Immunotherapy as First Line therapy in Cancer Treatment: A Chemotherapy Sparing Regimen?

Executive Summary

Immunotherapy has emerged as a transformative approach in oncology, leveraging the body’s immune system to combat cancer. As a first-line therapy, immunotherapy—either alone or in combination with other modalities such as chemotherapy or targeted therapies—has gained regulatory approval for various cancers, including non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, and head and neck squamous cell carcinoma. By harnessing immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and emerging modalities like cancer vaccines, immunotherapy offers durable responses and improved survival outcomes for select patient populations. This white paper explores the current landscape, clinical applications, benefits, challenges, and future directions of immunotherapy as a first-line treatment in cancer care.

Introduction

Cancer remains a leading cause of morbidity and mortality worldwide, necessitating innovative therapeutic strategies. Immunotherapy, which activates the immune system to recognize and eliminate cancer cells, has shifted the treatment paradigm for many malignancies. As a first-line therapy, immunotherapy is now a cornerstone for certain cancers, driven by its potential for long-term remission and favorable toxicity profiles compared to traditional treatments. This article provides an overview of immunotherapy’s role as a primary treatment, focusing on mechanisms, approved indications, clinical outcomes, challenges, and ongoing advancements.

Mechanisms of Action

Immunotherapy as a first-line therapy primarily involves immune checkpoint inhibitors, which target proteins that cancer cells exploit to evade immune detection. Key mechanisms include: 

• Checkpoint Inhibitors: Drugs like pembrolizumab and nivolumab block programmed cell death protein 1 (PD-1) or its ligand (PD-L1), while ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These agents restore T-cell activity against tumors. 
• CAR T-Cell Therapy: Genetically modified T-cells are used to target specific cancer antigens, particularly in hematologic malignancies. 
• Cancer Vaccines and Bispecific Antibodies: Emerging modalities aim to enhance immune recognition of tumor-specific antigens.

These mechanisms enable precise immune activation, making immunotherapy effective for tumors with high immunogenicity, such as those with elevated PD-L1 expression or high tumor mutational burden (TMB).

Approved Indications and Clinical Evidence

As of August 2025, immunotherapy is approved as a first-line therapy for several cancers, supported by robust clinical trial data:

1. Non-Small Cell Lung Cancer (NSCLC): 

• Pembrolizumab monotherapy is standard for patients with PD-L1 expression ≥50% and no EGFR/ALK mutations (KEYNOTE-024). The 5-year overall survival rate is approximately 18%. -
• Pembrolizumab plus chemotherapy is approved for NSCLC regardless of PD-L1 status, improving progression-free survival (PFS) and overall survival (OS) (KEYNOTE-189, KEYNOTE-407). 

2. Melanoma: 

• Nivolumab combined with ipilimumab is a first-line option for advanced melanoma, with a median PFS of ~11.5 months (CheckMate-067). 

3. Renal Cell Carcinoma (RCC): 

• Nivolumab plus ipilimumab is approved for intermediate- or high-risk advanced RCC, demonstrating superior OS compared to sunitinib (CheckMate-214). 

4. Head and Neck Squamous Cell Carcinoma (HNSCC): 

• Pembrolizumab is approved for PD-L1-positive recurrent or metastatic HNSCC, showing improved response rates (KEYNOTE-048). 

5. Other Cancers: - 

• Hodgkin lymphoma and microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancers are also candidates for first-line immunotherapy due to high response rates.

Benefits of First-Line Immunotherapy

• Durable Responses: Unlike chemotherapy, immunotherapy can achieve long-term remission in responders, with some patients remaining disease-free for years. 
• Improved Tolerability: While not without side effects, immunotherapy often has a more favorable toxicity profile than cytotoxic chemotherapy. 
• Biomarker-Driven Efficacy: Biomarkers such as PD-L1 expression, MSI-H status, and TMB allow for personalized treatment selection, optimizing outcomes.

Next-Generation Immunotherapy

Perhaps the most transformative breakthrough in modern oncology has been the rise of immunotherapy—a set of treatments that awaken the immune system to recognize and attack cancer cells. It is an idea as beautiful as it is powerful: train the body to see the enemy hiding in plain sight.

Checkpoint inhibitors were the first major triumph in this domain. Cancers like melanoma, lung cancer, and Hodgkin’s lymphoma once carried grim prognoses. Now, drugs such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab have offered durable responses—sometimes even complete remission—by blocking the “brakes” cancer places on immune cells.

Advances in immunotherapy continue to improve survival rates. Novel checkpoint inhibitors, CAR-T cell therapies, and bispecific antibodies are expanding treatment options for hard-to-treat cancers like pancreatic and brain tumors.

Using immunotherapy as a Neo-adjuvant Strategy (before surgery or other treatments) is gaining traction, with evidence that checkpoint inhibitors alone may be sufficient in some cases, potentially changing standard care protocols (AACR 2025).

Intra-tumoral immunotherapy represents a promising strategy to convert tumors into in situ vaccines, offering targeted immune activation with reduced toxicity. While clinical success has been observed in accessible tumors like melanoma, challenges persist in achieving consistent systemic responses and treating visceral metastases. Future advancements in delivery techniques and combination therapies hold significant potential to broaden its applicability.

Challenges and Limitations

Despite its promise, first-line immunotherapy faces several challenges:

• Variable Response Rates: Not all patients respond, and predictive biomarkers are not universally reliable. For example, some PD-L1-negative patients may still benefit, while others with high PD-L1 expression may not. 
• Immune-Related Adverse Events (irAEs): Toxicities such as colitis, pneumonitis, hepatitis, and endocrinopathies require vigilant monitoring and management with corticosteroids or other immunosuppressants. 
• Cost and Access: High costs of drugs like checkpoint inhibitors and CAR T-cell therapies, combined with limited availability in some regions, pose barriers to widespread adoption. - **
• Combination Therapy Toxicity**: Combining immunotherapy with chemotherapy or other agents increases efficacy but also elevates the risk of adverse events.

Future Directions

• Expanded Indications: Ongoing clinical trials are evaluating immunotherapy in additional cancer types, such as triple-negative breast cancer and gastric cancer, as first-line options. 
• Novel Therapies: Bispecific antibodies and next-generation checkpoint inhibitors targeting LAG-3 or TIGIT are under investigation. 
• Combination Strategies: Trials are exploring immunotherapy combined with targeted therapies, radiation, or novel immunomodulators to enhance efficacy.
• Biomarker Refinement: Advances in genomic profiling and liquid biopsies aim to improve patient selection and predict treatment response more accurately.

Conclusion

Immunotherapy has redefined first-line treatment for several cancers, offering durable responses and improved survival for appropriately selected patients. Its success hinges on biomarker-driven strategies, careful management of immune-related toxicities, and ongoing research to expand its applicability. As clinical trials and real-world evidence accumulate, immunotherapy’s role as a first-line therapy is likely to grow, potentially transforming outcomes across a broader spectrum of malignancies. Stakeholders, including clinicians, researchers, and policymakers, must address access barriers and optimize treatment protocols to fully realize its potential.

References

- KEYNOTE-024, KEYNOTE-189, KEYNOTE-407, KEYNOTE-048 clinical trial data. - CheckMate-067, CheckMate-214 clinical trial data. - National Comprehensive Cancer Network (NCCN) guidelines, 2025.

Related: 

• Combining Repurposed Drugs with Immunotherapy: A Novel Approach to Cancer Treatment
• Immunotherapy 101: What You Need to Know 2025 (Part 1)
• Approaches to Overcome the Current Treatment Plateau in Immunotherapy (European Journal of Cancer 2025)