At the European Society for Medical Oncology (ESMO) 2018 Congress, important studies were presented for every cancer type. Here, The ASCO Post offers some snapshots of lung cancer studies that may inform approaches to treating this common cancer, which—despite the advances in recent years—remains the leading cause of cancer death in the United States.

Neoadjuvant Erlotinib

Neoadjuvant erlotinib (Tarceva) improved progression-free survival in patients with stage IIIA/N2 epidermal growth factor receptor (EGFR)-positive non–small cell lung cancer (NSCLC) compared with gemcitabine/cisplatin, according to the results of the randomized CTONG1103 trial.¹ The median progression-free survival was 21.5 months with erlotinib vs 11.9 months with cisplatin/gemcitabine (P = .003). Overall survival data are not yet mature.

This is the first study to demonstrate progression-free survival superiority for erlotinib over gemcitabine/cisplatin in the neoadjuvant/adjuvant setting of stage IIIA/N2 EGFR-mutated NSCLC.

— Yi-Long Wu, MD

Tweet this quote

“This is the first study to demonstrate progression-free survival superiority for erlotinib over gemcitabine/cisplatin in the neoadjuvant/adjuvant setting of stage IIIA/N2 EGFR-mutated NSCLC,” stated principal study investigator, Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute, Guangzhou, China.

“Our results suggest promise for the use of biomarker-guided neoadjuvant EGFR tyrosine kinase inhibitor treatment strategies in stage IIIA/N2 NSCLC,” he added.

Of 379 screened patients from 17 centers in China, 72 were randomly assigned 1:1 to receive treatment with neoadjuvant erlotinib vs gemcitabine/cisplatin. Erlotinib was given for 42 days as neoadjuvant therapy and then for 12 months after surgery; gemcitabine/cisplatin was given for 2 cycles as neoadjuvant therapy and then for 2 cycles after complete resection.

In an intent-to-treat analysis, the objective response rate was 54.1% with neoadjuvant erlotinib vs 34.3% with the platinum doublet. Following neoadjuvant therapy, surgery was conducted in 83.8% of the erlotinib group vs 68.6% of the platinum group. Lymph-node downstaging occurred in 13% of the erlotinib group and 4.2% of the gemcitabine/cisplatin group. A major pathologic response was documented in 3 of 28 patients (10.7%) of the erlotinib group vs no patients in the chemotherapy group. There were no grade 3 or 4 toxicities in the erlotinib group vs 29.4% in the gemcitabine/cisplatin group.

Clinical Implications

Commenting on the CTONG1103 study, Tony Mok, MD, of The Chinese University of Hong Kong, said this study was long-awaited. “This randomized study is the first to demonstrate improvement in multiple parameters, including tumor response rate, resection rate, major pathologic response, and progression-free survival, with the use of neoadjuvant EGFR tyrosine kinase inhibitor followed by an adjuvant tyrosine kinase inhibitor.”

Tony Mok, MD

Dr. Mok said that the impact of a neoadjuvant EGFR tyrosine kinase inhibitor was “relatively modest. The response rate of 54% is lower than expected of tyrosine kinase inhibitors in stage IV disease [about 70%], and only 13% of patients had attained a major pathologic response. The reason is unclear, but perhaps the duration of the neoadjuvant EGFR tyrosine kinase inhibitor for 42 days is not sufficient. Overall, this important study offers us the rationale to consider a neoadjuvant EGFR tyrosine kinase inhibitor.”

Suresh S. Ramalingam, MD

Also commenting on the CTONG1103 study, Suresh S. Ramalingam, MD, Director of Medical Oncology at Emory University Winship Cancer Institute, Atlanta, stressed, “This is a randomized phase II study, and it cannot be used to change standard of care.”

Earlier Timing of Immunotherapy

A subgroup analysis of the phase III PACIFIC trial suggests that earlier timing of immune checkpoint inhibition could provide a more pronounced clinical benefit for patients with locally advanced unresectable NSCLC whose disease did not progress after two or more cycles of chemoradiotherapy.² The results of the subgroup analysis were presented by Corinne Faivre-Finn, MD, of the University of Manchester and The Christie NHS Foundation Trust, United Kingdom.

Corinne Faivre-Finn, MD

In the primary analysis of the overall trial, 713 patients were randomly assigned to receive consolidation therapy with durvalumab (Imfinzi; n = 473) or placebo (n = 236). The median progression-free survival was 16.8 months in the durvalumab arm vs 5.6 months in the placebo arm. The median overall survival was not reached in the durvalumab arm vs 18.7 months in the placebo arm. The median follow-up was 25.2 months.

The unplanned subgroup analysis presented at the ESMO 2018 Congress found that durvalumab provided clinical benefit compared with placebo regardless of the time from radiotherapy to randomization. However, the analysis suggests that the benefit was more pronounced in patients who started durvalumab earlier—within 14 days of completion of radiotherapy. Toxicity profiles did not differ in patients started on therapy earlier or later (ie, < 14 days vs ≥ 14 days).

The median progression-free survival in the durvalumab arm was not reached in patients treated within less than 14 days vs 4.8 months with placebo; and in those treated 14 days and later, the median progression-free survival was 14 months with durvalumab vs 5.6 months with placebo. In addition, the time to distant metastases and objective response rates favored durvalumab, regardless of the time of randomization.

The incidence of any-cause treatment-related grade 3 to 4 adverse events based on the time to randomization was 34.2% for those treated within 14 days vs 31.3% for those treated 14 days and later. Serious adverse events were reported in 30% vs 28.2%, respectively.

Johan F. Vansteenkiste, MD, PhD

Study discussant Johan F. Vansteenkiste, MD, PhD, of the University Hospitals Leuven, Belgium, commented: “More studies are needed to clarify the optimal timing and duration of durvalumab treatment, although these exploratory data suggest that the interaction between radiotherapy and immunotherapy matters for these patients and that an earlier start results in better outcome.”

Asian Patients Seem to Benefit From Alectinib

The results of the phase III ALESIA study show that the central nervous system (CNS)-active ALK inhibitor alectinib (Alecensa) demonstrated superior efficacy compared with crizotinib (Xalkori) as first-line therapy in Asian patients with advanced ALK-positive NSCLC.³ The study met its primary objective, which was to show that

Caicun Zhou, MD

progression-free survival in Asian patients was consistent with that reported in the global ALEX trial, which also compared alectinib with crizotinib. These study findings were presented by Caicun Zhou, MD, of the Shanghai Pulmonary Hospital, China.

Patients enrolled in the ALESIA trial (n = 187) had ALK-positive, stage IIIB/IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2. Asymptomatic CNS metastases were allowed. Patients were randomly assigned 2:1 to receive alectinib at 600 mg/d or crizotinib at 250 mg/d.

At a median follow-up of 16.2 months for alectinib and 15 months for crizotinib, the risk for disease progression or death was significantly reduced with alectinib vs crizotinib. Investigator-assessed median progression-free survival was not estimable for alectinib vs 11.1 months for crizotinib (P < .0001). For purposes of comparison, in the global ALEX trial, the median progression-free survival was 34.8 months with alectinib vs 10.9 months with crizotinib.

All secondary endpoints support the primary endpoint, including objective response rate, duration of response, overall survival, CNS objective response rate, quality of life, and safety. The objective response rate in patients with CNS lesions at baseline was 72.7% for alectinib vs 21.7% with crizotinib. Complete response rates in the CNS were 50% vs 13%, respectively. The time to CNS disease progression favored alectinib (P < .0001). Overall survival data were immature, but the event rates seemed to favor alectinib (6.4% vs 21% with crizotinib). Although the treatment duration was 2 months longer with alectinib, there were fewer grades 3 to 5 adverse events (29% vs 48%, respectively).

Pembrolizumab’s Survival Benefit Confirmed

With an additional 30 months of follow-up (median, 42 months) of the KEYNOTE-010 trial, the 3-year survival rates with pembrolizumab (Keytruda) were 23% vs 11% with docetaxel in patients with previously treated advanced NSCLC.⁴ Among 79 patients who completed 35 cycles of pembrolizumab, the 3-year overall survival rate was 99%, with 95% having a partial or complete response as their best response.

Progressive disease was documented in 25 of 79 patients after stopping 35 cycles, and 14 patients were able to restart a second pembrolizumab course. The best overall response among the 14 patients was a partial response in 43% and stable disease in 36%. Ongoing response was documented in 44 patients (59%), and the median duration of response has not yet been reached.

Roy S. Herbst, MD, PhD

KEYNOTE-010 enrolled 1,034 patients with previously treated advanced NSCLC and programmed cell death ligand 1 expression on at least 1% of tumor cells. Patients were randomly assigned to receive pembrolizumab at 2 mg/kg or docetaxel at 75 mg/m² every 3 weeks.Long-term safety was similar to what was reported in the primary analysis of the trial. The rate of grades 3 to 5 treatment-related adverse events was 16% with pembrolizumab vs 36% with docetaxel.

“Long-term treatment with pembrolizumab continued to prolong overall survival vs docetaxel, with manageable safety,” said lead study author Roy S. Herbst, MD, PhD, of Yale School of Medicine, New Haven, Connecticut. “Most patients who completed 2 years of pembrolizumab were able to receive a second course of pembrolizumab.”

Acquired Resistance to Osimertinib

Osimertinib (Tagrisso), a third-generation EGFR tyrosine kinase inhibitor, is effective in treating NSCLC harboring the EGFR T790M mutation, but many patients develop resistance and disease progression within the first year of treatment. Two studies presented at the ESMO 2018 Congress identified genetic changes that characterize resistance to first- and second-line osimertinib.

The first study analyzed paired plasma samples from patients enrolled in the phase III FLAURA trial whose disease progressed on first-line osimertinib (n = 113) or standard-of-care EGFR tyrosine kinase inhibitor with erlotinib or gefitinib (n = 159) and harbored detectable EGFR mutations.⁵ The most common mechanisms of resistance in the osimertinib arm were MET amplifications (15%) and EGFR C797S mutations (7%). There was no evidence of acquired EGFR T790M. Other mechanisms of resistance were found in smaller numbers of patients. By contrast, in patients enrolled in the standard-of-care arm, EGFR T790M was identified in 47%; MET amplification, in 4%; and HER2 amplification, in 2%. Both MET and HER2 amplifications were found in 2%.

This is still early work, and it is based on plasma samples, noted Dr. Ramalingam, who was the presenting author. “Although these data are helpful in moving the field forward, we feel that definitive tissue-based testing is required to understand the full spectrum of resistance mutations and aberrations for patients treated with osimertinib,” he stated.

The second late-breaking abstract supports these findings after second-line osimertinib treatment. In the phase III AURA3 trial, patients with T790M-positive advanced NSCLC whose disease progressed on or after a first-line EGFR tyrosine kinase inhibitor were randomly assigned to receive osimertinib or platinum-based chemotherapy.⁶ Paired plasma samples (n = 73) were analyzed in patients with baseline detectable circulating tumor DNA EGFR mutations whose disease progressed on or after osimertinib.

Vassiliki Papadimitrakopoulou, MD

A diverse set of resistance mechanisms was detected, according to Vassiliki Papadimitrakopoulou, MD, of MD Anderson Cancer Center in Houston, who presented these findings. MET amplification (around 19%), EGFR C797S (14%), and PIK3CA (4%) were the most common genetic alterations identified. No unexpected resistance mechanisms were found after second-line osimertinib treatment. “Understanding resistance mechanisms in the first- and second-line settings will help define appropriate combination therapies,” she predicted. ■

DISCLOSURE: Dr. Wu has received honoraria from Roche, Sanofi, Pfizer, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, and Lilly; is a consultant/advisor with AstraZeneca, Roche, Merck, Boehringer Ingelheim; and received institutional research funding from Roche and Boehringer Ingelheim. Dr. Mok has received honoraria from AstraZeneca, Lilly, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, Pfizer, Merck Serono, SFJ Pharmaceuticals Group, ACEA Biosciences, Vertex, Celgene, Ignyta, Fishawack Facilitate Ltd, Takeda, Janssen, Hutchison MediPharma, Roche/Genentech, and Merck Sharp & Dohme; is a consultant/advisor with Hutchison MediPharma, Lilly, Merck Serono, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Clovis, Novartis, Vertex, SFJ Pharmaceuticals Group, ACEA Biosciences, Merck Sharp & Dohme, geneDecode, OncoGenex, Celgene, Ignyta, Cirina, AstraZeneca, and Roche/Genentech; has a leadership role with Hutchison MediPharma and Sanomics Limited; has stock and other ownership interests in Sanomics Limited and Hutchison MediPharma; has received institutional research funding from Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Group, Roche, Merck Sharp & Dohme, Clovis, Bristol-Myers Squibb, Xcovery, and AstraZeneca. Dr. Faivre-Finn has received research funding and travel support travel support from MSD, AstraZeneca, and Elekta; and travel support from Pfizer (honoraria are paid into the Christie Hospital’s research account). Dr. Vansteenkiste has received honoraria from AstraZeneca and Bristol-Myers Squibb; is a consultant/advisor (honoraria to institution) with Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, AstraZeneca, MSD Oncology, and Merck Serono; and has received institutional research funding from MSD. Dr. Zhou has received honoraria from Eli Lilly, Roche, Boehringer Ingelheim, and Hengrui Therapeutics. Dr. Herbst is a consultant/advisor with AstraZeneca, Genentech/Roche, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Lilly, EMD Serono, Heat Biologics, Jun Shi Pharmaceuticals, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Pharmaceuticals, and Infinity Pharmaceuticals. Dr. Ramalingam is a consultant/advisor with Amgen, Boehringer Ingelheim, Celgene, Genentech/Roche, Lilly/ImClone, Bristol-Myers Squibb, AstraZeneca, AbbVie, Merck, and Takeda; has received reimbursement for travel/accommodations expenses from EMD Serono, AstraZeneca, and Pfizer; and has received institutional research funding from Astra Zeneca, Merck, Tesaro, Bristol Myers Squibb and Amgen. Dr. Papadimitrakopoulou is a consultant/advisor with Clovis Oncology, Genentech, Merck, Biothera, Lilly, Janssen, Genentech, Gensignia Life Sciences, AstraZeneca, Ariad, and Nektar; and has received institutional research funding from Pfizer, Janssen Oncology, Merck, Celgene, Clovis Oncology, Bayer, Bristol-Myers Squibb, Novartis, AstraZeneca, and ACEA Biosciences.

REFERENCES

1. Zhong W-Z, et al: Erlotinib versus gemcitabine plus cisplatin as neo-adjuvant treatment for stage IIIA–N2 EGFR-mutation non-small-cell lung cancer (EMERGING). ESMO 2018 Congress. Abstract LBA48_PR. Presented October 21, 2018.

2. Faivre-Finn C, et al: Efficacy and safety evaluation based on time from completion of radiotherapy to randomization with durvalumab or placebo in patients from PACIFIC. ESMO 2018 Congress. Abstract 1363O. Presented October 21, 2018.

3. Zhou C, et al: Primary results of ALESIA. ESMO 2018 Congress. Abstract LBA10. Presented October 22, 2018.

4. Herbst RS, et al: Long-term survival in patients with advanced NSCLC in the KEYNOTE-010 study overall and in patients who completed 2 years of pembrolizumab. ESMO 2018 Congress. Abstract LBA63. Presented October 21, 2018.

5. Ramalingam SS, et al: Mechanisms of acquired resistance to first-line osimertinib. ESMO 2018 Congress. Abstract LBA50. Presented October 19, 2018.

6. Papadimitrakopoulou VA, et al: Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. ESMO 2018 Congress. Abstract LBA51. Presented October 19, 2018.