The Role of Immunotherapy in the Treatment of First-Line ES-SCLC

This article was sponsored by AstraZeneca.

This article includes expert insight from Afshin Dowlati, MD, associate director for clinical research at the Case Comprehensive Cancer Center and professor in the department of medicine, division of hematology and oncology at Case Western Reserve University in Cleveland, OH.

Small cell lung cancer (SCLC) accounts for approximately 14% of all lung cancer cases.1 It is an aggressive form of lung cancer, and its hallmark is high-grade malignant tumors that spread rapidly or quickly metastasize.1 Most patients with SCLC are diagnosed with extensive-stage (ES) SCLC, which is when the cancer has already spread outside of the lung and potentially to distant organs.2,3 Further complicating the prognosis, approximately 20% of patients with SCLC present with brain metastases at diagnosis and up to 80% of patients will develop central nervous system (CNS) involvement during the course of the disease.4,5

Prior to the availability of FDA-approved immunotherapy options, first-line treatment of ES-SCLC focused on systemic therapies with etoposide plus platinum-doublet chemotherapy.6 However, responses to these chemotherapy only first-line regimens have not been durable.6 Just 2% of patients with ES-SCLC reach 5-year survival with chemotherapy alone; typical overall survival for these patients is between 9 and 10 months.7,8

“Historically, the systemic treatment of ES-SCLC had remained unchanged over the past few decades,” Afshin Dowlati, MD, noted.6,9 He explained in the first-line treatment of ES-SCLC the combination of carboplatin or cisplatin with etoposide remain standard-of-care, first-line regimens.8 Dr Dowlati added, “The addition of immune checkpoint inhibitors (ICIs) to frontline chemotherapy has been an important step forward in treating first-line ES-SCLC.”1

Treatment Combinations in First-line ES-SCLC with Immunotherapy

The use of such first-line combination regimens that add immunotherapy to the standard-of-care chemotherapy treatment (etoposide plus carboplatin or cisplatin) has helped patients with first-line ES-SCLC.1,10,11

IMFINZI® (durvalumab) in combination with etoposide plus carboplatin or cisplatin chemotherapy (EP) is an FDA-approved regimen for first-line treatment of adult patients with ES-SCLC.12 This regimen is an American Society of Clinical Oncology guideline-recommended treatment supported by data from the CASPIAN Phase III trial (NCT03043872).10,13

CASPIAN Clinical Trial Design

The Phase III, randomized open-label, multicenter CASPIAN study investigated the efficacy and safety of IMFINZI plus EP compared with EP alone in the first-line treatment of patients with ES-SCLC.10

Treatment-naive patients (N = 805) were randomized to receive 4 cycles of IMFINZI plus EP followed by maintenance IMFINZI (until disease progression or unacceptable toxicity), 4 cycles of IMFINZI plus EP plus tremelimumab-actl followed by IMFINZI maintenance, or up to 6 cycles of EP alone.10 Overall, baseline characteristics, such as gender, age, and smoking history, were well-balanced between the IMFINZI plus EP and EP alone arms.10

Having the choice between 2 platinum-based chemotherapy options allows treating physicians to have flexibility in being able to choose the platinum-based chemotherapy option that is the best option for their patients.13 “Although carboplatin is the option more commonly combined with etoposide, cisplatin is still used,” Dr Dowlati commented.14

Clinical Results

The primary endpoint of the CASPIAN study was overall survival (OS), and a key secondary endpoint was objective response rate (ORR).10

At the time of the planned interim OS analysis with a median duration of follow-up of 14.2 months, median OS was 13.0 months (95% CI, 11.5-14.8) with IMFINZI plus EP vs 10.3 months (95% CI, 9.3-11.2) with EP alone (HR, 0.73; 95% CI, 0.59-0.91; P = 0.0047).12

Notably, IMFINZI plus EP is the only FDA-approved immuno-oncology combination in first-line ES-SCLC with 3-year OS data from a randomized phase III study.15-17 The planned exploratory 3-year OS analysis was conducted approximately 3 years after the last patient was randomized and was not formally tested for statistical significance. At the time of the 3-year analysis, median OS was 12.9 months (95% CI, 11.3-14.7) with IMFINZI plus EP and 10.5 months (95% CI, 9.3-11.2) with EP alone. OS rates at 12, 24, and 36 months (estimated proportion of patients alive based on the 3-year analysis) for the IMFINZI plus EP arm and the EP alone arm were (52.8% and 39.3%; 22.9% and 13.9%; 17.6% and 5.8%, respectively).15

At a median duration of follow-up 25.1 months, IMFINZI plus EP provided a high response rate.9 The investigator-assessed confirmed ORR was 68% (95% CI, 62%-73%) in the IMFINZI plus EP arm and 58% (95% CI, 52%-63%) in the EP alone arm. The planned exploratory analysis was not tested for statistical significance.9,12

Safety

Serious adverse events (SAEs) occurred in 31% of patients receiving IMFINZI plus EP. Fatal adverse reactions (ARs) occurred in 4.9% of patients in the IMFINZI plus EP arm; pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis occurred in 1 patient each and sudden death occurred in 2 patients.12 The most frequent serious ARs reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and expansion of COPD (1.1%).12 In the CASPIAN study, 7% of patients receiving IMFINZI plus EP discontinued IMFINZI treatment due to ARs, including pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis, and pancytopenia (1 patient each).12 The most common ARs (occurring in ≥10% of patients) were cough/productive cough (15%), nausea (34%), constipation (17%), vomiting (15%), diarrhea (10%), hyperthyroidism (10%), alopecia (31%), rash (11%), fatigue/asthenia (32%), and decreased appetite (18%).12

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI® (durvalumab).

Immune-Mediated Adverse Reactions
Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Please see additional Important Safety Information throughout and Full Prescribing Information, including Medication Guide for IMFINZI.

The Future of ES-SCLC Treatment and the Role of Immunotherapy

The addition of ICI to the standard chemotherapy options, such as IMFINZI plus EP, give physicians an option in the first-line treatment of ES-SCLC that may offer improved OS benefits.10,16 Ongoing therapeutic areas of research are essential to the pursuit of further improving outcomes for this challenging disease.1

IMPORTANT SAFETY INFORMATION

There are no contraindications for IMFINZI® (durvalumab).

Immune-Mediated Adverse Reactions
Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy.

Immune-Mediated Colitis

IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions.

Immune-Mediated Hepatitis

IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions.

Immune-Mediated Endocrinopathies

  • Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
  • Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI.
  • Thyroid Disorders: IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.
  • Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
  • Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI.
  • Hypothyroidism: Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.
  • Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI.

Immune-Mediated Nephritis with Renal Dysfunction

IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

Immune-Mediated Dermatology Reactions

IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.

  • Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
  • Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
  • Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
  • Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
  • Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.
  • Endocrine: Hypoparathyroidism.
  • Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Infusion-Related Reactions
IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZI

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and advise them to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI.

Lactation

There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for 3 months after the last dose.

Adverse Reactions

  • In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), the most common adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%), and alopecia (31%). The most common Grade 3 or 4 adverse reaction (≥3%) was fatigue/asthenia (3.4%).
  • In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy.

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Indication:

IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

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