Impact of PD-1 and PD-L1 Expression on Overall Survival in Patients With NSCLC and Melanoma

The conventional treatment paradigms for melanoma and non–small cell lung cancer (NSCLC) have historically centered around surgery, radiation, and chemotherapy. Although potentially effective in the early stages of the disease, these methods often reach a therapeutic impasse when confronted with metastatic spread. The fields of melanoma and NSCLC, however, are witnessing a remarkable shift in treatment strategy, emphasizing the body’s immune response as a potent weapon against cancer’s formidable ability to spread and resist conventional therapies.^1,2 Immunotherapy has emerged as a promising option, enhancing the specificity and potency of the immune system’s responses to these cancers.³

Lung cancer, primarily NSCLC, accounts for the highest incidence and mortality rates among all cancers, with a significant proportion of patients diagnosed at advanced stages.⁴ Despite advancements in metastatic NSCLC treatment, resistance to targeted therapies remains challenging. However, therapies targeting the PD-1/PD-L1 pathway offer promising avenues for treatment. PD-L1 expression in NSCLC correlates with poorer outcomes, and selecting the appropriate FDA-approved PD-1/PD-L1 inhibitor for metastatic NSCLC can be difficult because of variations in patient and disease characteristics.⁵ The use of PD-1/PD-L1 inhibitors in advanced or metastatic NSCLC is based on PD-L1 expression levels (categorized as over 50% or ≥ 1%-49%). For PD-L1 over 50%, options include pembrolizumab (Keytruda; Merck Sharp & Dohme LLC), cemiplimab (Libtayo; Regeneron Pharmaceuticals, Inc), and atezolizumab (Tecentriq; Genentech, Inc) as monotherapy, whereas combination therapy involves nivolumab (Opdivo, Bristol Myers Squibb), cemiplimab, durvalumab (Imfinzi; AstraZeneca Pharmaceuticals LP), pembrolizumab, or atezolizumab. For PD-L1 expression (ranging from ≥ 1% to 49%), pembrolizumab may be used as monotherapy, and combination therapy options may include nivolumab, cemiplimab, durvalumab, pembrolizumab, or atezolizumab.⁶

Arising from the malignant alteration of melanocytes, melanoma develops from neural crest cells. It can emerge in diverse locations where these cells migrate, primarily in the skin and central nervous system areas, such as the brain and gastrointestinal tract. Although stage 0 melanoma has a favorable 5-year survival rate of approximately 97%, this figure sharply declines to 10% for individuals diagnosed with stage IV metastatic disease.⁷

In melanoma, staging is crucial for choosing the most suitable treatment approach. The primary factor in staging is the depth of tumor invasion, and the presence of metastases categorizes melanoma as stage IV, indicating advanced disease. The National Comprehensive Cancer Network (NCCN) recommends specific treatment plans for initial therapy of metastatic melanoma, such as combinations of immunotherapy (ie, dual therapy) or anti–PD-1 therapy alone. The oncologist may opt for either monotherapy or dual therapy based on individual patient factors, with guidance from the pharmacist in therapy selection. In advanced melanoma, pembrolizumab or nivolumab can be administered alone or with other immunotherapy agents. However, atezolizumab is FDA approved solely for use with targeted agents when the BRAF V600 mutation is present.⁸ With the 2020 FDA approval of atezolizumab, 3 FDA-approved PD-1 or PD-L1 inhibitors exist, including nivolumab and pembrolizumab. Nonetheless, there are limited comparative data on the effectiveness of monotherapy with these agents in advanced melanoma.^9,10

Immunotherapy and Variation in Response

Immunotherapy has demonstrated significant clinical efficacy by reducing tumor growth and metastasis. Its clinical advantages encompass enduring effects, manageable toxicity, and broad applicability across various solid tumors. An important breakthrough in immunotherapy emerged with the identification of immune checkpoint (IC) proteins, which are potent immune system suppressors via diverse mechanisms.¹¹

Among these, PD-1 and PD-L1 inhibitors, a subset of IC inhibitors (ICIs), serve as neoadjuvant and adjuvant strategies, either alone or in combination with chemotherapy, radiation, and targeted therapy.¹² The interaction between PD-1, expressed on T cells, and PD-L1, typically expressed by antigen-presenting cells, leads to T-cell suppression, hampering proliferation and cytotoxicity.^13,14

Although this interaction acts as a negative feedback mechanism in the normal human immune response, tumors resistant to conventional therapies like chemotherapy and radiation may exploit it by overexpressing PD-L1, facilitating interaction with PD-1 and subsequent immune response suppression. By disrupting this mechanism, ICIs can bolster CD8+ cell proliferation, which traditional treatments might stifle. Consequently, PD-1/PD-L1 inhibitors are emerging as pivotal tools in managing metastatic melanoma and NSCLC.¹⁴

The efficacy of anti-PD therapy varies among patients, prompting inquiries into potential resistance mechanisms and susceptibility markers. Specific driver mutations may impact a tumor’s vulnerability to T cells, contributing to resistance. Given the variable responses, the use of immunohistochemistry to identify biomarkers associated with PD-L1 tumor expression is increasingly crucial for guiding ICI usage and assessing efficacy.^15-17

This article delves into the pivotal role of PD-L1 expression as a biomarker in NSCLC and melanoma, alongside documented applications of PD-1/PD-L1 inhibitor monotherapy and combination therapy (See Table).^18-21 It underscores the need for improved testing protocols to overcome existing limitations and better inform treatment decisions.

Assessing the Impact of PD-L1 Expression on the Efficacy of PD-1/PD-L1 Inhibitors in NSCLC and Melanoma

Nivolumab

In NSCLC treatment, PD-L1 expression critically determines the efficacy of PD-1 inhibitors such as nivolumab, as underscored in the randomized, open-label phase 3 trials CheckMate 057 (NCT01673867) and CheckMate 017 (NCT01642004). Specifically, higher PD-L1 levels (≥ 1%, ≥ 5%, and ≥ 10%) in patients with nonsquamous NSCLC were associated with significantly better outcomes with nivolumab than with chemotherapy in CheckMate 057. The trial revealed a trend where nivolumab response rates increased alongside higher PD-L1 levels, nearly doubling median overall survival (OS) at elevated expression thresholds. Conversely, in squamous NSCLC, PD-L1 levels did not predict nivolumab’s efficacy, indicating distinct immune responses between squamous and nonsquamous NSCLC types. PD-L1 protein expression was retrospectively examined in tumor-biopsy specimens before treatment using an automated immunohistochemical assay. Nivolumab demonstrated significant survival advantages with enhanced safety compared with standard treatment in patients with squamous cell NSCLC who had advanced disease and were previously treated, regardless of their initial PD-L1 expression levels. Nonetheless, additional research is needed to pinpoint biomarkers possessing sufficient sensitivity and specificity to determine which patients are likely to derive the most benefit.^22-24

In a series of clinical trials, including the randomized, double-blind, phase 3 study CheckMate 915 (NCT03068455), the efficacy of nivolumab alone and in combination with ipilimumab (a CTLA-4 checkpoint inhibitor, Yervoy; Bristol Myers Squibb) was assessed against ipilimumab alone in patients with metastatic melanoma. Despite the known complementary actions of these inhibitors in treating metastatic melanoma, the impact of PD-L1 expression levels on OS and treatment effectiveness remains unclear. Initial findings from a phase 1 trial and subsequent studies suggest that baseline tumor PD-L1 expression and absolute lymphocyte count may have limited relevance as predictors of response in the presence of these active combination therapies. These results indicate that although PD-L1’s role in tumor immune resistance is acknowledged, its utility as a predictive marker for anti–PD-1 therapy response is not definitive. It underscores the need for further research to establish any potential predictive significance.^25-27

Pembrolizumab

The efficacy of PD-1 inhibitors in treating NSCLC based on PD-L1 expression was significantly demonstrated in the KEYNOTE series of trials evaluating pembrolizumab. In the phase 1b KEYNOTE-001 study (NCT01295827), patients with a PD-L1 expression of 50% or greater notably achieved higher OS than those with lower or absent PD-L1 expression. This finding was further substantiated in the KEYNOTE-010 (NCT01905657) and KEYNOTE-024 (NCT02142738) trials. Data from KEYNOTE-010, a randomized, open-label, phase 2/3 study, showed that patients with high PD-L1 expression (≥ 50%) had markedly improved survival rates, indicating significant benefits of pembrolizumab for refractory NSCLC across all histologies. Similarly, KEYNOTE-024 data confirmed that pembrolizumab significantly improves OS compared with chemotherapy, especially in patients with PD-L1 expression of at least 50%. These results underscore the drug’s efficacy across various levels of PD-L1 expression, assessed via formalin-fixed tumor samples analyzed at a central laboratory utilizing the commercially available PD-L1 IHC 22C3 pharmDx assay. These studies collectively highlight PD-L1 as a crucial biomarker for predicting NSCLC responses to PD-1 blockade, supporting using pembrolizumab as a potent monotherapy, particularly for those with high PD-L1 expression.^28-30

In the randomized, controlled phase 3 study comparing pembrolizumab with another form of immunotherapy in advanced melanoma, the interpretation of PD-L1 expression’s impact on treatment efficacy was complicated by several factors. PD-L1 levels varied significantly across different melanoma metastases, even within the same patient. This variability presents a challenge in using PD-L1 expression as a reliable predictor of treatment success, indicating that PD-L1 expression did not consistently influence the effectiveness of the therapies tested in this randomized, controlled trial.³¹

Cemiplimab

Data from the EMPOWER-Lung 1 trial (NCT03088540), a multicenter, open-label, global phase 3 study, underscored the efficacy of PD-1 inhibitors in treating advanced NSCLC with high PD-L1 expression. Findings demonstrated a statistically significant improvement in OS for patients with a PD-L1 expression of at least 50%, marking cemiplimab as a potential new monotherapy option alongside pembrolizumab, which previously was the only PD-1 antibody to show a survival benefit in this setting. Adult patients diagnosed with histologically confirmed squamous or nonsquamous advanced NSCLC with PD-L1 tumor expression of 50% or more were included in the study. Participants were randomly assigned 1:1 to receive either cemiplimab (administered intravenously at a dose of 350 mg every 3 weeks for 108 weeks or until disease progression) or 4 to 6 cycles of platinum-based doublet chemotherapy, with the specific chemotherapy regimen determined for each patient before randomization. At the 35-month follow-up, cemiplimab monotherapy offered significant survival benefits compared with platinum-based doublet chemotherapy in patients with advanced NSCLC and PD-L1 expression of at least 50%. Interestingly, the response to cemiplimab was more evident at the 35-month follow-up than at the 11-month mark. Additionally, the trial results indicated comparable outcomes between patients with NSCLC with lower PD-L1 expression levels (< 50%) treated with cemiplimab and those receiving chemotherapy, emphasizing the significance of PD-L1 as a pivotal biomarker for treatment decisions in NSCLC.³²

Atezolizumab

The POPLAR (NCT01903993) and OAK (NCT02008227) trials, which were multicenter, randomized phase 2 and phase 3 studies, respectively, highlighted the effectiveness of atezolizumab in treating advanced or metastatic NSCLC, with a particular focus on the impact of PD-L1 expression on survival rates. In the POPLAR trial, higher PD-L1 expression was associated with improved OS among patients treated with atezolizumab. Notably, those with low PD-L1 expression had similar survival outcomes to those receiving alternative chemotherapy agents, such as docetaxel, which is a crucial component in treating advanced-stage NSCLC. Similarly, the OAK trial findings demonstrated significantly prolonged OS with atezolizumab compared with docetaxel, regardless of PD-L1 expression or histology. Patients with high PD-L1 expression experienced the most significant benefits, consistent with findings from the KEYNOTE-042 trial (NCT02220894) involving pembrolizumab, whereas those with low PD-L1 expression had survival rates comparable to those in patients receiving alternative chemotherapy agents. These findings emphasize the intricate role of PD-L1 in NSCLC and affirm its importance in regulating anticancer immunity and advocating for atezolizumab monotherapy, especially in patients with high PD-L1 levels.^33-35

In contrast to its indication for NSCLC, atezolizumab is not recommended as monotherapy for melanoma. Patients need to test positive for the BRAF V600 mutation to qualify for combination therapy with atezolizumab. In data from a phase 1 trial (NCT04020809) of atezolizumab for melanoma treatment, PD-L1 expression on immune cells has emerged as a potential predictive biomarker for therapy response. Unlike many clinical trials in advanced melanoma, which typically overlook PD-L1 expression as an influencing factor on treatment efficacy, this trial recognizes the significance of analyzing such end points. However, it is worth noting that most trials lack comprehensive analyses, including post hoc assessments, to evaluate the impact of PD-L1 expression thoroughly. This trial sets a precedent by incorporating evaluation measures that could better determine the effectiveness of atezolizumab based on PD-L1 expression levels on immune cells, potentially offering more precise and efficient treatment strategies for patients with melanoma.³⁶

Durvalumab

The phase 3 PACIFIC trial (NCT02125461), a placebo-controlled study involving patients with unresectable stage III NSCLC post chemoradiotherapy, investigated the efficacy of durvalumab vs placebo. The trial results suggested that durvalumab generally improved OS across all PD-L1 subgroups, except in patients with PD-L1 expression less than 1%, for whom it did not show a survival benefit. Furthermore, post hoc analysis data from the trial indicated a negative correlation between PD-L1 levels and OS, with higher PD-L1 expression associated with lower OS. However, these data were not adjusted for multiplicity, raising questions about their reliability. These findings underscore the intricate role of PD-L1 as a biomarker in assessing the effectiveness of immunotherapy in NSCLC, particularly within the parameters of the PACIFIC trial. Further investigation is necessary to confirm these findings and fully comprehend PD-L1’s predictive value in this context.^37,38

Challenges and Considerations in Choosing a PD-1/PD-L1 Inhibitor

Clinical trial data have revealed that higher PD-L1 expression corresponds to better response rates with PD-1/PD-L1 inhibitors, yet the correlation varies among inhibitors, complicating treatment selection solely based on this biomarker.^22-39 The limitations of PD-L1 immunohistochemistry, including sensitivity and reliability issues, alongside variability in expression within and between tumor areas, underscore the need for standardization efforts. Analyzing only 1 slide or time point may not capture PD-L1’s dynamic expression, further complicated by inter- and intra-tumoral heterogeneity and factors such as cancer stage, sample age, biopsy type, and treatment history. Despite PD-L1’s inconsistent expression in melanoma, diminishing its significance as a biomarker for PD-1 inhibitors due to high tumor mutational burden (TMB), it remains crucial in NSCLC treatment success despite similar TMB levels. Standardizing TMB assessment could enhance immunotherapy strategies, highlighting the importance of precise PD-L1 testing across cancers, with further clinical trials necessary to identify new predictive biomarkers and optimize immunotherapy approaches.^39-42

The landscape of immunotherapies presents a multifaceted challenge in selecting the most suitable treatments for patients. Despite their shared mechanism of action, PD-1 and PD-L1 inhibitors exhibit nuanced differences in clinical efficacy and safety profiles. Crafting personalized treatment plans requires meticulous evaluation of patient-specific variables, including adverse effect (AE) profiles, dosing schedules tailored for patient convenience, and cost considerations to ensure treatment accessibility. In addition to patient-centered considerations, a health care provider’s familiarity and past experiences with certain drugs can sway their treatment decisions. If a provider has encountered pronounced AEs with a specific PD-1/PD-L1 inhibitor in previous cases, they may exhibit reluctance in prescribing it for future patients.

In addition to tailoring treatments to individual patients, health care providers rely on standardized approaches, such as adhering to guidelines. Consulting the NCCN guidelines is a common practice for assessing the appropriateness of PD-1/PD-L1 inhibitors, with a preference for therapies categorized as category A or 2A.^6,8

Although these guidelines are based on empirical evidence, complementing them with an analysis of available literature and clinical trials is vital. For instance, data from a comparison of studies such as KEYNOTE-407 (NCT02775435) and IMpower131 (NCT02367794) demonstrated improved OS and progression-free survival rates with pembrolizumab plus chemotherapy. Moreover, treatment decisions are influenced by specific tumor types and relevant biomarkers, such as PD-L1 expression. For instance, PD-1 inhibitors are often favored in treating patients with lung cancer based on existing data.43 Assessing the trial designs of relevant studies is also crucial for accurately predicting real-world outcomes. Leveraging real-world data helps anticipate patient tolerance levels toward therapy, particularly when trial demographics differ from the patient’s profile.

Several factors play a role in determining the choice of ICIs. Despite thorough consideration of individual patient factors, treatment decisions may ultimately be influenced by factors such as hospital formulary inclusion and treatment costs, as treatment availability directly impacts patient access. Furthermore, conducting population-based studies or large-scale comparative trials is essential to delve deeper into potential differences among PD-1/PD-L1 inhibitors and their implications for efficacy and safety. This understanding can inform the selection of the most suitable patient population for clinical application.

Conclusion

The use of PD-L1 as a biomarker in guiding PD-1/PD-L1 inhibitor therapies exhibits significant variability that necessitates standardized and precise testing methodologies. Although data in NSCLC have shown improved outcomes in patients with with high PD-L1 expression, the predictive value of PD-L1 in melanoma is inconsistent, warranting further research. Standardization would refine treatment strategies and advance personalized medicine, improving survival rates across cancer types. In NSCLC management, treatment disparities arise from varying efficacy levels, with agents such as nivolumab and pembrolizumab offering improved survival benefits as second-line therapies, and pembrolizumab proving superior in first-line monotherapy over traditional chemotherapy. Optimal treatment selection requires consideration of individual patient characteristics, and additional data comparing PD-1 and PD-L1 inhibitors are crucial for refining therapeutic approaches and guiding health care practitioners effectively.⁴³

Role of Pharmacists in Immunotherapy

Pharmacists play a crucial role in managing immunotherapy for NSCLC and melanoma. Prior to initiating therapy, pharmacists educate patients about the importance of PD-L1 expression levels. They explain how these biomarkers influence treatment choices, ensuring patients understand their options. When managing immune-related AEs (irAEs), pharmacists educate patients and caregivers on quickly recognizing and reporting potential, serious irAEs, aiding in early intervention. During initial visits, pharmacists cover essential topics such as the distinct AE profile of ICI therapies, providing details about potential irAE signs and symptoms, and guiding patients on symptom-reporting procedures. Patients are assured that timely management typically resolves irAEs, allowing treatment to continue.

The Oncology Nursing Society provides educational resources, including immunotherapy patient wallet cards that summarize ICI therapy details, irAE symptoms, and oncology team contact information. Pharmacists can distribute these resources to patients and review them to confirm patients’ comprehension of their treatment. They can also advise patients to carry these cards and other relevant materials, even after treatment completion. Pharmacist-led patient education, integrating toxicity assessments and guidance on irAE symptoms, enhances patient understanding and early detection, improving outcomes. Continual patient education involves pharmacists evaluating irAE symptom recognition during interactions, enhancing patient-reported outcome measures’ reliability.^44,45

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