populations,” study coauthor Mark A. Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando, said in discussing the findings at AACR.

IMpower150 is the only first-line trial that has recruited 

-positive patients, Socinski said in an interview with

. Of the 800 patients in the ITT population, 108 had a sensitizing 

 translocation (14%). “It was the first time that we saw the impact of immunotherapy in this population,” he said. “Historically, these are populations that, at least with immuno-monotherapy, there’s really not been a suggestion of great benefit in the 

Of note, patients with these aberrations who participated in IMpower150 had already “exhausted” tyrosine kinase inhibitor (TKI) therapy and were appropriate candidates for chemotherapy, Socinski said.

As far as the impact of the frontline study results presented at AACR are concerned, Socinski said there has been “more confusion than clarity.” For example, he said the patient populations in the KEYNOTE-189 and IMpower150 trials were different. To be eligible for IMpower150, patients had to be candidates for bevacizumab therapy, which excludes more than half of those who would have gone on the KEYNOTE-189 regimen.

Before the IMpower150 findings, patients who were eligible for bevacizumab therapy would have received that drug plus carboplatin and paclitaxel or pemetrexed. Those who were not bevacizumab candidates would have received carboplatin plus pemetrexed. In light of the new study results, Socinski said, the atezolizumab regimen for patients eligible for bevacizumab and the pembrolizumab combination for those who are not would be the paradigm to consider. Other experts noted the potential impact of IMpower150. “For folks with oncogenic drivers who are TKI refractory, that may be a very attractive go-to regimen,” Langer said. If the full study results bear out the favorable PFS data, they will drive more studies on incorporating immunotherapy in patients with actionable mutations in the resistance setting, Leal said.

Socinski said the combination’s efficacy apparently stems from the enhancement of atezolizumab’s T-cell—mediated tumor cell killing through bevacizumab’s reversal of VEGF-mediated immunosuppression.

Given its effectiveness against tumors with oncogenic drivers, researchers should continue studying how the combination functions and how it may be further refined, Leal said. “What really is driving that benefit? It seems to be the interaction between bevacizumab and atezolizumab. So how much is chemotherapy adding, if that’s correct? Those are things that are going to be important to investigate in future trials,” she said.

One concern that may limit the combination’s uptake, if it is approved, is that it includes 4 drugs—atezolizumab, bevacizumab, carboplatin, and paclitaxel&mdash;of which 2 are still under patent. “When you do quadruple therapy as opposed to double or triple, you are absolutely increasing costs associated with them dramatically. We have to consider cost against the real benefits and how we are doing in term of the quality of life of patients. Is it in fact really improving their day-to-day lives, which ultimately becomes one of the most important endpoints?” Bauman asked.

The combination of 2 immunotherapies, nivolumab and ipilimumab, also offered intriguing results. The regimen more than tripled the 1-year PFS rate versus chemotherapy for treatment-naïve patients with NSCLC with high TMB.

 The 1-year PFS rate was 42.6% for patients with high TMB (≥10 mutations/megabase) assigned to the immunotherapy combination compared with 13.2% for those assigned to platinum-doublet chemotherapy. The median PFS was 7.2 versus 5.5 months, respectively, representing a 42% reduction in risk of disease progression or death (HR, 0.58; 97.5% CI, 0.41-0.81; 

The combination’s prospects remain unclear pending release of survival data and of results for the overall CheckMate-227 study, but the data on the TMB subpopulation have stimulated debate over the biomarker and its utility in guiding immunotherapy treatment. Bauman said it was striking that TMB was predictive of response to nivolumabipilimumab irrespective of PD-L1 status.

“Until now we’ve really been looking to PD-L1, but we know that PD-L1 is an imperfect test. We all have patients who have PD-L1 zero who respond well to immunotherapy and people who have PD-L1 positivity who don’t respond,” she said. “Tumor mutation burden is a new, very different biomarker. It’s showing us another population of patients with lung cancer who may have an individual therapy that might be better for them than standard chemotherapy.”

Langer said he expected TMB will become an increasingly important marker as it is tested in more immunotherapy combinations, particularly if liquid biopsy assays for TMB become available in the next several years.

However, TMB testing also faces skepticism, at least in its current form. David Rimm, MD, PhD, a professor of pathology at Yale University School of Medicine, said TMB testing costs 5 to 10 times as much as immunohistochemistry and requires 10 times as much tissue as a PD-L1 assay.

It is not standardized and perhaps not standardizable, Rimm said. CheckMate-227 used 2 cutpoints, 10 mutations and 13 mutations per megabase, and labs use different assays to determine TMB. He also questioned the marker’s predictive power, pointing out that the CheckMate-026 study found improved PFS from nivolumab compared with chemotherapy but no OS benefit among high-TMB patients.

“I’d like to raise the possibility that what we’re seeing is going to be seen in many studies as we let overall survival [data] mature,” Rimm said at the AACR conference. “When you have a tumor with a lot of mutational skill, that has a high tumor mutation burden, that tumor can also mutate further to avoid immune therapy or become mutant and thus further become resistant to immune therapy. Is TMB ready for prime time? I don’t believe so. I think it’s not ready yet for use for patient care.”

Langer and others were also cautious about using the nivolumab-ipilimumab combination, due largely to the toxicity profile of the CTLA-4 inhibitor. Langer said he dug into the supplementary data tables for CheckMate-227 and saw noticeably higher incidences of adverse events (AEs) in the TMB group than in the overall study population. In the overall study population, the incidence of serious grade 3/4 treatment-related AEs in the combination arm was 17.7% with ipilimumab compared with 10.7% with chemotherapy.9 The discontinuation rates due to any grade AE were 17.4% and 8.9% in the combination and chemotherapy groups, respectively.

“This combo is not as easy as people would assume it might be,” he said. “I’d rather deal with the toxicity of pemetrexed-carboplatin over the toxicity of ipilimumab-nivolumab. Once it does get an approval, I’m not sure the uptake’s going to be that brisk.”

Langer said nivolumab-ipilimumab could be useful for patients who categorically refuse chemotherapy or those with zero PD-L1 expression and high TMB. Leal noted that the combination improved PFS across NSCLC histologic subtypes with high TMB and said it could help patients with squamous cell cancer, a group that has not yet benefited from immunotherapy combinations.

Although much more research lies ahead, Langer described himself as not only “bedazzled” by findings from KEYNOTE-189 and other trials but also astounded by the broader advance of immunotherapy from the second line to primary therapy. “A lot of my colleagues said, ‘Well, it will be hard to see a benefit in the frontline,’ but we have a bunch of positive trials now,” he said. “Can you remember a time when we saw so many positive trials in advanced lung cancer?”

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT075. abstractsonline.com/pp8/#!/4562/presentation/11129.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer [published online April 16, 2018].

Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 Investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. 

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Keytruda (pembrolizumab) monotherapy met primary endpoint in phase 3 KEYNOTE-042 study, significantly improving OS as first-line therapy in locally advanced or metastatic NSCLC patients expressing PD-L1 in at least 1 percent of tumor cells [news release]. Kenilworth, NJ: Merck; April 8, 2018. investors.merck.com/news/press-release-details/2018/KEYTRUDA-pembrolizumab-Monotherapy-Met-Primary-Endpoint-in-Phase-3-KEYNOTE-042-Study-Significantly-Improving-OS-as-First-Line-Therapy-in-Locally-Advanced-or-Metastatic-NSCLC-Patients-Expressing-PD-L1-in-at-Least-1-Percent-of-Tumor-Cells/default.aspx. Accessed May 7, 2018.

Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 9002. meetinglibrary.asco.org/record/160275/abstract.

Kowanetz M, Socinski MA, Zou W, et al. IMpower150: Efficacy of atezolizumab plus bevacizumab and chemotherapy in 1L metastatic nonsquamous NSCLC across key subgroups. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT076. abstractsonline.com/pp8/#!/4562/presentation/11130.

Hellmann MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT077. abstractsonline.com/pp8/#!/4562/presentation/11132.

Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018]. 

Carbone DP, Reck M, Paz-Ares L, et al; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non—small-cell lung cancer.

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Novel combination regimens anchored by pembrolizumab (Keytruda), atezolizumab (Tecentriq), or nivolumab (Opdivo) are opening the door to new options and an opportunity to personalize therapy in non–small cell lung cancer.

Meir Rinde

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