Expanded Targets, Synergistic Regimens Are Needed to Propel NSCLC Beyond Anti–PD-1 Therapy

Although the addition of novel TIGIT inhibitors, anti-LAG3 agents, and bispecific antibodies to PD-1 inhibitors has yielded incremental benefits for select patients with non–small cell lung cancer (NSCLC), identifying additional biomarkers and developing more synergistic combinations will be crucial to move beyond the gold standard of anti–PD-1 inhibition into the next phase of immunotherapy, according to Melissa L. Johnson, MD.1

“I'd say we're stuck firmly in the middle of [asking] ‘what else can I add to PD-1 [inhibition]?’ And I worry that some of our current strategies may do [nothing except] improve upon the benefit that our long-term responders are currently enjoying, rather than improving outcomes for patients with a higher need,” Johnson said in a presentation delivered during the 22nd Annual Winter Lung Cancer Conference, an event held by Physicians’ Education Resource, LCC.

In her presentation, Johnson discussed future of immunotherapy in lung cancer, highlighting key trials establishing the efficacy of anti–PD-1 therapies and influence of PD-L1 expression levels on patient outcomes; research with emerging targets for checkpoint inhibition beyond PD-1; and the wide array of emerging therapeutics in the NSCLC and small cell lung cancer (SCLC) field.

Johnson is the director of lung cancer research at Sarah Cannon Research Institute and chair of the Cancer Committee at TriStar Centennial Medical Center, both in Nashville, Tennessee.

Anti–PD-1 Therapy Reigns Supreme in First-Line NSCLC

Johnson started by reflecting that over the past decade, the field of NSCLC has been profoundly shaped by the advent of immunotherapy The standard approach to treatment selection in newly diagnosed NSCLC involves next-generation sequencing (NGS), which is used to rule out oncogenic drivers, and immunohistochemistry (IHC) to elucidate PD-L1 expression, she explained. PD-L1 testing, despite its limitations as an imperfect biomarker, remains the most utilized clinical biomarker for therapeutic selection in the majority of cases.

Findings from the pivotal phase 3 KEYNOTE-24 trial (NCT02142738) published in the New England Journal of Medicine in October 2016 established pembrolizumab (Keytruda) as the gold standard for patients with PD-L1 expression of at least 50%. The study demonstrated improved overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) vs chemotherapy in patients with PD-L1–positive locally advanced/metastatic NSCLC. After 5 years of follow-up, 5-year OS rates ranged from 16.6% to 21.9% with pembrolizumab vs 8.5% to 10.1% with chemotherapy.2 Moreover, higher PD-L1 tumor proportion score (TPS) was associated with greater benefit with pembrolizumab, with estimated 5-year OS rates being two-fold higher than that of the chemotherapy group.

The role of pembrolizumab in the first line was further solidified with the phase 3 KEYNOTE-42 trial (NCT02220894) evaluating pembrolizumab monotherapy in patients with PD-L1 expression of 1% or greater.1 The study revealed a gradient of benefit where higher PD-L1 expression correlated with superior outcomes. The phase 3 EMPOWER-Lung 1 study (NCT03088540) further expanded the scope of PD-1 inhibition, demonstrating greater PFS and OS benefits with single-agent cemiplimab-rwlc (Libtayo) vs chemotherapy among patients with PD-L1 expression of 90% or greater.

The role of PD-L1 also extends to chemoimmunotherapy combinations. Five-year outcomes from both Cohort G of the phase 3 KEYNOTE-021 (NCT02039674) study and the phase 3 KEYNOTE-189 trial (NCT02578680) showed higher OS rates with first-line pembrolizumab plus pemetrexed/carboplatin, prompting discussions about potential synergy between chemotherapy-induced tumor antigen release and immune activation with checkpoint inhibition, Johnson noted.

“Combination chemoimmunotherapy has captured our imagination somewhat,” she explained. “But if we're honest, the combinations of these therapies resulted in additive benefits, rather than synergistic ones.”

More is More: The Current Arsenal of PD-L1/CTLA-4 Regimens

The PD-1 era has been characterized by a principle of escalation, Johnson stated. This concept has driven exploration into triplet regimens incorporating PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, and chemotherapy. Long-term data from the phase 3 CheckMate 9LA trial (NCT03215706) showed a durable OS benefit and improved 5-year survivorship with nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) plus 2 cycles of chemotherapy vs chemotherapy alone, regardless of PD-L1 expression or histology. This supported the addition of CTLA-4 blockade to PD-1 inhibition, particularly for patients with low or absent PD-L1 expression and those with squamous histology, Johnson said.

Similarly, the phase 3 POSEIDON trial (NCT03164616) evaluated a limited course of CTLA-4 inhibition with tremelimumab (Imjudo) plus durvalumab (Imfinzi) and chemotherapy. Results indicated that the addition of CTLA-4 inhibition improved PFS and OS vs chemotherapy alone, particularly in patients with low PD-L1 expression. Notably, a trend favoring the triplet was observed in subgroups with historically poor prognoses, including those harboring KRAS, STK11, and KEAP1 mutations, Johnson said.1

Although PD-1 inhibition is considered a universal component of treatment for patients with advanced NSCLC, significant unanswered questions remain.

“We have a variety of PD-1–containing options,” Johnson said. “Still, as we sit across from a patient in an examining room with a PD-L1 score in hand, there's a lot that we don't know. Among patients with PD-L1–high tumors, who needs more than PD-1 monotherapy? Who's destined to experience immune-related adverse effects [AEs] and therefore should get a shorter course of PD-1? And for whom is it safe to add CTLA-4 [inhibition]? Are there even patients who shouldn't get PD-1 in the first line, who could be better served having something else added to their platinum chemotherapy?”

These uncertainties have set the stage for the next era in NSCLC treatment, Johnson concluded.

Targets in NSCLC Beyond PD-1/PD-L1

Anti-TIGIT Agents

Efforts to enhance the efficacy of PD-1/PD-L1 inhibition have explored the addition of novel checkpoint inhibitors, with the rationale that dual checkpoint blockade could yield superior outcomes. However, this strategy has proven more challenging than anticipated.

Building on prior results from the phase 2 CITYSCAPE trial (NCT03563716), which showed an initial improvement in ORR and PFS with the anti-TIGIT antibody tiragolumab in combination with atezolizumab (Tecentriq) in treatment-naive patients with stage IV NSCLC, the phase 3 SKYSCRAPER program was initiated. This program included the phase 3 SKYSCRAPER-01 trial (NCT04294810) in NSCLC and SKYSCRAPER-02 study (NCT04256421) in extensive-stage SCLC (ES-SCLC).

Final results from SKYSCRAPER-01 failed to confirm a trend toward favorable OS in a second interim analysis, which showed that the combination produced an estimated median OS of 22.9 months (95% CI, 17.5–not evaluable) vs 16.7 months (95% CI, 14.6-20.2) with atezolizumab alone (HR, 0.81; 95% CI, 0.63-1.03).3,4

The anti-TIGIT antibody vibostolimab, coformulated with pembrolizumab, was also evaluated in several phase 3 trials, including the KEYVIBE-008 study (NCT05224141) in ES-SCLC. Interim data presented at the 2024 SITC Annual Meeting showed that the regimen plus etoposide and platinum produced a median OS of 11.5 months (95% CI, 9.8-12.6) vs 12.9 months (95% CI, 11.6-14.8) with atezolizumab plus chemotherapy (HR, 1.26; 95% CI, 1.00-1.59; P = .9762).5 The median PFS was 5.3 months (95% CI, 4.4-5.4) vs 4.5 months (95% CI, 4.4-5.3), respectively (HR, 1.01; 95% CI, 0.82-1.23). Due to the unfavorable benefit/risk profile, the trial and Merck’s vibostolimab program were discontinued, Johnson noted.

Despite these setbacks, trials evaluating anti-TIGIT agents are ongoing. Data from the phase 2 GALAXIES Lung-201 study (NCT05565378) evaluating belrestotug plus dostarlimab-gxly (Jemperli) in unresectable, locally advanced NSCLC showed a clinically meaningful improvement in ORR across dose levels (63.3%, Dose A; 65.6%, Dose B; 76.7%, Dose C) vs dostarlimab alone (37.5%).6 Additionally, part 1 of the phase 2 ARC-10 study (NCT04736173) demonstrated a 36% reduction in risk of death (HR, 0.64) with domvanalimab plus zimberelimab in first-line inoperable stage IIIB to IV NSCLC.7

“With so much work being done to elucidate TIGIT’s mechanism and so many phase 2 trials that have been recently reported, maybe it's a little soon to throw in that towel just yet,” Johnson added.1 “Yet, if we're honest, there was only meager monotherapy activity [with anti-TIGIT agents] in phase 1, and really we don't have a biomarker. [Only time will tell if] we can possibly identify the patients in whom the TIGIT/PD-1 combo might really change outcomes, or if it is just a sidecar for the real vehicle, PD-1.”

Anti-LAG3 Agents

Targeting LAG3 in combination with PD-1 inhibition has been a different story. Findings from the phase 2 RELATIVITY-104 study (NCT04623775), presented at the 2024 ESMO Congress, demonstrated that adding the LAG-3 inhibitor relatlimab to nivolumab (Opdualag) plus platinum-doublet chemotherapy provided a modest clinical benefit vs nivolumab plus chemotherapy alone in stage IV or recurrent NSCLC with a PD-L1 expression of at least 1%.

The combination achieved a median PFS of 6.7 months (90% CI, 5.6-8.4) vs 6.0 months (90% CI, 5.5-6.9) for nivolumab plus chemotherapy (HR, 0.88; 90% CI, 0.71-1.11). Additionally, the ORR was 51.3% in the relatlimab arm vs 43.7% in the nivolumab-only arm.

These findings supported the initiation of the phase 3 RELATIVITY-1093 study (NCT06561386), an open-label, randomized trial comparing nivolumab plus relatlimab and platinum-doublet chemotherapy against the current standard-of-care regimen of pembrolizumab plus chemotherapy in the first-line treatment of patients with metastatic NSCLC, a PD-L1 expression between 1% and 49%, and nonsquamous histology.8

Bispecific Antibodies

Dual blockade of PD-1 and VEGF pathways with ivonescimab may offer an advantage over PD-1 inhibition alone by simultaneously enhancing immune activation and targeting tumor angiogenesis.1

Findings from the phase 3 HARMONi-2 trial (AK112-303; NCT05499390) presented at the 2024 IASLC World Conference on Lung Cancer showed a significant improvement in PFS among Chinese patients with PD-L1–positive advanced NSCLC treated with ivonescimab compared with pembrolizumab. At a median follow-up of 8.67 months, the median PFS was 11.14 months (95% CI, 7.33-not estimable) with ivonescimab (n = 198) vs 5.82 months (95% CI, 5.03-8.21) with pembrolizumab (n = 200; stratified HR, 0.51; 95% CI, 0.38-0.69; P < .0001). The 9-month PFS rates were 56% (95% CI, 47%-64%) with ivonescimab and 40% (95% CI, 32%-48%) with pembrolizumab.9

These findings provided the rationale for two additional phase 3 trials evaluating ivonescimab plus chemotherapy in the United States: HARMONi-3 (NCT06767514), which is assessing the agent in the first-line treatment of metastatic squamous NSCLC; and HARMONi-7 (NCT06767514), which is evaluating ivonescimab in first-line PD-L1–high NSCLC.

Other bispecific antibodies advancing in clinical development include the dual PD-L1/TIGIT inhibitor rilvegostomig and the dual PD-L1/CTLA-4–targeted agent volrustomig (MEDI5752).

According to data from the phase 1/2 ARTEMIDE-01 trial (NCT04995523), rilvegostomig generated ORRs of 29% (95% CI, 14.2%-48.0) and 61.8% (95% CI, 43.6%-77.8%) among patients with checkpoint inhibitor-naive metastatic NSCLC and a PD-L1 TPS between 1% to 49%; or at least 50%, respectively.11

Ongoing phase 3 studies of the agent include the phase 3 TROPION-Lung10 study (NCT06357533) alongside datopotamab deruxtecan in first-line advanced nonsquamous NSCLC with a PD-L1 TPC of 50% or greater; ARTEMIDE-Lung02 (NCT06692738) evaluating rilvegostomig vs pembrolizumab plus chemotherapy in stage IV NSCLC with squamous histology; ARTEMIDE-Lung03 (NCT06627647) evaluating the same regimens in nonsquamous stage IV NSCLC; and ARTEMIDE-Lung04 evaluating these regimens in nonsquamous stage IV NSCLC with a PD-L1 expression of 50% or greater.1

Updated data from a phase 1b trial (NCT03530397) evaluating volrustomig plus platinum-doublet chemotherapy in first-line advanced NSCLC showed demonstrated robust T-cell proliferation and clonal expansion, exceeding that observed with co-administered anti–PD-L1 and anti–CTLA-4 agents.11 The ORR across all tested doses was 19.8%, including 1 complete and 16 partial responses, and the median duration of response (DOR) of 17.5 months. Molecular responses, defined as a 50% or greater reduction in circulating tumor DNA, were observed in 36.5% of patients.

These findings supported the development of the phase 3 eVOLVE-Lung02 trial (NCT05984277), which will evaluate volrustomig plus chemotherapy in approximately 900 patients with squamous or nonsquamous stage IV NSCLC and PD-L1 expression less than 50%.1

Bispecific T-Cell Engagers

In May of 2024, the FDA granted accelerated approval of tarlatamab-dlle (Imdelltra) in previously treated SCLC with disease progression on or after chemotherapy based on results from the phase 2 DeLLphi-301 study (NCT05060016).12 At a median follow-up of 16.6 months, patients treated with the 10 mg dose of tarlatamab (n = 100) in the dose-evaluation and -expansion portions of the study achieved an ORR of 40% (95% CI, 30.3%-50.3%) and median DOR was 9.7 months (range 2.7 to 20.7+).

“The impressive part about these data is how well tolerated this drug is in my experience, and the durable nature of the responses,” Johnson said. “We can give tarlatamab with a PD-1 inhibitor if we really wanted to, but maybe we don't have to.”

Johnson continued by stating that this agent may also have efficacy when administered in combination with the investigational B7-H3–directed antibody-drug conjugate (ADC), infinatamab deruxtecan. In an interim analysis of the phase 2 IDeate-Lung01 trial (NCT05280470) presented during the 2024 IASLC World Conference on Lung Cancer, patients with pretreated ES-SCLC who received the 12 mg/kg dose of infinatamab deruxtecan (n = 42) had an ORR of 54.8% (95% CI, 38.7%-70.2%) and a disease control rate of 90.5% (95% CI, 77.4%-97.3%).13

"I bring up this trial and this collaboration because it gives me a lot of hope. First of all, this is the first time that I have seen a novel combination being evaluated in trials that are rapidly becoming available to more and more patients…this shows us how we might start to innovate in new ways. It requires breaking down barriers that are uncomfortable and starting to figure out how to work together in innovative ways,” Johnson emphasized.

References

1. Johnson M. Future of immunotherapy in lung cancer: What’s next? Presented at: 22nd Annual Winter Lung Cancer Conference; January 31-February 2, 2025; Hollywood, FL. Accessed February 1, 2025.
2. de Castro G Jr, Kudaba I, Wu YL, et al. Five-year outcomes with pembrolizumab versus chemotherapy as first-Line therapy in patients with non-small-cell lung cancer and programmed death ligand-1 tumor proportion score ≥ 1% in the KEYNOTE-042 study. J Clin Oncol. 2023;41(11):1986-1991. doi:10.1200/JCO.21.02885
3. Roche reports update on phase III SKYSCRAPER-01 study results. News release. Roche. November 26, 2024. Accessed February 1, 2025. https://www.roche.com/media/releases/med-cor-2024-11-26
4. [Ad hoc announcement pursuant to Art. 53 LR] Roche provides update on phase III Skyscraper-01 study in PD-L1-high metastatic non-small cell lung cancer. News release. Roche. August 23, 2023. Accessed February 1, 2025. roche.com/media/releases/med-cor-2023-08-23
5. Sands J, Lu S, Aerts JG, et al. Coformulated vibostolimab/pembrolizumab plus chemotherapy as first-line therapy vs atezolizumab plus chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC): randomized, phase 3 KEYVIBE-008 trial. JTC. 2024;12:doi: 10.1136/jitc-2024-SITC2024.1463
6. iTeos announces clinically meaningful objective response rate observed at every dose in follow-up interim analysis of GALAXIES Lung-201 study of belrestotug + dostarlimab in first-line, PD-L1 high non-small cell lung cancer patients. iTeos. News Release. September 14, 2024. Accessed February 1, 2025. https://investors.iteostherapeutics.com/news-releases/news-release-details/iteos-announces-clinically-meaningful-objective-response-rate
7. Arcus Biosciences announces that domvanalimab plus zimberelimab improved overall survival in ARC-10, a randomized study in patients with PD-L1-high non-small cell lung cancer.Arcus.News Release. November 5, 2024. Accessed February 1, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Arcus-Biosciences-Announces-that-Domvanalimab-Plus-Zimberelimab-Improved-Overall-Survival-in-ARC-10-a-Randomized-Study-in-Patients-with-PD-L1-High-Non-Small-Cell-Lung-Cancer/default.aspx
8. A study to compare the efficacy of nivolumab and relatlimab plus chemotherapy vs pembrolizumab plus chemotherapy for stage IV/​recurrent non-squamous non-small cell lung cancer with PD-L1 expression ≥ 1% (RELATIVITY1093). Clinicaltrials.gov. Updated January 29, 2025. Accessed February 1, 2025. https://clinicaltrials.gov/study/NCT06561386
9. Zhou C, Chen J, Wu L, et al. Phase 3 study of ivonescimab (AK112) vs. pembrolizumab as first-line treatment for PD-L1-positive advanced NSCLC: HARMONi-2. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract PL02.04.
10. Hiltermann J, Izumi H, Cho BC, et al. Efficacy and safety of rilvegostomig, an anti-PD-1/TIGIT bispecific, for CPI-naïve metastatic NSCLC with PD-L1 1-49% or ≥50%. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract OA11.03.
11. Volrustomig + platinum doublet chemotherapy (CTx) in first-line non-small cell lung cancer (NSCLC): Phase 1b trial update. J. Thor Oncol. 2024; 19: doi: 10.1016/j.jtho.2024.09.062
12. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed February 1, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
13. Rudin C, Ahn, M, Johnson, M, et al. Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): interim analysis of IDeate-Lung01. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA04.03.