ADJUVANT OSIMETRINIB APPROVED BY FDA

 On December 18, the U.S. Food and Drug Administration (FDA) approved osimertinib (Tagrisso) for adjuvant therapy after tumor resection in patients with non–small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

ADAURA

Efficacy was demonstrated in the randomized, double-blind, placebo-controlled ADAURA trial. The study included patients with NSCLC and EGFR exon 19 deletions or exon 21 L858R mutations who had undergone a complete tumor resection, with or without prior adjuvant chemotherapy.

Eligible patients with resectable tumors (stage IB­–IIIA) were required to have predominantly nonsquamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas EGFR Mutation Test. A total of 682 patients were randomly assigned 1:1 to receive osimertinib at 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy, if given.

The major efficacy outcome measure was disease-free survival in patients with stage II–IIIA NSCLC determined by investigator assessment. Median disease-free survival was not reached (range = 38.8 months–not evaluable) in patients treated with osimertinib compared with 19.6 months (range = 16.6–24.5 months) in patients treated with placebo (hazard ratio [HR] = 0.17, 95% confidence interval [CI] = 0.12–0.23, P < .0001). Disease-free survival in the overall study population was a secondary efficacy outcome measure; the median was not reached (range = not evaluable–not evaluable) in patients in the osimertinib arm compared with 27.5 months (range = 22­–36 months) in the placebo arm (HR = 0.20, 95% CI = 0.15–0.27, P < .0001).

The most commonly reported (> 20%) adverse reactions in patients taking osimertinib, including laboratory abnormalities, were lymphopenia, leukopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.

The recommended osimertinib dose for adjuvant treatment of early-stage NSCLC is 80 mg orally once daily, with or without food, until disease recurrence, unacceptable toxicity, or for up to 3 years.

PLEURAL EFFUSION REDUCES IMMUNOTHERAPY EFFICACY?

 Patients with non–small cell lung cancer (NSCLC) who have pleural effusion, especially those requiring pleural evacuation, experienced poorer survival when treated with immune checkpoint inhibitors, according to findings presented by Epaillard et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Virtual Congress 2020 (Abstract 42P).

Researchers explained that the pleura is a common site of metastatic involvement in patients with NSCLC, and the pleura also acts as a natural barrier that can limit the penetration and efficacy of immune checkpoint inhibitors. These factors led to the PLUIE study assessment of the clinical outcome of patients with NSCLC who have pleural effusion and were treated with an immune checkpoint inhibitor.

PLUIE Details

This multicenter, international, retrospective study identified 538 patients with NSCLC who were treated with an immune checkpoint inhibitor from November 2012 to November 2019. The investigators stratified this cohort by pleural effusion (n = 196) vs no pleural effusion (n = 342) as of the immunotherapy baseline.

Photo credit: Getty

Overall survival and the early death rate served as the primary endpoints, and the secondary outcomes were progression-free survival and disease control rate. The association between outcomes and pleural effusion was evaluated using logistic regression, whereas univariate and multivariate Cox models were performed for overall and progression-free survival.

The median patient age in the overall population was 62.9 years; 34.6% of patients were female; 9.5% were never smokers; and 75.7% of patients had nonsquamous NSCLC. The characteristics were similar in the pleural effusion group: the patients’ median age was 64.4 years; 31.6% were female; 12.4% were never smokers, and 77.6% had nonsquamous NSCLC. Immune checkpoint inhibitors were administered as first- or second-line therapy in 66% of patients, and 94% of patients received immune checkpoint inhibitor monotherapy.

In terms of patient characteristics, an association was found between pleural effusion and a higher number of metastatic sites: the pleural effusion cohort had a median of 3.5 metastatic sites compared with a median of 2.7 metastatic sites in the no–pleural effusion cohort. Pleural effusion was also associated with a poorer Eastern Cooperative Oncology Group performance status: 90.8% of patients with pleural effusion vs 80.5% of those without pleural effusion had a performance status of at least 2.  

Key Findings

Regarding the primary objective, the overall cohort demonstrated a median overall survival of 9.7 months (95% confidence interval [CI] = 8.1–11.8 months), whereas the pleural effusion cohort had a median overall survival of 6.3 months (95% CI = 4.0–8.6 months) compared with 11.4 months (95% CI = 9.7–13.8 months) in the no–pleural effusion cohort (P = .002). The early death rate was 31.4% in the overall cohort, whereas the early death rates in the pleural effusion compared with no–pleural effusion cohorts were 38.3% vs 27.5% (odds ratio [OR] = 1.63, 95% CI = 1.13–2.37, P = .01). 

Progression-free survival was 1.8 months (95% CI = 1.7–2.5 months) in the pleural effusion cohort compared with 2.3 months (95% CI = 2.0–3.6 months) in the no–pleural effusion group (P = .04).

Following adjustment for performance status; liver, intracranial, or bone metastasis; the immunotherapy line; and the derived neutrophil-to-lymphocyte ratio, pleural effusion remained an independent prognostic factor for overall survival (hazard ratio [HR] = 1.38, 95% CI = 1.09–1.74, P = .007) and progression-free survival (HR = 1.35, 95% CI = 1.09–1.68, P = .006). The disease control rate was 49.9% in those with pleural effusion compared with 52.3% in those without pleural effusion (OR = 1.64, 95% CI = 1.14–2.40, P = .01).

Of the 196 patients in the pleural effusion cohort, 73 (37.2%) patients required pleural evacuation, which was associated with a significantly increased early death rate of 52% in patients who had it vs 30.5% in those who did not (P = .003).

The authors concluded that pleural effusion is associated with worse prognosis and lower responses to treatment with an immune checkpoint inhibitor.

INHERTU-TUCATINIB NEAR APPROVAL BY EMA

 The drug review panel for the European Medicines Agency (EMA) has endorsed the approval of several cancer therapies.

The Committee for Medicinal Products for Human Use (CHMP) has recommended granting conditional marketing authorization for trastuzumab deruxtecan (Enhertu) for the treatment of metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer.

Trastuzumab is a monoclonal antibody–drug conjugate that binds to HER2, disrupting signaling and mediating antibody-dependent cell-mediated cytotoxicity. It was reviewed under the EMA's accelerated assessment program and is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more anti-HER2-based regimens.

The second drug is fedratinib (Inrebic), which received a positive opinion for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocythemia myelofibrosis who are JAK-inhibitor naive or who have been treated with ruxolitinib (Jakafi).

The active substance is fedratinib, a protein kinase inhibitor with activity linked to the selective inhibition of JAKs involved in the signaling mediation of several cytokines and growth factors that play a role in hematopoiesis and immune function.

Marketing authorization under exceptional circumstances was recommended for moxetumomab pasudotox (Lumoxiti) for the treatment of relapsed or refractory hairy cell leukemia in patients who have already received at least two systemic therapies, including treatment with a purine nucleoside analogue.

The agent's active substance is moxetumomab pasudotox, a CD22-targeted immunotoxin that is designed to direct the cytotoxic action of the truncated Pseudomonas exotoxin to cells that express the CD22 receptor.

The most common adverse events reported are peripheral edema, nausea, fatigue, headache, and pyrexia. Identified risks include hemolytic uremic syndrome and capillary leak syndrome.

The committee also recommended granting marketing authorization to selpercatinib (Retsevmo), which is indicated for the treatment of cancers with a rearranged during transfection (RET) gene fusion. These cancers include RET-fusion-positive non–small cell lung cancer (NSCLC), RET-fusion-positive thyroid cancer, and RET-mutant medullary thyroid cancer (MTC).

Associated benefits observed with selpercatinib are the objective response rate and response duration in previously treated patients with RET-fusion-positive NSCLC or thyroid cancer and RET-mutant MTC. The most common reported side effects are increased aspartate transaminase level, increased alanine transaminase level, decreased lymphocyte count, dry mouth, increased creatinine level, diarrhea, fatigue, edema, and hypertension.

The CHMP also gave a positive opinion regarding tucatinib (Tukysa), which is indicated for use in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least two prior anti-HER2 treatment regimens.

Associated benefits are the drug's ability to increase progression-free survival and overall survival, including for patients with metastases. The most common observed side effects are diarrhea and increased liver enzyme levels.

New Generics

The CHMP has also given a positive recommendation for four generic medicines to be used in cancer care.

The first is lenalidomide Krka (KRKA, d.d., Novo mesto), which is recommended for the treatment of multiple myeloma and follicular lymphoma.

Lenalidomide Krka is a generic of Revlimid, which has been authorized for use in the European Union for over a decade. The generic formulation has demonstrated satisfactory quality and bioequivalence to the reference product. Lenalidomide Krka is indicated for use as monotherapy in maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplant; as combination therapy with dexamethasone or bortezomib and dexamethasone or melphalan and prednisone in previously untreated patients who are not eligible for transplant; and in combination with dexamethasone for patients who have received at least one prior therapy.

For previously treated adult patients with grade 1–3a follicular lymphoma, lenalidomide Krka is to be used in combination with rituximab (Rituxan).

Lenalidomide Krka d.d. has the same indications as lenalidomide Krka with the addition of myelodysplastic syndromes for adult patients with transfusion-dependent anemia at low risk or intermediate risk with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

Lenalidomide Krka d.d. Novo mesto has the same indications as lenalidomide Krka d.d. with the addition of mantle cell lymphoma, for which it is indicated for relapsed or refractory disease.

The CHMP has also adopted a positive opinion and recommended granting marketing authorization for Sunitinib Accord (Accord Healthcare SLU), the generic of Sutent, which has been marketed in the European Union since 2006. Studies have demonstrated that the generic product has satisfactory quality and bioequivalence to the reference product.

It is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumor in adults after failure of imatinib treatment due to resistance or intolerance; advanced/metastatic renal cell carcinoma in adults; and unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors with disease progression in adults.

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LORLATINIB FOR ALK+ NSCLC

As reported in The New England Journal of Medicine by Alice T. Shaw, MD, PhD, and colleagues, an interim analysis of the phase III CROWN trial has shown that first-line lorlatinib significantly improved progression-free survival and intracranial response rate vs crizotinib in patients with advanced ALK-positive non–small cell lung cancer (NSCLC).

As stated by the investigators, “Lorlatinib, a third-generation inhibitor of ALK, has antitumor activity in previously treated patients with ALK-positive NSCLC. The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.”

Alice T. Shaw, MD, PhD

Study Details

In the open-label trial, 296 patients from sites in 23 countries who had received no prior systemic treatment for metastatic disease were randomly assigned between May 2017 and February 2019 to receive lorlatinib at 100 mg daily (n = 149) or crizotinib at 250 mg twice daily (n = 147) continuously in 28-day cycles. Stage IV disease was present in 91% vs 95% of patients, and 44% of patients in each group were Asian.

The primary endpoint was progression-free survival on blinded independent central review. The current planned interim analysis occurred after 75% of expected progression-free survival events had occurred.

Progression-Free Survival

KEY POINTS

• Lorlatinib significantly improved progression-free survival vs crizotinib.
• Lorlatinib was associated with a higher intracranial response rate in patients with measureable brain metastases.

The median follow-up for progression-free survival was 18.3 months in the lorlatinib group and 14.8 months in the crizotinib group. Progression-free survival at 12 months was 78% (95% confidence interval [CI] = 70%–84%) in the lorlatinib group vs 39% (95% CI = 30%–48%) in the crizotinib group (hazard ratio [HR] = 0.28, 95% CI = 0.19–0.41, P < .001). Median progression-free survival was not reached (95% CI = not reached–not reached) vs 9.3 months (95% CI = 7.6–11.1 months).

Objective response was observed in 76% of patients in the lorlatinib group vs 58% in the crizotinib group (odds ratio [OR] = 2.25, 95% CI = 1.35–3.89), including complete response in four vs no patients. Median duration of response was not reached vs 11.0 months. Among 17 vs 13 patients with measurable brain metastases at baseline, an intracranial objective response was observed in 14 (82%) vs 3 patients (23%; OR = 16.83, 95% CI = 1.95–163.23), with complete response in 12 vs 1; the median duration of response was not reached vs 10.2 months.

Overall survival data were not mature at data cutoff. Death had occurred in 23 patients (15%) in the lorlatinib group and 28 patients (19%) in the crizotinib group (HR = 0.72, 95% CI = 0.41–1.25).  

Adverse Events

The most common adverse events of any grade occurring with > 10% greater incidence in either group were hypercholesterolemia (70%), hypertriglyceridemia (64%), and edema (55%) in the lorlatinib group, and diarrhea (52%), nausea (52%), vision disorder (39%), and vomiting (39%) in the crizotinib group. Grade 3 or 4 adverse events occurred in 72% vs 56% of patients; the most common were elevated triglycerides (20%), increased weight (17%), elevated cholesterol (16%), and hypertension (10%) in the lorlatinib group, and laboratory abnormalities in the crizotinib group.

Serious adverse events occurred in 34% vs 27%. Adverse events led to discontinuation of treatment in 7% vs 9%. Adverse events led to death in seven patients in each group.

The investigators concluded, “In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels.”

 

MRI HELPFUL FOR MESOTHELIOMA

NEW YORK (Reuters Health) - MRI offers advantages over CT for assessing primary-tumor volume in patients with mesothelioma, researchers from U.K. report.

"MRI measurements of tumor volume appeared more discriminatory in predicting subsequent survival than CT measurements of the same factor," Dr. Kevin G. Blyth of Queen Elizabeth University Hospital and the University of Glasgow, U.K., told Reuters Health by email. "We also observed that the volume of tumor seen using MRI was higher, which may explain this, as mesothelioma is known to be difficult to identify on CT."

Primary-tumor volume is a critical determinant of survival in malignant pleural mesothelioma (MPM). Tumor volume as assessed by CT is associated with overall survival, but CT volumetry is uncommonly used because of the laborious nature of the manual segmentation required.

Dr. Blyth and colleagues compared CT volumetry with a novel MRI volumetry protocol they developed for their study of 31 patients with a final diagnosis of MPM.

Using their MRI method, the mean analysis time was 14 minutes, the intraobserver agreement was 87.5%, and the interobserver agreement was 96.2%.

Mean CT analysis time was significantly longer (151 minutes), and interobserver agreement was only moderate (72%).

The mean primary-tumor volume was significantly higher by MRI (370 cc) than by CT (302 cc), and MRI tumor volumes were consistently larger than CT tumor volumes, the researchers report in Lung Cancer.

There was no correlation between either MRI tumor volume or CT tumor volume and clinical T-stage.

When dichotomized at 300 cc, higher MRI tumor volume was associated with a 4.03-fold greater risk of death, but there was no significant relationship between CT tumor volume at this cutpoint and overall survival.

"We need to look beyond traditional measures of tumor stage in mesothelioma and also look beyond CT imaging, which is the workhorse of chest radiology but has its limits," Dr. Blyth said.

"We need larger, multicenter validation studies to prove that the findings we report are reproducible," he said. "We are launching these now as part of the CRUK-funded PREDICT-Meso International Accelerator Network, of which I am chief investigator."

Dr. Blyth added, "We also need to complete large-scale studies to demonstrate that tumor volume (however you measure it) outperforms the currently used descriptors for T-stage (which don't account for volume or size - only the extent of invasion into adjacent structures)."

SOURCE: https://bit.ly/34EOfqf Lung Cancer, online October 1, 2020.

NO BENEFIT OF ADJUVANT IRINOTECAN FOR SCLC

In a Japanese phase III trial reported in the Journal of Clinical Oncology, Kenmotsu et al found that adjuvant irinotecan/cisplatin did not improve relapse-free survival vs etoposide/cisplatin in patients with completely resected, pathologic stage I–IIIA, high-grade neuroendocrine carcinoma of the lung.

Study Details

In the multicenter trial, 221 patients were randomly assigned between April 2013 and October 2018 to receive etoposide at 100 mg/m2 on days 1 to 3 plus cisplatin at 80 mg/m2 on day 1 every 3 weeks for up to four cycles (n = 111) or irinotecan at 60 mg/m2 on days 1, 8, and 15 plus cisplatin at 60 mg/m2 on day 1 every 4 weeks for up to four cycles (n = 110). The primary endpoint was relapse-free survival in the intention-to-treat population.

Relapse-Free Survival

At the second interim analysis, early termination of the trial was recommended due to futility. At median follow-up of 24.1 months, 3-year relapse-free survival was 65.4% in the etoposide/cisplatin group vs 69.0% in the irinotecan/cisplatin group (hazard ratio [HR] = 1.076, 95% confidence interval [CI] =0.666–1.738, P = .619).

KEY POINTS

• Adjuvant irinotecan/cisplatin did not improve relapse-free survival vs etoposide/cisplatin.
• The trial was ended early due to futility.

No significant difference in 3-year recurrence-free survival was observed between 59 vs 58 patients with histology of small cell lung cancer (SCLC) or combined SCLC (65.2% vs 66.5%, HR = 1.029, 95% CI = 0544–1.944) or between 52 vs 52 patient with large-cell neuroendocrine carcinoma or combined large-cell neuroendocrine carcinoma (66.5% vs 72.0%, HR = 1.072, 95% CI = 0.517–2.222). No significant differences were observed according to pathologic disease stage.

No significant difference in overall survival was observed. Overall, 13 patients in the etoposide/cisplatin group vs 19 in the irinotecan/cisplatin group had died at time of analysis; at 3 years, overall survival was 84.1% vs 79.0%.

Adverse Events

Grade 3 or 4 adverse events were more common in the etoposide/cisplatin group vs the irinotecan/cisplatin group, including neutropenia (97% vs 36%), leukopenia (60% vs 14%), and febrile neutropenia (20% vs 4%). Grade 3 or 4 nonhematologic adverse events occurred in 40.4% vs 31.2% of patients. Grade 3 or 4 anorexia (6% vs 11%) and diarrhea (1% vs 8%) were more common in the irinotecan/cisplatin group.

The investigators concluded, “Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving relapse-free survival in patients with completely resected high-grade neuroendocrine carcinoma of the lung; thus, etoposide plus cisplatin remains the standard treatment.”

Hirotsugu Kenmotsu, MD, PhD, of the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Japan Agency for Medical Research and Development and National Cancer Center Research and Development Funds. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

WHO BENEFITS FROM ADJUVANT CHEMOTHERAPY FOR NSCLC

Association of Adjuvant Chemotherapy With Survival in Early-Stage NSCLC: Do Tumor Size and High-Risk Features Have an Impact?

By Matthew Stenger

Posted: 10/13/2020 10:48:00 AM
Last Updated: 10/16/2020 2:19:35 PM

In a retrospective cohort study reported in JAMA Oncology, Pathak et al found that tumor size alone was not associated with improved survival with adjuvant therapy vs no adjuvant chemotherapy in patients with early-stage, node-negative non–small cell lung cancer (NSCLC).

As stated by the investigators, “Tumor size larger than 4 cm is accepted as an indication for adjuvant chemotherapy in patients with node-negative NSCLC. Treatment guidelines suggest that high-risk features are also associated with the efficacy of adjuvant chemotherapy among patients with early-stage NSCLC, yet this association is understudied.”

Study Details

The study involved National Cancer Database data from 50,814 treatment-naive patients with completely resected node-negative NSCLC diagnosed between January 2010 and December 2015. Patients had to have survived for at least 6 weeks after surgery. Overall survival with adjuvant chemotherapy vs observation was analyzed by tumor size and according to presence or absence of high-risk pathologic features (visceral pleural invasion, lymphovascular invasion, and high-grade histologic findings) and sublobar surgery.

“In this cohort study, tumor size alone was not associated with improved efficacy of adjuvant chemotherapy in patients with early-stage (node-negative) NSCLC. High-risk clinicopathologic features and tumor size should be considered simultaneously when evaluating patients with early-stage NSCLC for adjuvant chemotherapy.”

— Pathak et al

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Key Findings

Among the 50,814 patients, 4,220 (8.3%) received adjuvant chemotherapy and 46,594 (91.7%) did not.

Among patients with tumors ≤ 3 cm, adjuvant chemotherapy was not associated with improved overall survival vs no chemotherapy (overall hazard ratio [HR] = 1.10, P = .17). For patients with two or more high-risk factors, the hazard ratio was 0.92 (P = .40).   

Among patients with tumors > 3 cm to 4 cm, adjuvant chemotherapy was associated with improved survival among patients who underwent sublobar surgery (HR = 0.72, P = .004). The overall hazard ratio among all patients was 0.90 (P = .21).  

Among patients with tumors > 4 cm to 5 cm, adjuvant chemotherapy was associated with improved survival in patients with one or more high-risk pathologic feature (HR = 0.67, P = .02). The overall hazard ratio among all patients was 0.75 (P < .001). The hazard ratio among patients with no high-risk factors was 1.06 (P = .37).  

Among patients with tumors > 5 cm, adjuvant chemotherapy was associated with a survival benefit among all patients (HR = 0.69, P < .001). The hazard ratio among patients with no high-risk factors was 0.75 (P = .004).

The investigators concluded, “In this cohort study, tumor size alone was not associated with improved efficacy of adjuvant chemotherapy in patients with early-stage (node-negative) NSCLC. High-risk clinicopathologic features and tumor size should be considered simultaneously when evaluating patients with early-stage NSCLC for adjuvant chemotherapy.”

Daniel J. Boffa, MD, of the Section of Thoracic Surgery, Yale School of Medicine, is the corresponding author for the JAMA Oncology article.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

FIRST LINE NIVO-IPI APPROVED FOR MESOTHELIOMA

On October 2, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as first-line treatment for adult patients with unresectable malignant pleural mesothelioma.

CheckMate 743

Efficacy was investigated in CheckMate 743, a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma who had received no prior anticancer therapy. Patients were randomly assigned to receive either nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of combination chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302).

The trial demonstrated a statistically significant improvement in overall survival for patients treated with nivolumab plus ipilimumab compared with those who received chemotherapy. Median overall survival was 18.1 months (95% confidence interval [CI] = 16.8–21.5) vs 14.1 months (95% CI = 12.5–16.2) (hazard ratio [HR] = 0.74, 95% CI = 0.61–0.89, P = .002).

Median progression-free survival per blinded independent central review was 6.8 months (95% CI = 5.6–7.4) in the nivolumab plus ipilimumab arm and 7.2 months (95% CI = 6.9–8.1) in the chemotherapy arm (HR = 1.0, 95% CI = 0.82–1.21). Confirmed overall response rate per blinded independent central review was 40% (95% CI = 34–45) and 43% (95% CI = 37–49) in the nivolumab plus ipilimumab and chemotherapy arms, respectively. Median response duration was 11.0 months in the nivolumab plus ipilimumab arm and 6.7 months in the chemotherapy arm.

The most common adverse reactions (incidence ≥ 20%) in patients receiving the combination of nivolumab plus ipilimumab in CheckMate 743 were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.

The recommended doses for adult patients with unresectable malignant pleural mesothelioma are nivolumab at 360 mg every 3 weeks and ipilimumab at 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies. FDA approval occurred approximately 5 months ahead of the goal date.

FIRST LINE ATELIZUMAB IN NSCLC

As reported in The New England Journal of Medicine by Roy S. Herbst, MD, PhD, and colleagues, the phase III IMpower110 trial has shown significantly prolonged overall survival with first-line atezolizumab vs platinum-based chemotherapy in patients with metastatic non–small cell lung cancer (NSCLC) with high PD-L1 expression.

The trial supported the May 2020 U.S. Food and Drug Administration approval of atezolizumab for the first-line treatment of patients with metastatic NSCLC with tumors that have high PD-L1 expression and no EGFR or ALK genomic tumor aberrations. High PD-L1 expression was defined as PD-L1 staining of ≥ 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area.

Roy S. Herbst, MD, PhD

Study Details

The open-label trial included 572 patients from sites in 19 countries who had metastatic nonsquamous or squamous NSCLC and PD-L1 expression on ≥ 1% of tumor cells or tumor-infiltrating immune cells. Patients were randomly assigned between July 2015 and February 2018 to receive atezolizumab (n = 285) or chemotherapy (n = 287). Random assignment was stratified according to sex, Eastern Cooperative Oncology Group performance status score, histologic type, and PD-L1 status. The population with EGFR and ALK wild-type tumors consisted of 554 patients, including 277 patients in each group. The 18 patients with an EGFR mutation or ALK translocation were excluded from the primary analysis population.

Treatment consisted of atezolizumab at 1,200 mg or 4 or 6 cycles of platinum-based chemotherapy once every 3 weeks. In the chemotherapy group, patients with nonsquamous NSCLC (69% of atezolizumab group, 70% of chemotherapy group) received either cisplatin at 75 mg/m2 or carboplatin at AUC = 6 in addition to pemetrexed at 500 mg/m2. Patients with squamous NSCLC received cisplatin at 75 mg/m2 plus gemcitabine at 1,250 mg/m2 or carboplatin AUC = 5 plus gemcitabine at 1,000 mg/m2.

The primary endpoint was overall survival tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat primary analysis population. Testing was performed among patients with high PD-L1 expression, defined as expression on ≥ 50% of tumor cells or ≥ 10% of tumor-infiltrating immune cells; then among those with intermediate and high expression, defined as expression on ≥ 5% of tumor cells or tumor-infiltrating immune cells; and then among those with any expression, defined as expression on ≥ 1% of tumor cells or tumor-infiltrating immune cells.  

Overall Survival

Median follow-up ranged from 13.4 to 15.7 months according to PD-L1 groups. A total of 107 patients (38.6%) in the atezolizumab group and 98 (35.4%) in the chemotherapy group had high expression of PD-L1. Among these patients, median overall survival was 20.2 months in the atezolizumab group vs 13.1 months in the chemotherapy group (stratified hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.40–0.89, P = .01). Median overall survival was 20.2 vs 10.5 months (HR = 0.62, 95% CI = 0.40–0.96) among patients with nonsquamous histology and not reached vs 15.3 months (HR = 0.56, 95% CI = 0.23–1.37) among those with squamous histology.

KEY POINTS

• Atezolizumab significantly prolonged overall survival vs chemotherapy in patients with high PD-L1 expression.
• Median overall survival in this group was 20.2 months vs 13.1 months.

A total of 166 patients (59.9%) in the atezolizumab group and 162 (58.5%) in the chemotherapy group had high or intermediate PD-L1 expression. Among these patients, median overall survival was 18.2 months vs 14.9 months (stratified HR = 0.72, 95% CI = 0.52–0.99, P = .04).

The testing boundary for overall survival was not crossed in this analysis, and thus overall survival among patients with any PD-L1 expression (277 in each group) was not formally tested. Median overall survival among these patients was 17.5 months vs 14.1 months (stratified HR = 0.83, 95% CI = 0.65–1.07).

Among patients with high PD-L1 expression, median progression-free survival was 8.1 months in the atezolizumab group vs 5.0 months in the chemotherapy group (stratified HR = 0.63, 95% CI = 0.45–0.88). Among patients with high or intermediate PD-L1 expression, median progression-free survival was 7.2 months vs 5.5 months (stratified HR = 0.67, 95% CI = 0.52–0.88).

Adverse Events

Grade 3 or 4 adverse events occurred in 30.1% of patients in the atezolizumab group and in 52.5% of the chemotherapy group. Those occurring in ≥ 5% of either group were anemia (18%), neutropenia (18%), and thrombocytopenia (7%), all in the chemotherapy group. Serious adverse events occurred in 28.3% vs 28.5% of patients. Adverse events led to death in 11 patients (3.8%) in the atezolizumab group and 11 patients (4.2%) in the chemotherapy group. Immune-related adverse events occurred in 40.2% vs 16.7% of patients and were grade 3 or 4 in 6.6% and 1.5%. No immune-related adverse events led to death.

The investigators concluded: “Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type.”

Disclosure: The study was funded by F. Hoffmann–La Roche/Genentech. For full disclosures of the study authors, visit nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

FIRST LINE ATEZOLIZUMAB FOR NSCLC

 In a small group of selected patients with metastatic non-small-cell lung cancer, first-line treatment with atezolizumab extends median overall survival by just over 7 months, or 41%, compared to platinum-based chemotherapy, according to interim results of the IMpower110 study funded by Roche and Genentech.

The findings, published in The New England Journal of Medicine, only apply to patients with metastatic NSCLC who had wild-type epidermal growth factor receptors (EGFR) or anaplastic lymphoma kinase (ALK) mutations and had the highest expression of programmed death ligand 1 (PD-L1).

Of the more than 1.5 million people diagnosed with lung cancer each year, probably 20% to 30% of them could be candidates for the treatment under the terms of the study, lead author Dr. Roy Herbst, chief of medical oncology at the Yale University Cancer Center, told Reuters Health in a telephone interview.

Out of the 572 volunteers enrolled in IMpower10, 205 fell into that category. None had previously received chemotherapy for their stage IV non-squamous or squamous lung cancer tumors.

The results prompted the U.S. Food and Drug Administration (FDA) to approve the drug on May 18 for first-line therapy for such patients.

The drug, sold under the brand name Tecentriq, is a monoclonal antibody that acts as a "checkpoint inhibitor." It targets the PD-L1 protein on the surface of tumor cells that prevents the T cells of the immune system from attacking the tumor. With the PD-L1 protein neutralized, the T cells can do their job.

A similar drug for this group of patients, Merck's Keytruda (lambrolizumab), was approved by the FDA five years ago.

"The drugs look very equivalent," said Dr. Herbst, and that may affect whether doctors start using Tecentriq as first-line treatment.

The overall survival was 13.1 months for the volunteers who received conventional chemotherapy and 20.2 months with atezolizumab (P=0.01).

The median overall survival for patients with wild-type tumors who had any degree of PD-L1 expression was longer with atezolizumab, but not significantly so.

Progression-free survival in the 205-patient group with the highest PD-L1 expression was 8.1 months with atezolizumab and 5.0 months with conventional chemotherapy.

The 12-month overall survival rate was 64.9% with the drug and 50.6% with chemotherapy, with a median follow-up of 15.7 months.

Fatigue and weakness were the most common side effects.

The rates of grade 3 or 4 side effects also favored atezolizumab in all patients. They were seen in 30.1% of patients who received the drug versus 52.5% in the control group.

The companies helped collect, analyze and interpret the data from the 144 centers in 19 countries.

Dr. Herbst said that when he first started treating lung cancer, "nobody wanted to work in the field. The median time you survived was a couple of months -- maybe 6 months. If you got to a year, it was amazing. Now we're seeing people go on for years with these drugs."

"Now we have to build on this progress by combining them with other drugs" in hopes of getting even better outcomes, he said.

SOURCE: https://bit.ly/2Gea5IE The New England Journal of Medicine, online September 30, 2020.

FIRST LINE LORLATINIB FOR ALK+ NSCLC

First-line lorlatinib significantly prolonged progression-free survival (PFS) when compared with crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 3 CROWN trial.

Lorlatinib also produced a higher overall and intracranial response rate, prolonging progression to CNS disease.

These findings "support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC," said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne.

"The CROWN study clearly establishes lorlatinib as another option" among other first-line ALK inhibitors, Dr. Solomon said when presenting the findings at the European Society for Medical Oncology Virtual Congress 2020.

"We now have multiple options for first-line treatment of patients with ALK-positive lung cancer," noted study discussant Christine Lovly, MD, PhD, a medical oncologist and associate professor at Vanderbilt University Medical Center in Nashville, Tenn.

The question now, she said, is how to choose among these options. The drugs have all bested crizotinib in trials but haven't gone head to head against one another.

Lorlatinib and CROWN

Lorlatinib is currently approved in the United States to treat ALK-positive metastatic NSCLC that has progressed on crizotinib and at least one other ALK inhibitor. Lorlatinib was granted accelerated approval for this indication based on response rate and duration.

The CROWN study was intended to support the conversion to full approval, according to Pfizer, which is developing both lorlatinib and crizotinib. Pfizer also plans to use the results of CROWN to seek a first-line indication for lorlatinib in NSCLC.

CROWN enrolled 296 patients with stage IIIB/IV ALK-positive NSCLC who had received no prior systemic treatment. Patients with asymptomatic treated or untreated CNS metastases were eligible.

There were 149 patients randomized to lorlatinib at 100 mg daily and 147 randomized to crizotinib at 250 mg twice daily. Five patients in the crizotinib arm were included in the analysis but were not treated, Dr. Solomon said.

The median age was 61 years in the lorlatinib arm and 56 years in the crizotinib arm. Nearly all patients were White (48% in the lorlatinib arm and 49% in the crizotinib arm) or Asian (44% in both arms). A majority of patients were women (56% in the lorlatinib arm and 62% in the crizotinib arm), and more than half said they never smoked (54% in the lorlatinib arm and 64% in the crizotinib arm).

Response and PFS

According to blinded independent central review, the objective response rate was 76% with lorlatinib (113/149) and 58% with crizotinib (85/147). There were four complete responses with lorlatinib and none with crizotinib.

Among patients who had measurable or nonmeasurable brain metastases at baseline, the intracranial ORR was 66% with lorlatinib (25/38) and 20% (8/40) with crizotinib. In patients with only measurable brain metastases at baseline, the intracranial ORR was 82% with lorlatinib (14/17) and 23% with crizotinib (3/13).

The 12-month PFS rate was 78% in the lorlatinib arm and 39% in the crizotinib arm. The median PFS was 9.3 months in the crizotinib arm but was not reached in the lorlatinib arm, which "corresponded to a 72% reduction in the risk of death or progression [hazard ratio, 0.21; P < .001]," Dr. Solomon said.

"[T]he PFS for alectinib in the first line is approximately 3 years," Dr. Lovly noted. "We anxiously await additional data for lorlatinib to see how long the PFS will be."

The median time to intracranial progression was 16.6 months in the crizotinib arm but was not reached in the lorlatinib arm (HR, 0.07; P < .001).

"These data indicate the ability of lorlatinib not only to delay the progression of existing brain metastases, but also to prevent the development of new brain metastases," Dr. Solomon said.

Dr. Lovly noted that the efficacy of lorlatinib in the brain is "quite compelling," but other ALK inhibitors have demonstrated similar results.

As for overall survival, the data are still immature. The median overall survival was not reached with lorlatinib or crizotinib (HR, 0.72).

Toxicity

Dr. Solomon noted that lorlatinib "does have a different toxicity profile, compared to other ALK inhibitors." Specifically, lorlatinib is associated with hypercholesterolemia and hypertriglyceridemia, which have not been seen with other ALK inhibitors.

Lorlatinib is also associated with neurocognitive problems, including inattention, memory impairment, and mild confusion. Mood effects include emotional lability – "someone watching a movie might burst into tears when they wouldn't have otherwise," Dr. Solomon said – as well as anxiety and depression.

"So it's important to tell not just the patient but their family about these things so that they identify when [the events] happen," Dr. Solomon said. "That's key because [the events are] completely reversible when you stop the drug. With dose interruption, those effects will resolve."

Other adverse events that were more common with lorlatinib (a 10% or greater difference in frequency from crizotinib) included edema, weight gain, and peripheral neuropathy. Diarrhea, nausea, fatigue, vision disorders, constipation, and increased liver enzymes were more common with crizotinib. Grade 3-4 adverse events led to discontinuation in fewer than 10% of patients in each arm.

The study was funded by Pfizer, and the investigators included employees. Dr. Solomon is an adviser for Pfizer and other companies, and Dr. Lovly's industry ties included being both an advisor and speaker for Pfizer.

aotto@mdedge.com

SOURCE: Solomon B et al. ESMO 2020, Abstract LBA2.

NO BENEFIT OF MAINTENACE IMMUNOTHEARPY IN LIMITED SCLC

Giving nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) to small cell lung cancer (SCLC) patients after chemoradiotherapy does not offer a progression-free or overall survival benefit, suggests top-line data from a phase II trial.

However, there were signals that a longer follow-up period and a focus on patient subgroups could reveal a biomarker-driven population who will benefit from the treatment combination.

The research was presented at the ESMO Virtual Congress 2020 on September 19, which was held digitally this year due to the COVID-19 pandemic.

No Survival Benefits

For the STIMULI study more than 150 limited stage SCLC patients who had undergone chemoradiotherapy were randomised to either nivolumab plus ipilimumab induction followed by nivolumab maintenance monotherapy, or to the observation group.

Professor Solange Peters, ESMO president, and Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland reported that the immunotherapy combination did not significantly improve progression-free survival (PFS) or overall survival.

Prof Peters said that the study "did not meet its primary endpoint of improving PFS", adding that "a very short period on active treatment observed in the study, related to toxicity and subsequent treatment discontinuation, has certainly impacted the efficacy results".

"A longer follow-up...will allow the exploration of a possible late effect of immunotherapy consolidation on survival, which is already apparent" despite the short follow-up.

Noting the differential benefits of immunotherapy in certain subgroups, notably women and those who received twice daily radiotherapy fractions, Prof Peters said that exploratory work to identify potential biomarkers for response "is ongoing".

Study co-author Professor Sanjay Popat, Royal Marsden Hospital NHS Foundation Trust, London, told Medscape News UK that they were "of course" disappointed to see no improvement in survival.

"Nevertheless, this is an advance in the field because we’ve already showed this is not perhaps the best schedule" of immunotherapy due to the "relatively high rate of grade 3 and more adverse events".

But with greater understanding of the subgroups who showed a benefit and biomarker evaluation and several other trials ongoing, he has "no doubt that in the future we will be showing that checkpoint inhibitors are active in limited state SCLC".

Prof Popat added: "We just have to prove that benefit, and that’s why it’s absolutely important we continue to generate the evidence and ensure that our patients get access to clinical trials."

Disappointment

The results were described as "disappointing" by many on Twitter.

However, Stephen V. Liu director of thoracic oncology at Georgetown University, Washington DC, USA, said that, while STIMULI showed that the immunotherapy combination "did not improve" survival outcomes, the crossing of the curves pointed to the "statistical challenges" of the study.

https://twitter.com/stephenvliu/status/1307289636805513216?s=21

Dr Jonathan Lim, a PhD candidate at The Francis Crick Institute, London, highlighted the "interesting difference" in PFS between patients receiving twice daily and once daily radiotherapy.

"Are we potentially seeing the effect of immunogenic radiotherapy?" he asked.

https://twitter.com/drjonlim/status/1307281921941135360?s=21

 

'Frontline Standard of Care'

Prof Peters began her presentation by noting that the combination of nivolumab and ipilimumab has become a "frontline standard of care" in a number of metastatic cancers, including renal cell carcinoma and non-small cell lung cancer.

Moreover, CheckMate 032 showed that nivolumab monotherapy achieves durable responses and is well tolerated as a third or later line treatment in recurrent SCLC.

This did not translate into a longer PFS and overall survival, although there were signals for improved response in patients with a high tumour mutational burden.

For the phase II STIMULI trial, patients with treatment-naïve stage I–IIIB SCLC and a good performance status were given chemoradiotherapy followed by prophylactic cranial irradiation.

If they did not progress, they were randomised in a 1:1 fashion to immunotherapy consolidation or observation, with no further treatment.

Immunotherapy consisted of four cycles of induction treatment with nivolumab plus ipilimumab 3 times a week for four cycles, followed by nivolumab twice weekly for up to 12 months.

From an initial enrolment of 222 patients, 78 patients were assigned to immunotherapy consolidation and 75 to observation.

The median age of the patients was approximately 62 years. The majority (84%) had stage IIIA or IIIB disease, and between 80% and 83% had a partial response to chemoradiotherapy.

After a median follow-up of 22.7 months, 51 immunotherapy and 48 observation patients were still in the trial.

Prof Peters noted that most of the treatment failures in the observation group were due to disease progression, "while importantly in the nivolumab and ipilimumab arm most treatment failures were related not to disease progression but to toxicity, or to patient or investigator decision".

Trial Data

There was no significant difference between the immunotherapy and observation arms in terms of PFS, at 10.7 months and 14.5 months, respectively, or a hazard ratio of 1.02 (p=0.93).

Interestingly, patients with an ECOG performance status of 1 did better on immunotherapy than those with a status of 0, at a hazard ratio for PFS of 0.67 versus 2.06 (p for interaction=0.022).

A similar split was seen for patients who were treated with 2 radiotherapy fractions per day versus those who received one, at hazard ratios for PFS with immunotherapy of 0.63 and 1.34, respectively (p for interaction=0.096).

Overall survival was again not significantly different between the immunotherapy and observation arms, with the median not reached in the immunotherapy group, whilst it was 31.6 months - hazard ratio of 1.06 (p=0.83) – in the observation group.

However, and "very importantly in this secondary endpoint," she said, the curves crossed, suggesting that a survival benefit with immunotherapy accrued over time.

Indeed, the hazard ratio for survival for immunotherapy versus observation fell from 1.91 (p=0.14) between months 0 and 12 to 0.97 (p=0.95) between months 12 and 24, to 0.25 (p=0.087) from month 24.

There were also certain patients who appeared to benefit with immunotherapy, with women having a hazard ratio for overall survival of 0.34 versus 1.55 for men (p for interaction=0.034).

Patients with an ECOG status of 1 had a hazard ratio for overall survival with immunotherapy of 0.44 versus 4.62 versus those with a status of 0 (p for interaction=0.0009).

Two radiotherapy fractions per day was also associated with an overall survival benefit, at a hazard ratio with immunotherapy of 0.41 versus 1.75 for 2 fractions per day (p for interaction=0.015).

The combination treatment resulted in "significant toxicity" versus observation, Prof Peters said, with any cause adverse events of grade ≥3 seen in 62% versus 25%.

She said that most of the adverse events recorded for immunotherapy "unfortunately" led to treatment discontinuation, at 55% for any cause events.

The most common adverse events reported for immunotherapy were fatigue (49%), anorexia (32%), diarrhoea (28%), and vomiting (27%).
 

'Too Toxic'

Invited discussant Professor Corinne Faivre-Finn, professor of thoracic radiation oncology at the University of Manchester, said that, based on the current results, the combination nivolumab and ipilimumab therapy must be considered "too toxic" for this setting.

Moreover, results from phase 2 studies with less than 200 patients "cannot be considered definitive and practice-changing".

With a lack of more details on the radiotherapy regimens used in the study, and a lack of biomarker data to predict response to immunotherapy, she said that the standard of care in limited stage SCLC patients therefore remains radiotherapy at 45 Gy twice daily.

Prof Faivre-Finn nevertheless said that, with other trials of immunotherapy and chemoradiotherapy combinations currently recruiting, the message is: "watch this space".

The STIMULI trial was sponsored by the European Thoracic Oncology Platform (ETOP) and financed by a grant from Bristol Myers Squibb.

Prof Peters declares consultation/advisory role: Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovia, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody; Talk’s: AztraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffman La Roche, Illumina, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, Takeda; Grants/research support: Amgen, AstraZeneca, Biodesix, Boehringer-Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffman La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, and Pfizer.

Prof Popat declares Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): EMD Serono; Honoraria (self): Guardant Health; Honoraria (self): AbbVie; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): OncLive; Honoraria (self): Medscape; Honoraria (self): Incyte; Honoraria (self): Paradox Pharmaceuticals; Honoraria (self): Eli Lilly.

Prof Faivre-Finn declares research funding: AZ, MSD, Elekta; Advisory Board: AZ, Pfizer, Boehringer Ingelheim (institutional).

No other relevant financial relationships declared.

ESMO Virtual Congress 2020: Abstract LBA84. Presented September 19.

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Cite this: Liam Davenport. A Glimmer of Hope for Immunotherapy in SCLC? - Medscape - Sep 23, 2020.