Challenges & Progress in Lung Cancer Today
Lung cancer has long been the leading cause of cancer death globally, with limited treatment options.1 Fortunately, research over the last decade has ushered in a number of advances and approaches for certain patients, including targeted agents and immunotherapy.
Non-small cell lung cancer (NSCLC) is an area of particular interest for researchers as it accounts for the vast majority of lung cancer cases (84%).1,2 While NSCLC is typically associated with a better prognosis than other forms of lung cancer due in large part to treatment advances, in 2015 the five-year survival rate for advanced disease was approximately 6%.3
“Advanced lung cancer has always been the most challenging to treat. Most patients will inevitably progress on first-line treatment, and historically their options and outcomes could diminish with each round of subsequent therapy,” said Samantha Gothelf, PharmD, head, U.S. Medical Oncology, Bristol Myers Squibb.4,5
“Thankfully, the advent of newer treatment modalities has provided additional options for certain patients who progress following first-line treatment with chemotherapy, and may offer improved outcomes.”
Long-term Survival in Previously-Treated NSCLC Patients
Immunotherapy is one of the important advances in the treatment of metastatic NSCLC, and as options have been introduced, researchers continue to analyze follow-up data to understand the impact of these treatments over time.
In fact, data representing the longest follow-up of two phase 3 trials of an immunotherapy treatment in second-line metastatic NSCLC (mNSCLC) patients were recently presented.6
The pivotal trials, CheckMate -017 and -057, which studied Opdivo (nivolumab) in patients with either squamous or non-squamous previously-treated NSCLC, showed an overall survival benefit versus chemotherapy in the initial analyses. A follow-up analysis at five years showed that more patients treated with Opdivo were alive after beginning treatment than those treated with chemotherapy.
CheckMate -017 and CheckMate -057 support the current U.S. Food and Drug Administration (FDA) indication for Opdivo (nivolumab) – a PD-1 inhibitor – for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on an FDA-approved therapy for these aberrations prior to receiving Opdivo.7
Opdivo is available in either a 240 mg intravenous infusion every two weeks or 480 mg intravenous solution every four weeks and treatment is continued until disease progression or unacceptable toxicity.7
Opdivo can cause problems that can sometimes become serious or life threatening and can lead to death. Opdivo is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion-related reactions; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.7
CheckMate -017 and -057 Study Design
Patients randomized 1:1 to receive Opdivo or docetaxel7
3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=135)7
75 mg/m2 intravenously every 3 weeks (n=137)7
Patients randomized 1:1 to receive Opdivo or docetaxel7
3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=292)7
75 mg/m2 intravenously every 3 weeks (n=290)7
In the initial analysis of CheckMate -017, with a minimum follow up of 11 months, half of the 135 patients with previously-treated advanced squamous NSCLC were alive 9.2 months after starting treatment with Opdivo, versus 6 months for the 137 patients who received docetaxel (HR 0.59 [95% CI, 0.44-0.79] P=0.0002).7 The risk of dying was reduced by 41% with Opdivo compared to docetaxel and the confirmed overall response rate (ORR) was 20% (one complete response [95% CI: 14-28]) versus 9% for docetaxel (0 complete responses [95% CI: 5-15]; P=0.0083).7 Median progression-free survival (mPFS) was 3.5 months in the Opdivo arm, compared to 2.8 months with docetaxel (HR 0.62 [95% CI: 0.47-0.81] P=0.0004).7
In the initial analysis of CheckMate -057, with a minimum follow up of 13.2 months, half of the 292 patients with previously-treated advanced non-squamous NSCLC were alive at 12.2 months after starting treatment with Opdivo, versus 9.4 months for the 290 patients who received the chemotherapy (docetaxel) (HR 0.73 [95% CI, 0.60-0.89] P=0.0015).7 The risk of dying was reduced by 27% with Opdivo compared to docetaxel, and the ORR in the Opdivo arm was 19% (four complete responses [95% CI: 15-24]) versus 12% with docetaxel (one complete response [95% CI: 9-7] P=0.02).7 mPFS was 2.3 months in the Opdivo arm, compared to 4.2 months with docetaxel (HR 0.92 [95% CI: 0.77-1.11] P=0.39).7
The follow-up analysis at five-years with a minimum follow-up of 62.6 months for CheckMate -017 and 62.7 months for CheckMate -057 included a pooled patient population (n=427) for Opdivo and consisted of 292 with non-squamous and 135 with squamous histology. The pooled patient population (n=427) for docetaxel consisted of 290 patients with non-squamous and 137 with squamous histology. This analysis showed overall survival rates of 13.4% in patients with previously-treated NSCLC who were treated with Opdivo and 2.6% in patients treated with docetaxel [Figure 1].6
At five years, the overall survival rate for patients with previously-treated squamous NSCLC was 12.3% for patients treated with Opdivo and 3.6% for docetaxel. For patients with previously-treated non-squamous NSCLC, the overall survival rate was 14% for patients treated with Opdivo and 2.1% for docetaxel.6
In the primary analysis of Checkmate -017 and -057, serious adverse reactions occurred in 46% of patients receiving Opdivo (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate -017 and -057, the most common adverse reactions (≥20%) in patients receiving Opdivo (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Safety results from the five-year analysis were consistent with the primary analysis and no new safety signals were observed. Please see additional Important Safety Information below.
Driving Continued Progress in Second-Line NSCLC
The follow-up analysis of the CheckMate -017 and CheckMate -057 trials continues to demonstrate the important role of Opdivo for patients with previously-treated advanced NSCLC.
“Previously-treated advanced NSCLC can be a particularly daunting form of cancer as historically, very few patients are alive five years after diagnosis. The observed impact of Opdivo on overall survival versus docetaxel at five years is a very encouraging outcome for both physicians and patients,” said Gothelf.6
“As we think about the next wave of research to improve outcomes, extending the curve and achieving long-term survival for more patients across lines of therapy will be an important focus.”
OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
IMPORTANT SAFETY INFORMATION
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients.
OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.
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. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.
OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients.
OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients.
Immune-Mediated Skin Adverse Reactions
OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients.
OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion-related reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.
Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.
Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women not to breastfeed during treatment and for at least 5 months after the last dose.
Serious Adverse Reactions
In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure.
Common Adverse Reactions
In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Please see U.S. Full Prescribing Information for OPDIVO.
For more information about Opdivo, please visit www.opdivo.com.
Opdivo is a registered trademark of Bristol-Myers Squibb Company.
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