Introduction
Despite significant treatment advances over the last two decades, lung cancer remains the leading cause of cancer mortality worldwide, accounting for one in five cancer deaths.[1] Non-small cell lung cancer (NSCLC) accounts for 80%–85% of all lung cancer diagnoses.[2] Recent developments in the use of immunotherapy in NSCLC (alone or in combination with chemotherapy) have significantly improved outcomes.[3,4]
While many people with NSCLC without identifiable oncogenic driver mutations have a significant unmet clinical need,[3] it is important to also acknowledge those with KRAS mutations. Given their overlap with CEACAM5 expression and their rapid progression, KRAS patients similarly have a pressing need for additional therapeutic options. Identification of novel tumour-specific biomarkers could facilitate the development of new targeted therapies that fill this gap.
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a highly expressed cell-surface protein in multiple solid tumour types.[5,6] In non-squamous NSCLC, CEACAM5 is highly expressed in approximately 25% of patients while being virtually undetectable in normal lung tissue.[7]
Given its differential expression, CEACAM5 is under investigation as a viable target for antibody drug conjugates (ADCs).[7]
Treatment strategies in non-small cell lung cancer (NSCLC)
Biomarker testing and its impact on therapeutic planning
Martin Dietrich (MD): Many first-line therapeutic options are available in NSCLC. How can molecular testing guide therapeutic decisions?
Keith Kerr (KK): Obtaining a molecular/biomarker profile for each patient at diagnosis is crucial for optimising treatment at first line and later.[8] Identifying oncogenic drivers enables clinicians to use targeted therapies that yield superior outcomes compared with standard chemotherapy or chemo-immunotherapy.[9] These form the default option if no targets are found.[10]
Numerous therapies are approved for NSCLC[11] but access varies by country and institution. Availability within your hospital's formulary is key to choosing tests; if you are limited to EGFR and ALK inhibitors and an immune checkpoint inhibitor, test accordingly. Additional testing can then identify other actionable targets.[12]
Commercial next-generation sequencing (NGS) panels generate numerous additional targets; some of these may guide patient selection for relevant clinical trials.[12]
MD: What challenges arise when attempting to obtain a broad biomarker profile prior to first line therapy?
Jyoti Patel (JP): The tiny tissue specimens generated by endobronchial ultrasound (EBUS) or interventional radiology (IR) biopsy can limit diagnostic testing, so it is important to practice good tissue stewardship. We prioritise diagnosis, restricting immunohistochemistry (IHC) to preserve tissue for biomarker assays, then select tests based on drug access, tissue quantity required, and tissue availability.
A comprehensive NGS panel based on RNA analysis is reflexively conducted on all samples in our institution. This assesses 500 genes and includes capture of genomic alterations across the genome. We have observed that internal testing at our institution conserves tissue more effectively than sending samples out to external laboratories and reduces time to treatment with more timely results.
When NSCLC patients progress, they frequently do so quickly, so any delay due to the need for retesting can have serious consequences. It can be problematic to get tissue back from another institution to retest, and re-biopsy can pose serious risks to the patient. Ideally, therefore, we need a multiplex biomarker package that could be deployed prior to first line to obtain all the information required to plan out first line, second line, and third line therapies for an individual patient.
MD: Do tumour biomarkers tend to be stable or are they more dynamic?
KK: In my opinion, most oncogenic drivers, be they fusion genes or mutations, tend to be truncal drivers of tumourigenesis that are present across the entire tumour cell population. While molecular alterations may evolve in other tumour genes as mechanisms of resistance, the primary truncal drivers are inherently stable.
Protein expression, however, is much more dynamic. Expression of PD-L1, for example, is an adaptive response to the tumour's interaction with the immune system.[13] Other proteins may also undergo upregulation or downregulation due to various factors, whether predictable (first-line therapy), or unpredictable (disease progression). This is an area that needs further investigation.
MD: How long does IHC assay validation take once a biomarker is adopted in clinical practice?
KK: Biomarker assay validation usually takes several months because of the work involved. Additionally, the process must compete with other laboratory priorities. We aim to anticipate biomarker approval, but financial and system constraints often limit pre-approval work, leading to delays. Once validated, continuous quality control of the assay is necessary in clinical practice.
MD: What are the relative merits of DNA vs RNA sequencing in NGS for NSCLC biomarkers?
KK: DNA sequencing is optimal for identifying gene mutations such as EGFR, KRAS, HER2, and BRAF. mRNA sequencing, transcribed into copy DNA, is void of interfering intron sequences that can affect tertiary structures and interfere with sequencing efforts. This makes it superior for detecting fusion products like ALK, ROS1, RET, or NTRK fusions, as well as post-transcriptional modifications like c-MET exon 14 skipping mutations.
MD: Can liquid biopsy complement tissue biopsy?
JP: Tissue testing remains the gold standard in NSCLC, but many institutions incorporate liquid biopsy to help overcome tissue scarcity and testing constraints.[14] This can be done sequentially, with blood testing performed only after tissue testing has proved non-diagnostic, or concurrently.[15] Results from tissue and blood biopsy show up to 80% concordance[15] and simultaneous blood and tissue testing complement each other to a more holistic biomarker profile, capturing tumour heterogeneity, and can frequently accelerate treatment selection if an actionable mutation is identified.[16]
Analysing results from liquid biopsy can be challenging; some patients are low- or non-shedders, lacking sufficient circulating tumour DNA for analysis. Oncogenic driver mutations at times may only be detected in either blood or tissue.[14] A positive detection in liquid biopsy has been shown to be equally actionable compared to tissue. Understanding the implications of both these scenarios is crucial for informed treatment decisions.
KK: Liquid biopsy is a powerful and important complementary tool in diagnostic profiling but, as a pathologist, I hesitate to bypass tissue biopsy if liquid biopsy results are informative. Histology and protein expression markers like PD-L1 can only be detected through analysis of tissue samples.[17] However, as our knowledge advances, I think liquid biopsy will become increasingly valuable.
First line therapy strategies in NSCLC
MD: What is your first-line treatment strategy in patients without oncogenic driver mutations?
JP: Initial therapy is predicated on PD-L1 expression:[18]
A third of patients are PD-L1++ (>50% expression),
A third are PD-L1+ (1-49% expression),
The remaining third are PD-L1-.
PD-L1++ patients are more likely to respond to monotherapy with a PD-L1 inhibitor such as pembrolizumab. However, a typical 'good' response is around 50%, compared to a ~80% response rate usually obtained with some targeted therapies in patients with activating mutations.
When PD-L1++ patients are symptomatic or have critical disease volume, histology-specific chemotherapy is frequently combined with a PD-1/PD-L1 inhibitor.
For PD-L1+ patients, combining chemotherapy and immunotherapy is the preferred option, but immunotherapy combinations can also be considered. Recent data supports single-agent immunotherapy with atezolizumab in patients who are elderly or otherwise ineligible for platinum therapy.[19]
Beyond PD-L1 expression, we can consider tumour mutational burden (TMB) as a predictive marker, but this has proved challenging in patients receiving dual immunotherapy with CTLA4 inhibitors and PD-1 inhibitors. Questions remain over the clinical significance of sub-analysis data from the Checkmate227 trial, which suggest that patients with high TMB and low PD-L1 will do well.[20]
Evolving subset analyses across multiple trials suggest STK11 and KEAP1 may indicate an immune-poor microenvironment and predict suboptimal therapeutic responses.[21]
Second line treatment options in NSCLC
MD: If a patient does not respond to a PD-1/PD-L1 inhibitor and shows disease progression, what do you recommend second line?
JP: For patients treated with immunotherapy alone, platinum chemotherapy is started at progression. The INSIGNA trial in patients with PD-L1 > 1% non-squamous NSCLC will clarify whether carboplatin and pemetrexed should replace pembrolizumab or be added on to pembrolizumab at progression.[22]
In the US, non-squamous NSCLC patients treated initially with carboplatin/pemetrexed in addition to PD-1/PD-L1 inhibitor often receive docetaxel with or without ramucirumab as follow-up. In the REVEL study, which was conducted prior to immunotherapy in the first-line setting, docetaxel plus ramucirumab led to a response rate of 23%, and this serves as a benchmark for new therapies. There is some suggestion that response rates to docetaxel are higher in the post-immunotherapy setting. For squamous histology patients, docetaxel +/- ramucirumab and sometimes gemcitabine is often used after first-line paclitaxel.[23]
As part of the PRAGMATICA trial, ramucirumab, an anti-VEGF receptor antibody that may alter the immune microenvironment is being studied in combination with pembrolizumab after progression on immunotherapy.[24]
Multiple lines of therapy can exacerbate patient toxicity, with neuropathy and myelosuppression having a significant impact on quality of life. These side effects are frequently cumulative with repeat exposure and can lead to discontinuation even when the regimen remain effective.
MD: Are second biopsies required prior to second-line treatment?
KK: Regulatory approvals largely determine which tests are necessary. In NSCLC, second-line therapies are approved if they show superiority to the current standard of care and, as discussed earlier, the bar is low, favouring approval of biomarker-agnostic drugs.
Biomarker-agnostic drug approval minimises the incentive for additional testing due to reimbursement issues.
JP: Many clinical trials rely on archival specimens, which is a potential problem given the dynamic nature of cancer. I generally perform repeat biopsies on patients with driver oncogenes in whom I may be able to target acquired resistance. I usually don’t obtain repeat biopsies on wild-type patients in whom I have confidence in prior testing.
MD: Do we need to re-biopsy for dynamic markers like CEACAM5?
KK: The dynamics of CEACAM5 expression before and after first-line therapy are unknown. Clinical trials on CEACAM5-specific ADCs use specific validated assays on initial diagnostic samples. If re-evaluating CEACAM5 status before ADC administration was shown to optimise patient selection, re-biopsy might be indicated but would pose logistical challenges.
MD: Do liquid re-biopsies prior to second line treatment have any value?
JP: I perform liquid re-biopsies only on patients who initially presented with a trackable mutation. Liquid re-biopsies are conducted as required in patients participating in clinical trials but, generally, their value remains uncertain.
MD: Some regions in Asia have utilized CEA as a tumour marker for non-invasive tracking of disease in addition to liquid biopsy.[25] If validated and aligned with precision medicine, a blood-based surrogate marker for CEACAM5 could significantly streamline our approach and help identify eligible patients.
The role of CEACAM5 in potential tumour targeting with ADCs
MD: What is CEACAM5 and how is it defined as a biomarker?
KK: CEACAM5 is a member of the CEACAM family of cell adhesion molecules, which are all predominantly membrane-bound complex glycoproteins that play a role in cell motility, differentiation, and adhesion. These molecules are involved in many physiological processes, including embryogenesis and tumourigenesis.[26]
CEACAM5 and its variants are often upregulated in gastrointestinal (GI) and lung cancers, while minimally expressed in normal tissues.[27] Upregulation of CEACAM5 in cancer correlates with greater tumour invasiveness, reduced immune sensitivity, and altered cellular differentiation.[27]
In clinical settings, CEACAM5 expression is categorized as high or moderate based on immunohistochemical staining, commonly using assays designed for specific clinical trials. For example, a tumour with 50% or more cells showing moderate to high CEACAM5 staining is classified as having high expression.[28] CEACAM5 is also used as a target for delivering cytotoxic agents via ADCs.[29]
MD: How do ADCs work? What potential targets, payloads, and linkers are used in ADCs relevant to NSCLC?
JP: ADCs combine the targeted efficacy of monoclonal antibodies with the potency of cytotoxic agents.[29] The number of ADCs approved for cancer is increasing rapidly and approximately and, as of 2023, more than 100 ADCs are in development.
ADCs consist of three primary components:[29]
The antibody component selectively targets tumour-specific antigens to minimise off-target systemic toxicities, a common challenge with standard chemotherapy regimens. Antigen choice is critical for increasing specificity and minimizing toxicity.
The linker binds the antibody to the cytotoxic payload. Most linkers are cleavable, designed to release the payload only within the tumour microenvironment, not the plasma, further decreasing systemic toxicity.
The payload, such as a microtubulin inhibitor or a topoisomerase inhibitor is intended to be minimally toxic while circulating in the plasma but highly lethal at low concentrations when delivered to the tumour microenvironment.
The bystander effect is also important in ADCs, as the payload is released it exerts its effects on target tumour cells and neighbouring cancer cells that may not express the target antigen.[30]
When and how should we test for CEACAM5 as a biomarker when treating patients with CEACAM5-targeting ADCs?
KK: The optimal timing remains uncertain. One option is to conduct immunohistochemical tests concurrently with next-generation sequencing (NGS) and PD-L1 testing. However, this approach may face reimbursement challenges.
The original sample may have been completely used by NGS, but there are also questions about its biological relevance for second-line therapy. As additional ADCs emerge, we will need to devise an optimal test sequence for all that are available.
NSCLC: Future therapeutic outlook
MD: Several ADCs with differing constructs are under active investigation in NSCLC, particularly in the metastatic setting. How do the ADCs trastuzumab-deruxtecan, Dato-DXd, patritumab-deruxtecan, and tusamitamab ravtansine compare in terms of efficacy and safety in NSCLC?
JP: TDXd is FDA-approved for lung cancer, targeting HER2 exon 20 mutations.[31] It is under investigation also for HER2 amplification and overexpression. Data demonstrates response rate around 60% in the second-line metastatic setting.[32] Toxicities like interstitial lung disease and myelosuppression require proper patient selection and monitoring.[32]
HER3-DXd is not approved but clinical trial results are encouraging. In the HERTHENA-Lung02 phase II trial, patients with EGFR mutations who had progressed on prior third-generation EGFR tyrosine kinase inhibitors and platinum-based chemotherapy showed response rates to HER3-DXd of around 30%. CNS responses were also observed.[33]
MD: The patritumab-deruxtecan efficacy in the CNS was unexpected, as ADCs are not generally considered effective in the CNS compared to small molecule inhibitors like TKIs, but response rates were comparable to extra-cranial responses. Data for CNS responses with tusamitamab ravtansine are currently awaited.
JP: Data from TROPION-Lung04 trial[34] looking at Dato-DXd in treatment-naive patients with carboplatin and immunotherapy combinations show promising response rates and tolerability.[35] These developments prompt re-evaluation of the efficacy of single ADCs compared to traditional carboplatin doublets. Treatment paradigms will evolve based on emerging efficacy and toxicity data.
MD: In the CARMEN trials,[36,37,38,39] high expression levels were defined as CEACAM5 high with >50% cells staining at least 2+, or intermediate with CEACAM expression in 1-49% of tumour cells with at least 2+ staining intensity. The trials underway evaluate the efficacy in these respective subgroups. Initial approval for tusamitamab ravtansine is expected to be limited for patients with high CEACAM5 expression levels.[40] A correlation between expression levels and treatment response has been observed.[41]
MD: What toxicities are observed with tusamitamab ravtansine?
JP: Tusamitamab ravtansine has distinct toxicities, including GI effects and keratitis correlating with expression levels in the respective healthy tissues and could indicate an on-target effect in non-malignant tissue. These findings are from heavily pre-treated patient cohorts; the side effect profile may differ when the drug is used earlier in treatment.[42]
MD: Gastrointestinal side effects are expected due to the normal CEA expression in the gut. Keratitis, however, is a less commonly observed side effect in NSCLC. It has been observed with immunotherapy. Colleagues who treat myeloma, where keratitis-inducing drugs are more typical, often arrange for periodic ophthalmologic exams for monitoring of drug toxicity. These exams typically include an anterior slit lamp exam and are non-invasive and relatively simple. Pupil dilation is not required for these monitoring exams, allowing for easy in-and-out patient visits. We have no current preventative strategy for keratitis; primary management relies on early identification, supportive care, dose modification, and dose delays, if necessary.
MD: Does the risk of ILD influence your choice between ADCs with similar efficacy in a second-line setting?
JP: The risk of ILD with some ADCs is well recognized and require monitoring and early intervention if they occur.[43,44] Evaluating the balance of efficacy and safety in addition to patient and tumour-specific factors are crucial in selecting the optimal sequence of drugs in each patient scenario.
MD: ILD/pneumonitis is a mechanistically poorly understood inflammatory reaction in the lung interstitium, thought to be a cross-reaction between drug, interstitium of the lung and the immune system. These may be drug- or linker-specific and may not necessarily be a class effect of ADCs. Complications of ILD/pneumonitis are also observed with tyrosine kinase inhibitors and immunotherapy. These differentiating side effect profiles could potentially serve as factors in treatment selection.
JP: From using immunotherapies, we have learned that patient education on pulmonary symptoms is crucial. Dose modification and timely administration of steroids can reduce the risk of severe ILD while enabling treatment to continue.
MD: What sequence of second line treatments do you recommend?
JP: Unfortunately, some small molecule inhibitors such as sotorasib have not met expectations, offering limited PFS and response rate improvements compared to docetaxel, albeit with better quality of life.[45] With ADCs showing prolonged responses, the current strategy might favour initial use of the CEACAM5-targeting ADC tusamitamab ravtansine, followed by either adagrasib or sotorasib.
Summary
CEACAM5, a cell adhesion molecule, is frequently upregulated in gastrointestinal and lung cancers, making it a significant biomarker in clinical settings. Its prominence in tumours predicts responses to specific therapies. CEACAM5 serves as a target for antibody-drug conjugates (ADCs) which merge the specificity of antibodies with the potency of cytotoxic agents for targeted cancer treatment. Several ADCs, such as T-DXd and tusamitamab ravtansine, are under scrutiny for their efficacy and safety in non-small cell lung cancer (NSCLC), with varying results and associated safety concerns, notably interstitial lung disease.
Acknowledgement: Dr Kathryn Senior, independent medical writer, helped draft this article.
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Cite this: CEACAM5 in Non-Small Cell Lung Cancer - Medscape - Dec 21, 2023.
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