Emerging Therapies Expand Options in Lung Cancer

Benjamin P. Levy, MD

During the last 12 months, the treatment landscape for patients with non–small cell lung cancer (NSCLC) has expanded dramatically with FDA approvals of the first drugs directed at KRAS G12C and EGFR exon 20 mutations as well as continued progress in developing new therapies for subsets of patients with other molecularly targetable alterations and with PD-L1–high disease (TABLE).¹

New findings that shed light on the optimal use of liquid biopsies also are among the exciting advancements for patients with lung cancer, according to Benjamin P. Levy, MD. Levy, whose research has contributed to new therapeutic strategies for patients with thoracic malignancies, is clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC. He is also an associate professor of oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland.

In November, Levy will help elucidate the latest data in the lung cancer field during the 39th Annual CFS^®: Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow^®, which he cochairs for the sixth consecutive year. Physicians’ Education Resource^®, LLC (PER^®) is hosting the 3-day event (November 3-5) as a hybrid meeting featuring live, interactive presentations in New York, New York, along with a virtual option.

At CFS^®, leading experts will discuss practice-changing innovations in diagnosis, treatment, and supportive care that occurred over the past year across the spectrum of cancer types. The first day of the conference is devoted to hematologic malignancies, including acute leukemias, multiple myeloma, and myeloproliferative neoplasms. The second day includes sections on gynecologic and dermatologic malignancies as well as pan-tumor topics. The third day features tracts on lung; head, neck, and thyroid cancers; gastrointestinal; and genitourinary cancers.

As he prepares for the conference, Levy marvels at how rapidly therapies for patients with lung cancer have advanced since he first helped lead the annual meeting. “What I’ve seen is pretty remarkable in terms of the changes in the topics that have happened over the past 5 years,” Levy said in an interview with OncologyLive^®. “When I started, most of the talks were devoted to either chemotherapy or immunotherapy. The subject matter now has rapidly expanded to encompass all the new targeted therapies or immunotherapy combinations that are either under clinical investigation or FDA approved.”

Notably, topics will include a discussion of leveraging liquid biopsy into the diagnostic algorithm for lung cancer, an abiding subject of interest and research for Levy. With the utility of liquid biopsies now established for accurate genotyping of patients with lung cancer, new ways of using circulating tumor DNA (ctDNA) technology are being developed, he said.

“One is longitudinal assessment, looking at changes in ctDNA when patients are on a targeted therapy or immunotherapy as an early indicator of response or lack of response. The other strategy is looking in the minimal residual disease setting in patients who are cured and are being surveilled by scan. The question is, can you use ctDNA to detect recurrences earlier than a CT scan that then can inform treatment decisions? That’s really very, very exciting moving forward,” he said.

TABLE. A Year of FDA Approvals in Lung Cancer

A Focus on Precision Approaches

Of his many contributions to lung cancer research and oncology education, Levy is perhaps best known for his passion for biomarker testing and liquid biopsy in particular, as demonstrated by his enthusiasm for expanding the benefits of the assays for patients, colleagues say.

“He’s been an advocate for using ctDNA and blood-based platforms for quite some time. He was one of the early adopters of this technology and has contributed significantly through holding educational meetings and participating in studies. It ended up being an important component of what we do now. He gets a lot of credit for that,” said Hossein Borghaei, DO, MS, chief of the Division of Thoracic Medical Oncology and the Gloria and Edmund M. Dunn Chair in Thoracic Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Another focus of Levy’s work is the development and refinement of immunotherapy combinations for patients with EGFR-mutated NSCLC. He is serving as the Hopkins principal investigator on the phase 2 SAVANNAH trial (NCT03778229) evaluating the combination of savolitinib plus osimertinib (Tagrisso) in patients with EGFR-positive and MET-amplified locally advanced or metastatic advanced NSCLC following progression Hossein Borghaei, DO, MS on osimertinib.² Savolitinib is an investigational MET tyrosine kinase inhibitor (TKI), and osimertinib is a third-generation EGFR TKI. Levy’s research also includes studies of targeted drugs both for lung cancer and other malignancies such as thyroid cancer.

“He was instrumental in the development of some of our most active targeted agents, including the recent selective RET inhibitors. In general, he’s done a lot to develop the field of targeted therapy, and it goes everywhere from testing to treatment. I’m grateful we have him on our front lines getting our message across,” said Stephen V. Liu, MD, director of thoracic oncology and associate professor of medicine at Icahn School of Medicine at Mount Sinai and director of clinical research for the Multiple Myeloma Program at Mount Sinai School of Medicine, and Tiffany A. Traina, MD, a medical oncologist and vice chair of oncology care at Memorial Sloan Kettering Cancer Center (MSK), both in New York, New York.

In the lung cancer tract, Levy will share moderating duties with Alexander Drilon, MD, chief of the early drug development service at MSK. In addition to liquid biopsy, presentation topics will include therapies for emerging targets for aberrations including KRAS G12C and HER2 and the targeting of gene fusions in adenocarcinomas, namely involving ALK, ROS1, RET, and NTRK.

Experts will also review competing frontline immunotherapy strategies for patients with lung adenocarcinoma; evolving treatment strategies for EGFR-mutated lung cancer, including those with exon 20 aberrations; precision medicine uses in early-stage lung cancer; management of squamous cell lung cancer; novel therapeutic strategies for small cell lung cancer (SCLC); and updates in mesothelioma.

Sotorasib

Levy said participants will discuss new agents aimed at mutations that were previously considered undruggable or very difficult to target. One of them is sotorasib (Lumakras), the first treatment for adults with NSCLC whose tumors harbor KRAS G12C mutations. In May, the FDA granted an accelerated approval for sotorasib for patients with the mutation who have received at least 1 prior systemic therapy. The agency also approved the QIAGEN therascreen KRAS RGQ PCR kit tissue test and the Guardant360 CDx plasma assay as companion diagnostics for sotorasib, with the recommendation that tumor tissue be tested if no mutation is detected in a plasma specimen.³

The decision was based on findings from the CodeBreaK 100 trial (NCT03600883), which involved patients with locally advanced or metastatic NSCLC with KRAS G12C mutations.3 Efficacy was evaluated in 124 patients with disease that progressed on or after at least 1 prior systemic therapy. Patients received sotorasib 960 mg orally daily until disease progression or unacceptable toxicity.

The median age among all participants (N = 126) was 63.5 years (range, 37-80) and 117 patients (92.9%) were former or current smokers. In all, 72 (57.1%) had received 2 or 3 prior lines of anticancer therapy. Of the participants, 91.3% received anti–PD-1/PD-L1 immunotherapy and 81.0% received both platinum-based chemotherapy and anti–PD-1/ PD-L1 immunotherapy.

Median follow-up time was 15.3 months (range, 1.1-18.4+). There were 4 complete responses (CRs) and 42 partial responses (PRs), resulting in an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%). Among responders, the median duration of response (DOR) was 11.1 months (95% CI, 6.9-not estimable [NE]) and the median time to response was 1.4 months (range, 1.2-10.1). At the time of data cutoff on March 15, 16 (34.7%) patients who experienced a response were continuing therapy without disease progression. The median progression-free survival (PFS) among evaluable patients was 6.8 months (95% CI, 5.1-8.2).

Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients in the overall population and led to discontinuation in 9 (7.1%) patients. Grade 3 TRAEs were reported in 25 (19.8%) patients, and 1 (0.8%) patient had grade 4 TRAEs (dyspnea/pneumonitis). Grade 3 events included alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), and diarrhea (4.0%). No fatal TRAEs were reported.⁴

Amivantamab

In May, the FDA also granted an accelerated approval for amivantamab-vmjw (Rybrevant), a bispecific antibody directed against EGF and MET receptors, Levy noted. It was approved for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, with disease that has progressed on or after platinum-based chemotherapy.⁵ The agent is the first targeted therapy approved for exon 20 mutations, which are present in approximately 2% to 3% of patients with NSCLC. Guardant360 CDx was approved as a companion diagnostic for the drug.⁶

The decision was based on findings from an efficacy population of 81 patients treated with amivantamab after platinum-based chemotherapy during the phase 1 multicohort CHRYSALIS trial (NCT02609776). The median age of participants was 62 years (range, 42-84), the median prior lines of therapy was 2 (range, 1-7), and 53% were never smokers.

The ORR was 40% (95% CI, 29%-51%), including a CR rate of 3.7% and a PR rate of 36%. The median DOR was 11.1 months (95% CI, 6.9-NE) and 63% of patients had a response lasting 6 months or longer.⁵

All-grade adverse events (AEs) occurring in 10% or more of patients in the safety population (N = 129) included rash (84%), infusion-related reactions (IRRs; 64%), and paronychia (50%). Grade 3 or 4 AEs included rash (3.9%) and IRRs, paronychia, and diarrhea, each at 3.1%.

Trastuzumab deruxtecan

CFS® presenters also will discuss promising data for fam-trastuzumab deruxtecannxki (Enhertu), an antibody-drug conjugate (ADC) approved in HER2-positive breast cancer and gastric or gastroesophageal junction adenocarcinoma settings. In lung cancer, trastuzumab deruxtecan is being studied in the phase 2 DESTINYLung02 trial (NCT04644237) in patients with HER2-mutated metastatic NSCLC with disease recurrence or progression during or after at least 1 prior platinum-containing treatment regimen.⁷ The drug has a breakthrough therapy designation and could be approved later this year, Levy said.

Trastuzumab deruxtecan showed promising efficacy in interim findings from the phase 2 DESTINY-Lung01 study (NCT03505710) in patients with nonsquamous NSCLC that overexpresses HER2 or harbors a HER2 activating mutation. At a median treatment duration of 7.76 months (range, 0.7-14.3), the confirmed ORR by independent central review among 42 patients was 61.9% (95% CI, 45.6%-76.4%). At data cutoff, median DOR was not reached and 16 of 26 responders remained on treatment. The estimated median PFS was 14.0 months (95% CI, 6.4-14.0).

All patients had treatment-emergent adverse events (TEAEs); 64.3% were grade 3 or worse, including 52.4% that were deemed related to the drug. TEAEs included decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of grade 2 drug-related interstitial lung disease (ILD), with 1 case of grade 1 ILD pending adjudication. TEAEs led to dose interruption in 25 patients (59.5%), dose reductions in 16 (38.1%), and treatment discontinuation in 10 (23.8%).⁸

The data for these drugs are encouraging, Levy said. “Those are 3 exciting drugs that we have—2 now approved, 1 potentially approved—and the list keeps getting longer and longer,” he said.

More novel therapies for NSCLC

Although no ADCs are currently approved for lung cancer indications, clinical studies are advancing for several candidates besides trastuzumab deruxtecan, suggesting the potential for a new class of therapies. “These are, I think, really good efforts [for drugs] that we’re just beginning to learn about,” Levy said.

Levy is among the leading investigators evaluating datopotamab deruxtecan (DS-1062a) in patients with NSCLC as part of the phase 1 TROPION-PanTumor01 trial (NCT03401385). The novel ADC incorporates an antibody directed at TROP2. Also advancing is patritumab deruxtecan (U3-1402), an ADC directed at HER3 that is being tested in patients with metastatic or locally advanced EGFR-mutated NSCLC in the phase 2 HERTHENA-Lung01 study (NCT04619004).

Meanwhile, Levy also is pursuing studies of repotrectinib (TPX-0005), a next-generation TKI of ROS1 and TRK. He is serving as the Hopkins principal investigator on the phase 1/2 TRIDENT-1 study (NCT03093116) evaluating repotrectinib in patients with advanced NSCLC with ROS1 or NTRK1/2/3 gene rearrangements.

Activity in SCLC

At CFS^®, Liu is scheduled to discuss novel therapeutic strategies for SCLC. Since 2019, the FDA has approved combining chemotherapy with the PD-L1 inhibitors atezolizumab (Tecentriq) or durvalumab (Imfinzi) for the first-line treatment of patients with extensive-stage SCLC. Additionally, Levy noted the accelerated approval in June 2020 of lurbinectedin (Zepzelca), a chemotherapy agent, for treating adults with metastatic SCLC that has progressed after chemotherapy.⁹

Promising therapies in development include tarlatamab (AMG 757), a bispecific T-cell engager targeting DLL3 that is being tested as monotherapy and in combination with pembrolizumab (Keytruda) in a phase 1 trial (NCT03319940).

Understanding the Role of Immunotherapy

Earlier settings

Levy highlighted several other key areas of research that will be discussed during the CFS^® lung session, including efforts to take advantage of immunotherapy earlier in the treatment process.

“What has happened over the past, essentially 6 months, is that we’re starting to understand how to leverage immunotherapy for cure. We’re looking at immunotherapy potentially in the neoadjuvant space, prior to surgical resection, and then based on the most recent data that were presented at ASCO, looking at it in the adjuvant setting,” he said.

Findings from the phase 3 IMpower010 trial (NCT02486718) show that adjuvant treatment with atezolizumab led to a significant improvement in disease-free survival (DFS) vs best supportive care (BSC) in patients with resected stage II to IIIA NSCLC, particularly those with PD-L1–positive tumors.¹⁰

In patients with at least 1% PD-L1 expression, the median DFS was NE (95% CI, 36.1-NE) with atezolizumab (n = 248) vs 35.5 months (95% CI, 29.0-NE) for those who received BSC (n = 228), which translated into an HR of 0.66 (95% CI, 0.50-0.88; P = .004). The 2-year DFS rate was 74.6% with atezolizumab vs 61.0% with BSC. The 3-year DFS rates were 60.0% and 48.2%, respectively.

The benefit was less pronounced in all randomized patients with stage II to IIIA disease. The median DFS was 42.3 months (95% CI, 36-NE) among patients treated with atezolizumab (n = 442) vs 35.3 months (95% CI, 30.4-46.4) for those who received BSC (n = 440), which translated to an HR of 0.79 (95% CI, 0.64-0.96; P = .02). The 2-year DFS rate was 70.2% with atezolizumab vs 61.6% with BSC and the 3-year rates were 55.7% and 49.4%, respectively.

“I would be comfortable considering using that therapy,” Levy observed. “This is an unmet need. These patients have historically aggressive diseases and we need to do better.”

Liquid biopsy biomarkers

Levy noted that liquid biopsy is being studied as a way to measure response to immunotherapy. At CFS®, Charu Aggarwal, MD, MPH, will discuss her recent study that used serial monitoring of ctDNA by next-generation gene sequencing as a biomarker of response and survival in patients with advanced NSCLC receiving pembrolizumab-based therapy.¹¹ Aggarwal is the Leslye M. Heisler Associate Professor for Lung Cancer Excellence at Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

Aggarwal and colleagues found that molecular response values based on changes in ctDNA were significantly lower in patients with an objective radiologic response compared with nonresponders (log mean 1.25% vs 27.7%; P < .001). Patients achieving a durable clinical benefit had significantly lower molecular response values compared with patients with no durable benefit (log mean 3.5% vs 49.4%; P < .001). Molecular responders also had significantly longer PFS (HR, 0.25; 95% CI, 0.13-0.50) and overall survival (HR, 0.27; 95% CI, 0.12-0.64) compared with molecular nonresponders.

The results suggest that a reduction in ctDNA levels during treatment correlates with better outcomes and that assessments during therapy may yield a noninvasive method of predicting long-term efficacy of pembrolizumab therapy, investigators concluded.

“The big, broad question is: Are ctDNA changes more accurate or a more accurate surrogate for what a patient’s cancer is doing, vs a CT scan, which is a pretty rudimentary platform where you’re looking at a 2-dimensional thing,” Levy said. “It’s tough to know what’s going on, and maybe 50 DNA changes are a better indicator…We should be able to f ind out how to act on these changes.”

Levy is hoping to help advance the utility of liquid biopsies through a large phase 2 trial (NCT04410796) in which patients with metastatic EGFR-mutant NSCLC will receive first-line osimertinib therapy. Participants with persistent ctDNA detected in plasma samples will then be randomized to receive either osimertinib alone or with chemotherapy. MSK investigators are leading the study, which aims to recruit 571 patients throughout the United States.

Impact on mutations

Levy has made a number of contributions to the development of immunotherapies. He led or participated in several studies of checkpoint inhibitors, such as nivolumab (Opdivo) in refractory squamous NSCLC and durvalumab as third-line or later treatment for advanced NSCLC.^12,13

One outstanding question is how to use immunotherapy when treating patients with NSCLC with driver mutations, Levy said. “This field is sort of dichotomized into those patients who get targeted therapies and those who get immunotherapies. We’re still trying to understand how to leverage immunotherapy in the targeted therapy space,” he said.

Numerous studies are seeking to clarify immunotherapy’s role. Levy is on the steering committee for the phase 2 TH-138 study (NCT03786692) evaluating the addition of an immunotherapeutic agent to the combination of antiangiogenic therapy plus a platinum doublet. Investigators seek to recruit 117 patients who have stage IV nonsquamous NSCLC with tumors harboring an EGFR exon 19 or 21 mutation or who are never smokers with wild-type tumors.¹⁴

Patients with an EGFR mutation must have progression after receiving prior TKI therapy, and those with wild-type tumors must be treatment naïve. Participants will be randomized to receive carboplatin, pemetrexed (Alimta), and bevacizumab (Avastin) with or without atezolizumab.

The rationale for the study stems from prior trial findings suggesting such combinations may overcome resistance to PD-L1 inhibitors in these patients. Fox Chase Cancer Center and the National Comprehensive Cancer Network are sponsoring the study.¹⁴

“There are tremendous efforts going on across the country, looking at sorting out mechanisms of resistance and then determining what to do when you discover a mechanism of resistance,” Levy said.

For Levy, the pursuit of individualized therapies for patients with lung cancer is a mission that began during a hematology/ oncology fellowship at New York Weill Cornell Hospital in the mid-2000s. He started with a focus on prostate cancer research but shifted to lung cancer because at that time there were few options for patients.

“I had a real connection to potentially personalized medicine that was starting to take shape in lung cancer,” Levy said. “We had this single [target] with EGFR mutations potentially being druggable. Who would have thought in just a short time that there would be 10 more genes in non–small cell cancer that would be wedded to a targeted therapy?”

Importance of Addressing Resistance

As investigators continue to explore new therapies, the development of strategies for overcoming resistance has emerged as one of the most pressing needs in the field today, Levy said.

As investigators continue to explore new therapies, the development of strategies for overcoming resistance has emerged as one of the most pressing needs in the field today, Levy said.

He noted that similar questions to those being asked about immunotherapy apply to targeted therapies as well. Despite the substantial new benefits they have provided to patients with matching genotypes over the past several years, oncologists who treat patients with NSCLC still have much to learn about the best ways to use the agents and what to do when they stop working, Levy said.

“What do you do when resistance develops, what are those mechanisms of resistance, and how should we act on them? That’s a big question for targeted therapy. Are there optimal combination strategies with these newer targeted therapies such as bispecific antibodies or antibody drug conjugates? Should leverage these newer novel agents as standalone therapies? Or should we be adding other combination therapies like chemotherapy? That is clearly a real unmet need for patients with the right genotype,” he said.

References

1. Oncology (cancer)/hematologic malignancies approval notifications. FDA. Updated June 16, 2021. Accessed June 24, 2021. https://bit.ly/3dbnBKK 
2. Oxnard GR, Cantarini M, Frewer P, et al. SAVANNAH: a phase II trial of osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-driven (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC), following disease progression on osimertinib. J Clin Oncol. 2019;37(suppl 15):TPS9119. doi:10.1200/JCO.2019.37.15_suppl.TPS9119
3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. Updated May 28, 2021. Accessed June 22, 2021. https://bit.ly/3jdC7VY
4. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695
5. Rybrevant. Prescribing information. Janssen Biotech Inc; 2021. Accessed June 25, 2021. https://bit.ly/2T7L9t1 
6. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed June 25, 2021. https://bit.ly/3zW7oTe
7. DESTINY-Lung02 phase 2 trial of Enhertu initiated in patients with HER2 mutated metastatic non-small cell lung cancer. News release. Daiichi-Sankyo Company, Limited. March 29, 2021. Accessed June 22, 2021. https://bit.ly/3xRWbkW
8. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan in HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Thorac Oncol. 2021;16(suppl 173):MA11.03. doi:10.1016/j.jtho.2021.01.248
9. Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated December 18, 2020. Accessed June 25, 2021. https://bit.ly/2SqVZdc
10. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500
11. Thompson JC, Carpenter EL, Silva BA, et al. Serial monitoring of circulating tumor DNA by next-generation gene sequencing as a biomarker of response and survival in patients with advanced NSCLC receiving pembrolizumab-based therapy. JCO Precis Oncol. 2021;5:PO.20.00321. doi:10.1200/PO.20.00321
12. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-265. doi:10.1016/S1470-2045(15)70054-9
13. Garassino MC, Cho B-C, Kim J-H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 2018;19(4):521-536. doi:10.1016/S1470-2045(18)30144-X
14. Bodor JN, Patel JD, Ross EA, et al. Phase II randomized trial of carboplatin + pemetrexed + bevacizumab, +/- atezolizumab in stage IV non-squamous non-small lung cancer (NSCLC) patients who harbor a sensitizing EGFR mutation or have never smoked. J Clin Oncol. 2020;38(suppl 15):TPS9629. doi:10.1200/JCO.2020.38.15_suppl.TPS9629