Scenario

The treatment paradigm for non–small-cell lung cancer (NSCLC) experienced a substantial shift following the introduction of immunotherapy in the form of immune checkpoint inhibitors (ICIs). ICI-based regimens are now the standard of care for first-line systemic treatment of patients with NSCLC without actionable molecular mutations. Despite the benefits of immunotherapy in advanced NSCLC, most patients ultimately develop resistance to ICIs. This represents a substantial clinical challenge, as there is currently no approved standard treatment for patients with disease progression after ICI therapy due to resistance. Distinguishing primary and acquired resistance to ICIs can play an important role in second-line treatment decisions and present an additional challenge.

Historically, chemotherapeutic agents were used as monotherapy in the second-line setting. More recently, angiogenesis inhibitors have demonstrated improved outcomes when combined with chemotherapy, however, the significant toxicities associated with chemotherapy indicate the need for less toxic second-line options. New data are emerging that demonstrate favorable efficacy and tolerability of combination therapy involving angiogenesis inhibitors combined with immunotherapy as second-line treatment of NSCLC. With the potential for new approaches in the second-line setting, clinicians may face challenges relating to the unique spectrum of adverse events and additive toxicities that can result. As patients often incorporate potential toxicities into their treatment preferences, clinicians need to accurately communicate adverse event data, as well as efficacy data to patients to arrive at optimal treatment decisions.

Let’s consider ICI resistance and 2nd-line treatment selection:

64-year-old patient with advanced and metastatic NSCLC presents to a follow up visit experiencing fatigue, and other adverse symptoms around their treatment.

Medical History:

• 45 pack per year smoking history
• Diagnosed with non-small cell lung cancer (NSCLC) 24.5 months ago
• Lung lesion, bone, and adrenal metastases detected
• Adenocarcinoma with PD-L1 expression at 55%
• No targetable mutation identified

Treatment History:

• Initiated treatment with carboplatin, pemetrexed, and pembrolizumab for 6 cycles
• Followed by pembrolizumab maintenance therapy (ongoing until toxicity, disease progression, or up to 2 years of immunotherapy)
• Patient showed clinical stability with stable disease for 16 months
• Recent scans indicated modest disease progression, meeting the criteria for progression; ECOG performance status of 1
• Started subsequent line therapy with docetaxel (75 mg/m2 IV) and ramucirumab (10 mg/kg IV) every 21 days

Current Status:

• Follow-up visit with the medical doctor prior to Cycle 4 showed evidence of a partial response based on scans
• Patient reports experiencing mild fatigue, particularly around the time of treatment, and alopecia
• Despite no previous history of hypertension, patient's blood pressure is consistently measured at 170/100

What type of resistance has occurred with the patient? How would you manage AEs related to antiangiogenic-based regimens? What role would molecular testing have in informing treatment selection

NEXT STEP

Practice shared decision making and involve the patient in this discussion.

Setting: Telehealth visit

Patient Name: Robert or Roberta Brown

Tasks:

• Discuss the patient’s current symptoms and treatment-related side effects.
• Discuss methods to mitigate treatment-related side effects, most notable fatigue, mouth sores, and hypertension with both additional treatment or home remedies and lifestyle changes.

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Visit Objective

1. Differentiate between primary and acquired resistance to first-line ICI-based therapy in advanced NSCLC
2. Appraise clinical efficacy data surrounding second-line combination therapies, including antiangiogenic regimens, for treatment of advanced NSCLC
3. Recognize and mitigate the unique spectrum of treatment-related adverse events (TRAEs) associated with second-line combination therapies in advanced NSCLC

Target Audience

Clinical Oncologist, Oncology PA and NP, Oncology Pharmacist