Tackling Resistance Mechanisms Is the Next Step in Immunotherapy Development for NSCLC

Immunotherapy administered alone or in combination with chemotherapy has become the standard of care across advanced non–small cell lung cancer (NSCLC) in several settings, with continued effort devoted to further enhancing and improving upon these treatments, said Solange Peters, MD, PhD, at the 24th Annual International Lung Cancer Congress^®.¹

As part of improving responses, Peters identified 3 steps to overcoming resistance: first establishing a clinical definition, then pinpointing the exact mechanism, followed by finding treatment strategies to overcome the mechanism. This is urgently important, she noted, as many patients with NSCLC progress on immunotherapy, with 5-year progression-free survival rates hovering at approximately 7.5% to 10%.¹

“There is not a 1-factor credible explanation for resistance to immunotherapy. The regulation is accurate, dynamic, and multifaceted, and we need to keep that in mind,” said Peters, chair of medical oncology at the Lausanne University Hospital and Ludwig Institute in Switzerland. “We need to look at immuno-oncology resistance, especially in adjuvant therapy, because it is standard of care and advancement of that in NSCLC is how we will overcome the disease.”

Resistance Definition

Resistance to immunotherapy manifests in several distinct clinical scenarios, Peters noted. The first are those with an innate primary resistance, whose disease never responds and progresses rapidly. The second are those who may achieve stable disease (SD) or partial response (PR) but never a deep response. The final scenario is those who respond well and experience a durable benefit and progression-free interval followed by an oligoprogression or systemic progression.

Peters noted that efforts have been undertaken to better define resistance to immune checkpoint inhibitors, specifically by the Society for Immunotherapy of Cancer and the European Society for Medical Oncology.^2,3 In both cases, the approach has been broad, looking at various timelines and levels of response to monotherapy or combinations across various types of cancer.

“Having a definition across disease types is very courageous because melanoma is not lung cancer and lung cancer is not colorectal cancer. We need to have specific definition for each disease,” Peters said. “We still don’t have a homogenous definition to describe resistance. Every trial we have run so far has probably used a different definition of resistance.”

Resistance Mechanisms

Resistance mechanism can be defined as tumor intrinsic or extrinsic, Peters noted.¹ Chief among the tumor extrinsic factors are immune cell dysfunctions, immunosuppressive cells, and host factors, such as gender, germline, and microbiome. Additionally, for tumor intrinsic factors, this could include heterogeneity or immune evasion.

At the cellular level, there could be defects in the antigen presentation machinery at human leukocyte antigen (HLA) class I, which presents antigens to CD8 cells. “HLA genes are the most polymorphic genes in the human genome,” she said. Germline HLA class I divergence has been associated with response to immunotherapy, with those with high levels of HLA class I evolutionary divergence showing better responses.⁴ The more divergence the HLA class I genotype shows the more diverse the immunopeptidomes, Peters noted.

Other alterations to the antigen presentation mechanisms can include those at the proteasome subunits, mutations in the chaperone protein β-2-microglobulin, mutations in the major histocompatibility complex itself, upregulation of other classes of HLA, and HLA loss of heterozygosity. Additionally, high levels of mutations can result in excessive levels of heterogenous neoantigens, which prevents the immune system from targeting all tumor cells. Other common alterations resulting in resistance include those in the interferon gamma (IFNγ) pathway, specifically JAK1/2 alterations that regulate PD-L1 expression. Loss of STK11 and KEAP1 have also been associated with immune escape.¹

As these agents have been developed, early in the process it was found that oncogene-driven tumors do not respond as favorably to immunotherapy. Moreover, combination strategies that were attempted were found to be too toxic. “Specific TKIs cannot be given combined or right after IO [immune-oncology] because of toxicity, especially osimertinib,” Peters said.

Treatment Strategies

Several strategies are being explored to overcome common causes of resistance, typically looking at combination approaches of an immune checkpoint inhibitor with another agent meant to overcome the specific mechanism. Depending on the target, Peters noted, these combinations aim to enhance antigenicity, modulate the tumor microenvironment, enhance immune cell activity, or overcome resistance from other upregulated checkpoints, such as CTLA-4 plus PD-1 inhibition. These approaches can take many shapes, from the combination of 2 immunotherapies to the addition of radiotherapy to immunotherapy.

There are currently several immunotherapy doublet studies underway seeking to tackle mechanisms of resistance, Peters noted. These studies are similar in construct, looking at an established PD-1 or PD-L1 inhibitor combined with an agent specific to a resistance mechanism. The breadth of targets for the combination agent includes TIGIT, TGF-β, VEGF, IL-1β, PARP, c-MET, LAG-3, CTLA-4, TIM-3, and S-15. Additionally, agents to stimulate immune response are also being examined, including OX-40, CD40, ICOS, CD137, and GITR.¹

One of the primary targets in development to overcome resistance is LAG-3, Peters noted. There are currently more than 13 different LAG-3 inhibiting agents in development, some of which are bispecific to LAG-3 and PD-1/PD-L1 or CTLA-4. Another promising target is TIGIT, Peters noted, which has demonstrated some promising results in recent clinical trials. To illustrate the interest in TIGIT, Peters highlighted 13 phase 3 studies that are exploring anti-TIGIT therapy with checkpoint inhibitors across settings of PD-L1–positive, all comers, and in stage III unresectable NSCLC.

“TIGIT has efficacy,” she said. “Will it be enough to change the paradigm and the management and guidelines? This is too early to tell, and still ongoing in trials.”

Bispecific antibodies are also an emerging area of interest in lung cancer, with several agents in development. These agents are primarily specific to PD-1 plus another target associated with resistance, such as VEGF, TIGIT, and CLTA-4. Additionally, antibody-drug conjugates (ADC) hold the potential to overcome resistance, especially when the 2 strategies are combined into bispecific ADCs. “Right now, this is less about counteracting against resistance, and more about exploiting an anticancer strategy,” Peters said.

References

1. Peters S. ADCs: the mechanisms of resistance to immunotherapy and how to overcome them. Presented at: 24th Annual International Lung Cancer Congress; July 27-29, 2023; Huntington Beach, CA.
2. Kluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer. 2020;8:e000398. doi:10.1136/ jitc-2019-000398
3. Schoenfeld AJ, Antonia SJ, Away MM, et al. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer. Ann Oncol. 2021;32(12):1597-1607. doi:10.1016/j.annonc.2021.08.2151
4. Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nat Med. 2019;25(11):1715-1720. doi:10.1038/s41591-019-0639-4