Caroline Seymour

An important milestone in the treatment landscape of extensive-stage small cell lung cancer (ES-SCLC) has been trials of first-line chemoimmunotherapy. However, a study that requires better understanding of the methods and can be used to determine patients who are likely to experience durable benefits to therapy is currently concentrated, according to

 a virtual presentation during the 15th Annual New York Lung Cancers Symposium by 

“In the past couple years, the big news has been immunotherapy,” said Rudin, medical oncologist and chief of the Thoracic Oncology Service, co-director of the Druckenmiller Center for Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research, at Memorial Sloan Kettering Cancer Center.

The two high-impact trials that have led to the rise of immunotherapy in the frontline setting of ES-SCLC are the phase 3 IMpower133 and CASPIAN trials, said Rudin. In IMpower133, patients with untreated ES-SCLC were randomized to atezolizumab (Tecentriq) plus etoposide and platinum vs etoposide and platinum alone. The results indicated a 30% reduction in the risk of death with the addition of atezolizumab vs chemotherapy (HR, 0.70; 95% CI, 0.54-0.91; 

 Moreover, the 12- and 18-month landmark overall survival (OS) analyses favored the chemoimmunotherapy combination vs chemotherapy alone, respectively (51.9% vs 39.0%; 34.0% vs 21.0%).

Data from the IMpower133 trial served as the basis for the March 2019 FDA approval of the combination as frontline therapy in ES-SCLC.

In CASPIAN, patients with untreated ES-SCLC were randomized to durvalumab (Imfinzi) plus platinum and etoposide vs platinum and etoposide alone. The addition of durvalumab led to a 27% reduction in the risk of death vs chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; 

 Similarly, the 12- and 18-, as well as 24-month landmark OS analyses favored the chemoimmunotherapy combination vs chemotherapy alone , at 52.8% vs 39.3%; 32.0% vs 24.8%; and 22.2% vs 14.4%, respectively.

In March 2020, the FDA approved the combination of durvalumab plus platinum and etoposide for the frontline treatment of patients with ES-SCLC, according to the results from the CASPIAN trial.

Another phase 3 trial, KEYNOTE-604, randomized patients with untreated ES-SCLC to receive the addition of pembrolizumab (Keytruda) to platinum and etoposide or chemotherapy alone in the first-line setting.

At the time of data cutoff in December 2019, the median progression-free survival (PFS) was 4.8 months with pembrolizumab vs 4.3 months with chemotherapy alone, meeting the co-primary end point of the study (HR, 0.73; 95% CI, 0.60-0.88).

However, the addition of pembrolizumab did not lead to a statistically significant improvement in OS, with a median OS of 10.8 months and 9.7 months in the pembrolizumab and chemotherapy-alone arms, respectively (HR, 0.80; 95% CI, 0.64-0.98; 

Across the IMpower133, CASPIAN, and KEYNOTE-406 trials, the 12-month median PFS rates in the experimental arms were 12.6%, 17.9%, and 15.9% vs 5.4%, 5.3%, and 5.0% in the control arms, respectively.

Immunotherapy has also shown activity in the recurrent setting, evidenced by findings from the phase 1/2 CheckMate-032 trial, which demonstrated a median PFS of 1.4 months with nivolumab (Opdivo; n = 147) and 1.5 months with the combination of nivolumab and ipilimumab (Yervoy; n = 96) in patients with SCLC and disease progression on 2 prior lines of chemotherapy.4Although the median PFS was modest, the curves suggested that patients who responded to the combination experienced durable benefit, with 6-month PFS rates of 15.9% and 22.1%, respectively.

A similar trend was seen in a pooled analysis of the phase 1b KEYNOTE-028 and phase 2 KEYNOTE-158 trials, where patients who received pembrolizumab after 2 prior lines of therapy experienced a median PFS of 2.0 months but 12- and 24-month PFS rates of 16.9% and 13.1%, respectively.

“The hockey stick appearance of the curves [is clear] where the curves just drop like a rock. Most of the patients do not benefit from this therapy, but then there’s a subset that clearly does,” said Rudin.

Although findings from these 2 trials served as the basis for the accelerated approvals of nivolumab and pembrolizumab as third-line treatment for patients with metastatic SCLC, the data are more indicative of the potential effects of immunotherapy than they are applicable for practicing clinicians now that immunotherapy has entered the first-line setting.

“In the third-line setting, we have these accelerated approvals for nivolumab and pembrolizumab, but we really don’t know how to give those now because we’re using PD-L1 checkpoint inhibitors in the first-line setting,” said Rudin.

Although immunotherapy has been the focus of discussion in ES-SCLC, other agents are entering the paradigm, explained Rudin, who cited lurbinectedin (Zepzelca) as a prime example of the potential actionability of alternative targets in the field.

“Lurbinectedin is a DNA-binder and an alkylating agent that affects transcription,” said Rudin.

The agent was evaluated in an open-label, single-arm, phase 2 basket trial (NCT-2454972) in patients with SCLC who had progressed on platinum-containing therapy. The results demonstrated an overall response rate (ORR) of 35.2% and a stable disease rate of 33.3%, which translated to a disease control rate of 68.6% (95% CI, 58.8%-77.3%).

The median durations of response, PFS, and OS were 5.3 months (95% CI, 4.1-6.4), 3.5 months (95% CI, 2.6-4.3), and 9.3 months (95% CI, 6.3-11.8).

“The real advantage of this drug over topotecan is on the toxicity side as much or more than on the efficacy side, particularly in terms of the hematologic toxicities” said Rudin.

On June 15, 2020, the FDA granted an accelerated approved to lurbinectedin for the treatment of adult patients with metastatic SCLC with disease progression, following platinum-based chemotherapy.

“About 10% of patients with SCLC really derive meaningful and potentially durable benefit from the addition of immunotherapy, regardless of which of these PD-1/PD-L1 agents you’re using. The other 90% really do not,” said Rudin. “One of the challenges for our field is to define that 10% and to think about what to do about that 90%.”

Potential pathways forward in this regard could include blocking other immunologic checkpoints such as TIGIT, stimulating other immunologic players such as natural killer cells and macrophages, epigenetic priming, targeting DNA damage repair pathways, and developing other novel targets, concluded Rudin.

Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. 

. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 

. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

Rudin CM, Awad MM, Navarro A, et al. KEYNOTE-604: pembrolizumab (pembro) or placebo plus etoposide and platinum (ep) as first-line therapy for extensive-stage (es) small-cell lung cancer (sclc). 

. 2020;38(suppl 15):9001. doi:10.1200/JCO.2020.38.15_suppl.9001

Ready NE, Ott PA, Hellmann MD, et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. 

. 2020;15(3):426-435. doi:10.1016/j.jtho.2019.10.004

Chung HC, Piha-Paul S, Lopez-Martin J, et al. Pembrolizumab after two or more lines of previous therapy in patients with recurrent or metastatic SCLC: results from the KEYNOTE-028 and KEYNOTE-158 studies. 

. 2020;15(4):618-627. doi:10.1016/j.jtho.2019.12.109

Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. 

. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1

Articles

An important milestone in the treatment landscape of extensive-stage small cell lung cancer has been trials of first-line chemoimmunotherapy. However, a study that requires better understanding of the methods and can be used to determine patients who are likely to experience durable benefits to therapy is currently concentrated.

Immunotherapy Advances Treatment Landscape for Small Cell Lung Cancer

In the phase 3 EMPOWER-Lung 1 trial, patients with advanced non–small cell lung cancer (NSCLC) with PD-L1 expression on at least 50% of their tumor cells had a significant improvement in overall survival (OS) and progression-free survival (PFS) with cemiplimab-rwlc (Libtayo) monotherapy compared with platinum-doublet chemotherapy.

At a median follow-up of approximately 10 months in the PD-L1 ≥50% intention-to-treat (ITT) population, the median OS was not reached (95% CI, 17.9–not estimable [NE]) in the cemiplimab arm versus 14.2 months (95% CI, 11.2-17.5) in the chemotherapy arm (HR, 0.57; 95% CI, 0.42-0.77; 

 = .0002). This translated to a 43% reduction in the risk of death with the PD-1 inhibitor.

The median PFS was 8.2 months (95% CI, 6.1-8.8) in the cemiplimab arm versus 5.7 months (95% CI, 4.5-6.2) in the chemotherapy arm, translating to a 46% reduction in the risk of progression or death with cemiplimab (HR, 0.54; 95% CI, 0.43-0.68; 

“The EMPOWER-Lung 1 study met its primary and secondary end points,” said Ahmet Sezer, MD, lead study author and professor in the Department of Medical Oncology at Başkent University, in Ankara, Turkey, in a virtual presentation of the data. “Taken together, our data provide the rationale for cemiplimab as a new first-line monotherapy option for patients with advanced NSCLC with PD-L1 expression ≥50%.”

For patients with advanced NSCLC with PD-L1 expression ≥50% and without targetable mutations, PD-1/PD-L1 inhibitors alone or in combination with chemotherapy are preferred treatment options. However, selecting the most effective treatment with minimal toxicity remains a challenge. Additional treatment options with survival benefits and optimization of chemotherapy-free regimens are needed for patients with PD-L1 ≥50%.

Cemiplimab is a high-affinity, highly potent, human PD-1 inhibitor approved for the treatment of patients with advanced cutaneous squamous cell carcinoma. In phase 1 and 2 studies, cemiplimab demonstrated antitumor activity with a safety profile similar to that described for other PD-1 inhibitors in other advanced solid tumors, including NSCLC.

In EMPOWER-Lung 1, eligible patients had treatment-naïve advanced NSCLC, PD-L1 ≥50%, no 

 mutations, and an ECOG performance status of 0 or 1. Patients with treated, clinically stable central nervous system metastases and controlled hepatitis B or C, or HIV were allowed on study.

Patients in the ITT population were randomized 1:1 to 350 mg of intravenous cemiplimab monotherapy every 3 weeks (n = 356) or 4 to 6 cycles of investigator’s choice chemotherapy (n = 354). Patients in the cemiplimab arm were treated until progressive disease or up to 108 weeks. Upon progressive disease, patients in the cemiplimab arm had the option of continuing cemiplimab plus 4 cycles of chemotherapy, and patients in the chemotherapy arm had the option of crossing over to the cemiplimab arm.

OS and PFS served as primary end points of the study. Secondary end points included objective response rate (ORR), duration of response (DOR), health-related quality of life (HRQoL), and safety.

All patients were subject to PD-L1 testing with the 22C3 pharDx assay. Patients who underwent testing prior to August 2018 (n = 235) were retested for PD-L1 expression ≥50%, per protocol, and grouped among those who had been tested after August 2018 (n = 475). A total of 563 patients with PD-L1 expression ≥50% comprised the PD-L1 ≥50% ITT population, wherein 283 received cemiplimab and 280 received chemotherapy.

Baseline characteristics were well balanced between arms in the ITT and PD-L1 ≥50% ITT populations. In the ITT population, 11.7% of patients had brain metastases at baseline, and 16.2% of patients had locally advanced disease, both populations which have been historically underrepresented in clinical trials of first-line PD-1/PD-L1 inhibitors, said Sezer.

Additional analysis from the PD-L1 ≥50% ITT population showed that the 12-month OS rate was 72.4% (95% CI, 65.6%-78.1%) in the cemiplimab arm versus 53.9% (95% CI, 46.2%-61.1%) in the chemotherapy arm. The 24-month OS rates were 50.4% (95% CI, 36.4%-62.9%) and 27.1% (95% CI, 13.7%-42.5%), respectively.

The 12-month PFS rate was 40.7% (95% CI, 33.7%-47.5%) in cemiplimab arm versus 7.1% (95% CI, 3.6%-12.1%) in the chemotherapy arm. The 18-month PFS rates were 27.8% (95% CI, 19.4%-36.7%) and NE, respectively.

At a median follow-up of 13.1 months in the ITT population, the median OS was 22.1 months (95% CI, 17.7–not estimable [NE]) with cemiplimab versus 14.3 months (95% CI, 11.7-19.2) with chemotherapy (HR, 0.68; 95% CI, 0.53-0.87; 

The 12-month OS rate was 70.3% (95% CI, 64.4%-75.4%) in cemiplimab arm versus 55.7% (95% CI, 49.2%-61.7%) in the chemotherapy arm. The 24-month OS rates were 48.6% (95% CI, 39.2%-57.3%) and 29.7% (95% CI, 18.8%-41.4%), respectively.

The median PFS was 6.2 months (95% CI, 4.5-8.3) in the cemiplimab arm versus 5.6 months (95% CI, 4.5-6.1) in the chemotherapy arm (HR, 0.59; 95% CI, 0.49-0.72; 

The 12-month PFS rate was 37.8% (95% CI, 31.9%-43.6%) in the cemiplimab arm versus 7.2% (95% CI, 4.3%-11.2%) in the chemotherapy arm. The 18-month PFS rates were 28.0% (95% CI, 21.7%-34.7%) and 3.9% (95% CI, 1.8%-7.5%), respectively.

“In both [the PD-L1 ≥50% ITT and ITT] populations, the PFS curves separate at approximately 6 months and remain well separated,” said Sezer.

All subgroups derived OS and PFS benefit from cemiplimab, with the exception of Asian patients (HR, 1.34; 95% CI, 0.52-3.42). However, the number of events in this subgroup is too small to draw a definitive conclusion from, said Sezer.

In the PD-L1 ≥50% ITT population, the ORR was 39.2% (95% CI, 33.5%-45.2%) in cemiplimab arm versus 20.4% (95% CI, 15.8%-25.6%) in the chemotherapy arm (

 < .0001). The median DOR was 16.7 months (range, 12.5-22.8) in the cemiplimab arm versus 6.0 months (range, 4.3-6.5) in the chemotherapy arm.

In the ITT population, the ORR was 36.5% (95% CI, 31.5%-41.8%) in the cemiplimab arm versus 20.6% (95% CI, 16.5%-25.2%) in chemotherapy arm (

 < .0001). The median DOR was 21.0 months (range, 14.9-NE) in the cemiplimab arm versus 6.0 months (range, 4.3-6.4) in the chemotherapy arm.

In the PD-L1 ≥50% ITT and ITT populations, patients in the cemiplimab and chemotherapy arms both had a median time to response of 2.1 months.

Investigators also evaluated the delta in target tumor volume and ORR with baseline PD-L1 levels and found that higher PD-L1 expression correlated with improved responses to cemiplimab but not chemotherapy. In patients with PD-L1 expression ≥90%, >60% to <90%, ≥50% to ≤60%, and 50% or unknown in the cemiplimab and chemotherapy arms, these rates were 45.9% vs 18.1%, 39.3% vs 20.0%, 32.3% vs 22.9%, and 26.0% vs 21.6%, respectively.

The PFS and OS curves favored cemiplimab, regardless of PD-L1 expression level. Moreover, higher PD-L1 expression was associated with improved PFS and OS to cemiplimab but not chemotherapy.

Regarding HRQoL, patients in the cemiplimab arm experienced a clinically meaningful improvement in Global Health Status/HRQoL, which was defined as at least a 10-point increase from baseline.

Among 355 patients who received cemiplimab, 139 remain on treatment and 6 completed treatment. A total of 210 patients discontinued treatment due to progressive disease (n = 133), death (n = 29), adverse effects (AEs; n = 23), patient decision (n = 9), withdrawn consent (n = 8), physician decision (n = 5), and lost follow-up (n = 3).

Among 342 patients who received chemotherapy, 45 remain on treatment and 149 completed treatment. A total of 148 patients discontinued treatment due to progressive disease (n = 84), death (n = 25), AEs (n = 14), patient decision (n = 7), withdrawn consent (n = 9), physician decision (n = 5), and lost follow-up (n = 4).

The majority of patients who progressed on chemotherapy (n = 150; 73.9%) received cemiplimab as a crossover treatment. Additionally, 31.6% of patients who progressed on cemiplimab (n = 50) received extended cemiplimab treatment with the addition of chemotherapy.

The median duration of treatment with cemiplimab was 27.3 months (range, 0.3-115.0) versus 17.7 months (range, 0.6-86.7) with chemotherapy.

Grade 3 or greater treatment-emergent AEs (TEAEs) occurred in 37.2% of patients in the cemiplimab arm versus 48.5% in the chemotherapy arm. Grade 3 or greater treatment-related AEs (TRAEs) occurred in 14.1% of patients in the cemiplimab arm versus 39.2% in the chemotherapy arm. Fatal TEAEs and TRAEs were comparable in both arms, at approximately 9.0% and 2.0%, respectively.

Grade 3 or greater AEs that occurred in the cemiplimab and chemotherapy arms, respectively, included anemia (3.4% vs 16.4%), decreased appetite (0.6% vs 0.3%), fatigue (1.1% vs 1.5%), pneumonia (4.8% vs 5.6%), nausea (0% vs 1.2%), vomiting (0% vs 1.2%), thrombocytopenia (0% vs 8.2%), neutropenia (0.6% vs 10.2%), decreased platelet count (0% vs 3.5%), alopecia (0% vs 0.6%), peripheral neuropathy (0.3% vs 0.3%), and decreased neutrophil count (0.3% vs 5.3%).

“The safety profile of cemiplimab was consistent with the previously reported profile for cemiplimab and other PD-1/PD-L1 inhibitors in NSCLC and other tumor types,” said Sezer. “Despite substantially longer exposure to cemiplimab, the safety profile of cemiplimab appeared to be better than chemotherapy.”

Sezer A, Kilickap S, Gümüş M, et al. EMPOWER-Lung 1: phase 3 first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA52.

In the phase 3 EMPOWER-Lung 1 trial, patients with advanced non–small cell lung cancer with PD-L1 expression on at least 50% of their tumor cells, had a significant improvement in overall survival and progression-free survival with cemiplimab-rwlc monotherapy compared with platinum-doublet chemotherapy. 

Survival Improvement Observed with Cemiplimab in Frontline Advanced PD-L1+ NSCLC

Findings from the phase 1 CHRYSALIS study (NCT02609776) showed that patients with advanced 

-mutant non–small cell lung cancer (NSCLC) who were treatment naïve or resistant to osimertinib therapy had high response rates when treated with the combination of amivantamab (JNJ-61186372; JNJ-6372) and lazertinib. Results also demonstrated a favorable safety profile for the regimen, according to results reported at the ESMO Virtual Congress 2020.

At a median follow-up of 7 months in treatment-naïve patients, the objective response rate (ORR) and the clinical benefit rate (CBR) was 100% (95% CI, 83%-100%), consisting of 20 partial responses (PRs).

At a median follow-up of 4 months in osimertinib-resistant, chemotherapy-naïve patients, the ORR was 36% (95% CI, 22%-51%). The ORR consisted of 1 complete response (CR) and 15 PRs, with 1 pending confirmation of PR. The CBR was 60% (95% CI, 44%-74%).

“Amivantamab with lazertinib is efficacious in advanced 

-mutant NSCLC and can be safety combined,” said Byoung Chul Cho, MD, PhD, lead study author and professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, in a virtual presentation of the data.

Amivantamab is a fully human bispecific antibody that targets EGFR and MET. The antibody has immune cell-directing activity, including antibody-dependent cell cytotoxicity, and demonstrated clinical activity in patients with primary and acquired 

Lazertinib is a potent third-generation EGFR TKI that demonstrated activity in patients with activating 

mutations, T790M resistance mutations, and central nervous system (CNS) disease. With low rates of EGFR-related toxicity, such as rash and diarrhea, the safety profile of the agent supports its use in combination with other EGFR inhibitors.

On March 10, 2020, the FDA granted breakthrough therapy designation

 to amivantamab for the treatment of patients with 

-positive metastatic NSCLC who harbor exon 20 insertion mutations, and whose disease has progressed on or after platinum-based chemotherapy.

The designation is supported by earlier findings from CHRYSALIS, in which amivantamab elicited preliminary responses in patients with NSCLC, including those who have relapsed 

-mutant disease and those with exon 20 insertions.

To be eligible for enrollment in the study, patients had to have metastatic or unresectable NSCLC and an 

 exon19 deletion or L858R mutation. In the expansion cohort, patients had to have measurable disease.

In the dose-escalation portion of the study, patients first received a weight-dependent dose of intravenous amivantamab (700 mg, < 80 kg; 1050 mg, ≥ 80 kg) every week for 4 weeks and every 2 weeks thereafter plus 240 mg of oral lazertinib once daily. Patients were then escalated to 1050 mg (< 80 kg) and 1400 mg (≥ 80 kg) of amivantamab. Among the 26 patients in the dose-escalation cohort, no dose-limiting toxicity was reported, and the recommended phase 2 dose was 1050/1400 mg of amivantamab and 240 mg of lazertinib.

“The recommended phase 2 combination dose was equivalent to the recommended monotherapy doses of each molecule,” said Cho.

The expansion cohorts included patients with osimertinib-resistant, chemotherapy-naïve 

mutant NSCLC (n = 45) and treatment-naïve 

The patient characteristics are consistent with those of patients with 

-mutant NSCLC, said Cho. The median age was 61, and more than half of patients were female (n = 52; 57%) and never smokers (n = 50; 55%). A total of 34 patients (37%) had previously reported brain metastases at baseline. Additionally, patients had received a median of 2 prior lines of therapy (range, 0-9), and the majority (n = 53; 58%) had received a prior third-generation EGFR TKI.

In the treatment-naïve cohort, the median treatment duration was 7 months (range, 3-10). The time to first response was rapid, at a median of 1.5 months (range, 1.2-2.6). The median duration of response was not estimable.

“All patients showed deep responses, regardless of EGFR genotype,” said Cho.

In the osimertinib-resistant, chemotherapy-naïve cohort, the median duration of treatment was 5 months (range, 0.3-15). Notably, responses were observed regardless of whether patients received osimertinib in the first- or second-line setting, or had any prior exposure to lazertinib.

Moreover, 14 of 16 patients have ongoing response, and 4 patients are continuing treatment beyond progression. Only 4 of 45 patients required dose reductions.

“With a median follow-up of 4 months, the majority of patients are still [on treatment],” said Cho. “Responses seem to be rapid and durable.”

Regarding safety in the total population (n = 91), the adverse effects (AEs) that occurred in at least 15% of patients included rash (85%), paronychia (53%), stomatitis (33%), pruritus (28%), diarrhea (18%), hypoalbuminemia (37%), peripheral edema (18%), infusion-related reaction (IRR; 65%), nausea (28%), decreased appetite (20%), increase alanine aminotransferase (21%), paresthesia (20%), constipation (18%), increased aspartate aminotransferase (18%), dizziness (17%), and fatigue (15%).

The majority of IRRs (65%) occurred during the first infusion and all were grade 1/2. Moreover, no discontinuations nor any impact on subsequent dosing due to IRRs was reported.

All-cause serious AEs occurred in 29% of patients, 6% of which were treatment related. All-cause and treatment-related grade 3 or greater AEs occurred in 34% and 11% of patients, respectively.

Grade 3 or greater treatment-related AEs included rash (4%), hypoalbuminemia (2%), increased gamma-glutamyl transferase (1%), hyponatremia (1%), paronychia (1%), and interstitial lung disease (1%). The median time to onset for rash was 16 days, with a median duration of 29 days (range, 1-272). One patient discontinued the combination due to rash.

All-cause AEs leading to death occurred in 3 patients; 1 treatment-related death was reported and was attributed to progressive disease. Related AEs that led to dose interruption or reduction of either or both drugs occurred in 19% of patients. Related AEs that led to discontinuation of either or both drugs occurred in 5 patients.

“There was similar incidence of adverse events across dose-escalation, treatment-naïve, and osimertinib-resistant cohorts,” said Cho.

Based on the promising safety and efficacy data reported herein, new studies with amivantamab and lazertinib have been initiated, including the phase 3 MARIPOSA and phase 2 CHRYSALIS-2 studies in the frontline and chemotherapy-relapsed settings, respectively, concluded Cho.

Cho BC, Lee KH, Cho EK, et al. Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced 

-mutant NSCLC. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1258O.

Janssen announces U.S. FDA breakthrough therapy designation granted for JNJ-6372 for the treatment of non-small cell lung cancer. News release. March 10, 2020. Accessed September 20, 2020. https://prn.to/2Q0EhsA.

Haura EB, Cho BC, Lee JS, et al. JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC). 

. 2019;37(suppl 15):9009. doi:10.1200/JCO.2019.37.15_suppl.9009

Findings from the phase 1 CHRYSALIS study showed that patients with advanced EGFR-mutant non–small cell lung cancer who were treatment naïve or resistant to osimertinib therapy had high response rates when treated with the combination of amivantamab and lazertinib. Results also demonstrated a favorable safety profile for the regimen, according to results reported at the ESMO Virtual Congress 2020.

Responses, Favorable Safety Profile Reported for Amivantamab Plus Lazertinib in EGFR+ NSCLC

Findings from the phase 3 monarchE trial (NCT03155997) reported at the ESMO Virtual Congress 2020 showed that the risk of invasive disease with ​abemaciclib (Verzenio) plus endocrine therapy was significantly reduced versus endocrine therapy alone in patients with high-risk early hormone receptor (HR)–positive, HER2-negative breast cancer.

In this patient population, abemaciclib reduced the risk of invasive disease by 25.3% versus endocrine therapy alone (HR, 0.747; 95% CI, 0.598-0.932; 2-sided 

 = .0096). Additionally, the 2-year invasive disease-free survival (iDFS) rates were 92.2% in the abemaciclib arm versus 88.7% in the endocrine-alone arm, reflecting an absolute improvement of 3.5%.

“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said Stephen Johnston, MA, PhD, FRCP, lead study author and professor of breast cancer medicine at the Royal Marsden NHS Foundation Trust, in a press release.

HR–positive breast cancer is the most common form of breast cancer, affecting 70% of patients. The majority of these patients are diagnosed with early disease, and although many of these patients can be cured with surgery, radiotherapy, chemotherapy, and hormone therapy, approximately 20% will experience local recurrence or distant relapse in the first 10 years of treatment. For patients with high-risk clinical and/or pathological features, the risk of recurrence is even greater, particularly during the first few years on adjuvant endocrine therapy.

Abemaciclib is an oral, continuously dosed CDK4/6 inhibitor that is approved in HR–positive, HER2-negative advanced breast cancer in combination with endocrine therapy. Based on the overall survival (OS) advantage abemaciclib has shown in combination with fulvestrant in the metastatic setting, investigators evaluated adjuvant abemaciclib in combination with endocrine therapy.

“These patients with high-risk early breast cancer show a degree of resistance to hormone therapy, relapsing early despite everything we currently give them,” said Johnston. “CDK4/6 inhibitors, such as abemaciclib, have transformed the way we treat metastatic breast cancer over the last few years, overcoming primary endocrine resistance and improving survival. So, it was an obvious step to see whether adding abemaciclib to hormone treatment in patients with high-risk early breast cancer could reduce the risk of their cancer returning.”

The international monarchE trial included 5,637 men and women with pre- and postmenopausal high-risk early HR–positive, HER2-negative breast cancer. Patients were eligible for enrollment regardless of whether they had received prior neoadjuvant and adjuvant chemotherapy. Though, the majority received prior anthracycline/taxane-based chemotherapy. Patients with distant metastases were excluded from enrollment.

In the study, high risk was defined as having at least 4 positive axillary lymph nodes or 1 to 3 axillary lymph nodes and at least 1 of the following disease characteristics: tumor size of at least 5 cm, histologic grade 3 disease, and centrally tested Ki67 of at least 20%.

After completing primary therapy, patients were randomized 1:1 to 150 mg of abemaciclib twice daily for up to 2 years plus 5 to 10 years of endocrine therapy (n = 2808) as clinically indicated versus endocrine therapy alone (n = 2829).

Patients were stratified by prior chemotherapy, menopausal status, and region.

IDFS served as the primary end point of the study, and secondary end points included distant relapse-free survival (DRFS), OS, safety, patient-reported outcomes, and pharmacokinetics.

Further results demonstrated that the addition of abemaciclib to endocrine therapy also had a significant impact on DRFS across all prespecified subgroups, reducing the risk of distant recurrence by 28.3% (HR, 0.717; 95% CI, 0.559-0.920; 

 = .0085). The 2-year DRFS rates were 93.6% with abemaciclib versus 90.3% with endocrine therapy alone, reflecting an absolute improvement of 3.3%.

A total of 92 patients experienced distant recurrence on abemaciclib versus 142 on endocrine therapy alone. The greatest reduction in metastatic sites with abemaciclib was seen in the bone and the liver, followed by the brain, lymph nodes, pleura, and central nervous system.

The safety was consistent with the known profile of abemaciclib. A total of 463 patients (16.6%) discontinued abemaciclib due to adverse effects; 306 of these patients continued on endocrine therapy. The most common reason for discontinuation was diarrhea (5%), which was otherwise well managed with antidiarrheals and dose adjustments. Notably, the protocol allowed dose reduction from 150 mg to 100 mg twice daily if necessary.

“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” said Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and Chair of the ESMO Guidelines Committee, in the press release.

Tissue and plasma samples, which were collected from all study participants for translational research, will include looking at genomic signatures and response to abemaciclib.

“This is the first study to show that adding a CDK4/6 inhibitor to endocrine therapy significantly improves IDFS in the adjuvant setting,” said Curigliano. “This is a very important trial, and the findings will change practice. Once approved for high-risk HR–positive, HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”

Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high risk, early breast cancer (monarchE). 

First new drug in years reduces recurrence in high-risk hormone receptor positive early breast cancer. ESMO. News release. September 19, 2020. Accessed September 19, 2020. https://esmo.app.box.com/s/8iba2eoisy7ol9dswtlgtxnmwtb1nsah/file/719926464752.

Findings from the phase 3 monarchE trial reported at the ESMO Virtual Congress 2020 showed that the risk of invasive disease with ​abemaciclib plus endocrine therapy was significantly reduced versus endocrine therapy alone in patients with high-risk early hormone receptor-positive, HER2-negative breast cancer.

Caroline Seymour | Authors

Articles

Immunotherapy Advances Treatment Landscape for Small Cell Lung Cancer

Survival Improvement Observed with Cemiplimab in Frontline Advanced PD-L1+ NSCLC

Responses, Favorable Safety Profile Reported for Amivantamab Plus Lazertinib in EGFR+ NSCLC

In High-Risk Early Breast Cancer, Risk of Recurrence Is Reduced With Abemaciclib