Beth Sandy, MSN, CRNP, thoracic oncology nurse practitioner, Abramson Cancer Center, University of Pennsylvania, discusses the evolving treatment landscape in small cell lung cancer (SCLC). 

Single-agent immunotherapy had shown encouraging data in the second- and third-line settings. However, the emergence of chemoimmunotherapy in the frontline setting has revolutionized the treatment landscape, says Sandy.

In 2019, the FDA approved the combination of atezolizumab (Tecentriq), carboplatin, and etoposide for the frontline treatment of patients with extensive-stage SCLC. Moreover, in March 2020, the FDA approved the combination of durvalumab (Imfinzi) and etoposide and either carboplatin or cisplatin in the same setting.

On June 15, 2020, the FDA grated an accelerated approval to lurbinectedin (Zepzelca) for patients with metastatic SCLC who have disease progression following platinum-based chemotherapy. Each FDA approval is a welcome addition to the armamentarium, Sandy concludes. 

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Introduction to Neoadjuvant Chemo-IO

Neoadjuvant chemotherapy combined with immuno-oncology (chemo-IO) agents is increasingly being used in various cancers, particularly for cancers like non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and others. The primary goal of this treatment approach is to shrink tumors before surgery and improve long-term survival outcomes.

• Pathologic Complete Response (pCR) refers to the absence of any residual cancer cells in the surgical specimen after neoadjuvant therapy.
• Major Pathological Response (MPR) is defined as a significant reduction in cancer cells but not complete eradication, usually resulting in less than 10% residual viable tumor.

Patients achieving pCR or MPR are generally considered to have a better prognosis while those who do not achieve these outcomes require different management strategies.

Challenges With Non-pCR and Non-MPR Patients

A failure to achieve pCR or MPR after neoadjuvant chemo-IO can signal the need for further interventions. These patients might have more aggressive disease, lesser immune responses, or resistance to chemotherapy and immunotherapy. Managing these cases is challenging and requires personalized, multidisciplinary approaches.

Steps in Treating These Patients

Reassessment of Treatment Strategy

• Reevaluation of Tumor Biology: Consider molecular profiling to assess for actionable mutations (eg, PD-L1 expression, tumor mutational burden, microsatellite instability) or resistance mechanisms. Tumors with low PD-L1 expression or high mutational burden may not respond well to IO therapies.
• Consider Alternative Chemotherapy Regimens: If chemotherapy is still an option, different agents or combinations may be considered.
• Switching IO Therapy: If initial IO therapy is ineffective, the use of other immunotherapies or combinations (eg, combination of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors) could be explored.

Surgical Decision-Making

• Delayed Surgery or Additional Neoadjuvant Therapy: Some patients may be candidates for further cycles of therapy before proceeding to surgery. This could involve additional chemotherapy, IO agents, or a different combination depending on tumor response.
• Operability Considerations: In some cases, tumor progression or insufficient response may make surgery less feasible. In such cases, reassessing the extent of disease and considering alternative interventions, such as radiotherapy, is crucial.

Exploring Clinical Trials

• Enrollment in Trials: For patients who do not achieve pCR or MPR, participation in clinical trials evaluating new agents or therapies may provide additional options. Trials investigating novel combinations of chemotherapy, IO agents, or targeted therapies could be valuable.
• Targeted Therapies: Depending on the molecular profile, targeted therapies (eg, HER2 inhibitors in breast cancer, EGFR inhibitors in lung cancer) may be considered to complement or replace neoadjuvant therapies.

Adjuvant Treatment

• Postsurgical Adjuvant Therapy: After surgery, adjuvant treatments may be warranted based on the extent of residual disease. Options include further chemotherapy, radiotherapy, or extended IO therapy.
• Biomarker-guided Adjuvant Therapy: If resistance to IO is a concern, adjuvant therapy with targeted treatments may improve the outcome, guided by the patient’s specific tumor markers and mutations.

Immune Profiling and Biomarker Assessment

• Exploring Resistance Mechanisms: Assessing the tumor’s immune microenvironment (such as T-cell infiltration or immune checkpoint expression) may provide insights into why chemo-IO therapy did not yield a pCR or MPR. This can guide the development of more personalized approaches to treatment.
• Exploring Immunotherapy Combinations: Investigating combinations of different immune modulators (eg, inhibitors of immune checkpoints or co-stimulatory agents) may offer additional benefits to patients who show poor response to single-agent immunotherapy.

Supportive Care and Symptom Management

• Managing Disease Progression: Symptom management becomes increasingly important in cases of disease progression after neo-adjuvant therapy. This includes addressing pain, fatigue, and other systemic symptoms related to the cancer or its treatment.
• Psychosocial Support: Providing counseling or psychological support for patients facing poor outcomes, especially those who did not achieve significant therapeutic responses, is key to improving patient well-being during this difficult phase.

Conclusion

The management of patients who do not achieve pCR or MPR after neoadjuvant chemo-IO therapy involves a comprehensive approach. It includes reevaluating the treatment regimen, considering surgery or alternative treatments, exploring clinical trials, and tailoring adjuvant therapies based on residual disease characteristics. Personalized care based on tumor biology, immune response, and the patient’s overall health status is paramount to improving outcomes.