The ASCO Post has published a wealth of practice-changing studies and news about other advances presented during the European Society for Medical Oncology (ESMO) Congress 2021. In addition to the biggest news from this international meeting, here are several summaries of interesting study findings in lung and gastrointestinal cancers that you might have missed.

Durvalumab Plus Platinum-Based Chemotherapy for Small Cell Lung Cancer

In patients with extensive-stage small cell lung cancer (SCLC), the addition of the monoclonal antibody durvalumab to platinum-based chemotherapy continued to show superior overall survival in updated results of the phase II CASPIAN trial, presented during this year’s ESMO Congress.¹

At a median follow-up of 39.4 months, durvalumab plus platinum/etoposide led to a median overall survival of 12.9 months vs 10.5 months with chemotherapy alone—a 29% improvement favoring durvalumab (P = .0003). The survival gain with the addition of durvalumab to chemotherapy remained consistent across all patient subgroups.

“Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus platinum/etoposide chemotherapy vs platinum/etoposide chemotherapy alone, with a majority still receiving durvalumab treatment at data cutoff. This further establishes [this regimen] as the standard of care for the first-line treatment of extensive-stage SCLC,” stated Luis Paz-Ares, MD, PhD, of the Spanish National Cancer Research Center, Madrid.

Luis Paz-Ares, MD, PhD

A previous report from CASPIAN with more than 2 years of follow-up showed a significant survival benefit with durvalumab plus platinum/etoposide vs chemotherapy alone in extensive-stage SCLC.² The updated survival analysis presented during the ESMO Congress was based on a median follow-up of more than 3 years.

The phase III study randomly assigned 805 treatment-naive patients with extensive-stage SCLC 1:1:1 to receive durvalumab plus platinum/etoposide chemotherapy every 3 weeks for four cycles; durvalumab plus tremelimumab and platinum/etoposide every 3 weeks for four cycles; or platinum/etoposide alone every 3 weeks for six cycles. An analysis of the tremelimumab-containing arm failed to show a statistically significant survival benefit at 2 and 3 years of follow-up.

The rate of overall survival at 12 months was 43.5% on the experimental arm vs 30.6% on the control arm; the 18-month overall survival rates were 39.8% vs 24.8%, respectively. At 36 months, the overall survival rates were 13.9% vs 5.8%, respectively.

The rate of serious adverse events was similar in both arms of the study. Treatment-related adverse events leading to death were reported in 2.3% of the durvalumab-treated patients vs 0.8% in those given chemotherapy alone. The highest rate of serious adverse events was reported in the tremelimumab arm (47%).

Antibody-Drug Conjugate in Advanced NSCLC With Actionable Mutations

The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) yielded antitumor activity in heavily pretreated patients with advanced or metastatic non–small cell lung cancer (NSCLC) with actionable genetic alterations, according to the results of the TROPION-Pan Tumor01 trial reported during the ESMO Congress.³

In a small trial, 34 heavily pretreated patients who have NSCLC and actionable genetic mutations received Dato-DXd. The objective response rate was 35% across three dose levels (8 patients received 4 mg/kg; 10 patients received 6 mg/kg; and 16 patients received 8 mg/kg). The median duration of response was 9.5 months. The median follow-up was 13 months.

The actionable genetic mutations identified in tumors of patients enrolled in the trial were ALK (n = 3), EGFR (n = 29), and ROS1 and RET (1 patient with both). A total of 82% of patients had at least three prior regimens, and 85% previously received tyrosine kinase inhibitors. Of the patients with EGFR alterations, 69% had previous treatment with the kinase inhibitor osimertinib.

Edward B. Garon, MD

“For patients who have actionable genetic alterations, such as EGFR mutations or ALK gene rearrangements, once patients have exhausted their tyrosine kinase inhibitor therapy as well as platinum-based chemotherapy, the options are not particularly good,” explained lead author Edward B. Garon, MD, of David Geffen School of Medicine, UCLA. “TROP2 is known to be highly expressed in NSCLC, including NSCLC with actionable mutations. Increased expression of TROP2 is associated with poor outcomes,” he continued.

Dato-DXd is an antibody-drug conjugate composed of a human anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable cleavable linker.

The most common adverse event of any grade in patients who received Dato-DXd included stomatitis (56%) and nausea (62%). There was a low incidence of hematologic toxicity of any grade. One fatal adverse event considered related to treatment was interstitial lung disease, reported in one patient treated at the 8-mg/kg dose level, which has since been discontinued for further development of this agent.

Previous phase I data from the TROPION-Pan Tumor01 trial showed antitumor activity in 210 patients with advanced or metastatic NSCLC who were heavily pretreated. The data presented during the ESMO Congress focused on safety, antitumor activity, pharmacokinetics, and biomarkers in patients with progressive NSCLC after standard treatment or there was no standard treatment available.

Dato-DXd is being evaluated further in patients who have NSCLC and actionable mutations in the TROPION-Lung05 study.

Brigatinib vs Crizotinib in ALK-Positive NSCLC

Brigatinib achieved a 52% reduction in the risk of disease progression or death and a 56% reduction in the risk of intracranial disease progression compared with crizotinib in patients with ALK-positive NSCLC. These findings are from the final analysis of the phase III ALTA-1L trial, presented during the ESMO Congress.⁴

Median progression-free survival by blinded radiology review was 24 months in the brigatinib-treated group vs 11.1 months in the crizotinib-treated group (P < .0001). The 3-year progression-free survival rate was 43% with brigatinib vs 19% with crizotinib. The 4-year rate of progression-free survival was 36% vs 18%, respectively.

Results for intracranial progression-free survival warrant attention. Median intracranial progression-free survival in the intent-to-treat population was 44.1 months with brigatinib vs 21.2 months with crizotinib (P < .0001). Among the 96 patients with brain metastases at baseline, the median intracranial progression-free survival rate was 24 months with brigatinib vs 5.5 months with crizotinib (P < .0001).

“Final ALTA-1L results confirm the significant improvement in progression-free survival with brigatinib compared with crizotinib in ALK-positive NSCLC, with no new safety signals. These results support brigatinib as a standard treatment option for treatment-naive ALK-positive NSCLC,” stated Sanjay Popat, FRCP, PhD, of the Royal Marsden Hospital, London.

Sanjay Popat, FRCP, PhD

ALTA-1L enrolled 275 patients with locally advanced or metastatic ALK-positive NSCLC; they were randomly assigned 1:1 to receive brigatinib at 180 mg/d with a 7-day lead-in of 90 mg/d vs crizotinib at 250 mg twice daily. Patients could have received one prior systemic therapy for locally advance or metastatic NSCLC. Previous treatment with an ALK inhibitor or a tyrosine kinase inhibitor was not allowed. Asymptomatic brain metastases were allowed. Stratification factors included the presence of brain metastasis at baseline and receipt of prior chemotherapy for advanced or metastatic disease. Crossover to brigatinib was allowed at disease progression on crizotinib.

A total of 47% of patients (n = 65) crossed over to the brigatinib arm at disease progression. In this group, the median duration of brigatinib treatment was 17.3 months. A total of 46% of 41 patients (n = 19) with brain metastasis at baseline crossed over to brigatinib. A total of 35% (n = 23) of these patients were still receiving brigatinib at data cutoff.

Overall survival was not yet completely mature at the time of the final analysis. A preliminary analysis suggested there may be a survival benefit among patients with brain metastasis at baseline treated with brigatinib as the first ALK inhibitor.

Safety results showed higher rates of grade 3 or 4 adverse events with brigatinib: 70% vs 56% with crizotinib. A total of 11 patients in each treatment arm had a grade 5 event deemed unrelated to treatment. Treatment discontinuation due to an adverse event was reported in 13% of the brigatinib arm vs 9% of the crizotinib arm. Dose reductions due to toxicity were reported in 44% of the brigatinib arm vs 25% of the crizotinib arm. Dose interruptions due to adverse events were reported in 72% and 47%, respectively.

First-Line Atezolizumab in pMMR Colorectal Tumors

The addition of the anti–PD-L1 agent atezolizumab to a standard first-line chemotherapy regimen for metastatic colorectal cancer significantly improved progression-free survival, regardless of mismatch repair status, reported Chiara Cremolini, MD, PhD, of the University of Pisa, Italy.⁵

Chiara Cremolini, MD, PhD

Immune check point inhibitors have yielded remarkable achievements in metastatic colorectal cancers that are mismatch repair–deficient (dMMR) but not in those that are mismatch repair–proficient (pMMR). It is thought that cytotoxic agents plus bevacizumab may promote tumor sensitivity to checkpoint inhibitors, the investigators explained.

The prospective open-label phase II comparative trial randomly assigned 218 molecularly unselected patients with previously untreated metastatic colorectal cancer to receive up to eight cycles of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab or the same regimen plus atezolizumab, followed by maintenance with fluorouracil/bevacizumab or the same regimen plus atezolizumab until disease progression. A total of 7% of the population had dMMR tumors.

“The primary endpoint was met,” Dr. Cremolini reported. “The addition of atezolizumab to FOLFOXIRI/bevacizumab provided a significant increase in progression-free survival. Although the magnitude of benefit is significantly higher in dMMR tumors, there are signals of efficacy also in the pMMR subgroup.”

Median progression-free survival was 13.1 months with atezolizumab vs 11.5 months without—a significant 31% improvement (P = .012). According to MMR status, in the dMMR subgroup, median progression-free survival was not reached with atezolizumab (at a median follow-up of 20.6 months) and was 6.6 months in the control arm—an 89% improvement (P = .002).

“However, also in the pMMR subgroup, there was a benefit,” Dr. Cremolini said. The median progression-free survival was 12.9 months vs 11.4 months, respectively—a 22% improvement (P = .071). “This was statistically significant according to the initial trial design,” she added.

Anti–PD-1 Agent Sintilimab in Gastrointestinal Tumors

Two phase III trials have shown overall survival to be improved in several gastrointestinal malignancies when the anti–PD-1 agent sintilimab was given with chemotherapy vs chemotherapy alone, as a first-line treatment of metastatic disease. Investigators from Beijing, China, reported the first results of the ORIENT-15 trial in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma⁶ and the ORIENT-16 trial in unresectable advanced gastric or gastroesophageal junction adenocarcinoma.⁷

“Sintilimab plus chemotherapy showed significant overall survival benefits vs chemotherapy alone, regardless of PD-L1 expression level,” said Lin Shen, MD, PhD, of Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) at Peking University Cancer Hospital and Institute, Beijing, China, who reported the findings of ORIENT-15.

Jianming Xu, MD

Reporting the results of ORIENT-16, Jianming Xu, MD, of the Fifth Medical Center of People’s Liberation Army General Hospital, noted: “This is the first double-blind phase III study in the Chinese gastric cancer population that demonstrated a statistically significant overall survival benefit with sintilimab in combination with chemotherapy in the primary endpoints of both CPS [combined positive score] ≥ 5 and all randomly assigned patients.”

Both speakers maintained that sintilimab plus chemotherapy will become a new standard first-line treatment option in these malignancies.

In ORIENT-15, the investigators randomly assigned 659 patients with unresectable advanced or metastatic esophageal squamous cell carcinoma to receive either sintilimab with cisplatin plus paclitaxel or fluorouracil or chemotherapy alone. The primary endpoints included overall survival in all randomly assigned patients and in the PD-L1–positive CPS ≥ 10 population.

Median overall survival in all patients was 16.7 months with sintilimab plus chemotherapy vs 12.5 months with chemotherapy alone—a 28% improvement with sintilimab (P < .0001). In patients with a PD-L1 CPS ≥ 10, median overall survival was 17.2 months vs 13.6 months, respectively—a 27% improvement (P = .0018), Dr. Shen reported.

ORIENT-16 enrolled 650 patients previously untreated for advanced, recurrent, or metastatic gastric or gastroesophageal junction cancer; they were randomly assigned to receive sintilimab plus oxaliplatin and capecitabine or chemotherapy alone. The primary endpoints were overall survival in all randomly assigned patients and in those with CPS ≥ 5, which in this trial was considered the threshold of PD-L1 positivity.

At a median follow-up of 18.8 months, median overall survival in the total population was 15.2 months in the experimental arm vs 12.3 months in the chemotherapy arm—a 24% improvement (P = .0090). In the PD-L1–positive population, it was 18.4 months vs 12.9 months, respectively—a 34% improvement (P = .0023). The overall survival benefit was observed at all prespecified CPS cutoffs (CPS ≥ 1, 5, and 10), Dr. Xu reported.

In both ORIENT-15 and ORIENT-16, benefits were consistent across prespecified subgroups. Sintilimab/chemotherapy also yielded significant improvements in progression-free survival, response rates, and duration of response. -Treatment-related adverse events were similar between the arms, with slightly more treatment discontinuations and deaths associated with toxicities with sintilimab.

In China, sintilimab has been approved for the treatment of relapsed or refractory classic Hodgkin lymphoma following two or more lines of chemotherapy; in combination with pemetrexed and platinum chemotherapy in the front-line treatment of nonsquamous NSCLC; and in combination with gemcitabine and platinum chemotherapy in the front-line treatment of squamous NSCLC. In May 2021, the U.S. Food and Drug Administration accepted for review the biologics license application for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous NSCLC.

DISCLOSURE: Dr. Paz-Ares has served on the board of Altum Sequencing and Genomica; has received honoraria or travel fees from AstraZeneca, AstraZeneca Spain, Bristol Myers Squibb, Lilly, MSD, Pfizer, Roche/Genentech, Bayer, Amgen, Blueprint, Celgene, Guardant, Merck Serono, Mirati, Novartis, PharmaMar, and Takeda; and has reported other relationships with HMP, Ipsen, Merck, Novartis, Sanofi, and Servier. Dr. Garon has served as a consultant or advisor to ABL Bio, Boehringer Ingelheim, Bristol Myers Squibb, Dracen, Eisai, EMD Serono, GlaxoSmithKline, Merck, Novartis, Sanofi, Shionogi, and Xilio Therapeutics; and has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Dynavax, EMD Serono, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. Dr. Popat has reported financial relationships with Janssen, Lilly, Merck KgaA, Novartis, Roche, and Takeda; has served as a subinvestigator to Amgen and MSD; has served as coordinating principal investigator to Ariad, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Takeda, Turning Point Therapeutics and a local principal investigator to AstraZeneca, GlaxoSmithKline, Roche, and Trizel. Dr. Cremolini has served as an advisory board member and/or invited speaker for Amgen, Bayer, Merck, MSD, Roche, and Servier. Dr. Shen has reported financial relationships with Bristol Myers Squibb, Zai Lab, CStone Pharmaceuticals, Boehringer Ingelheim, Ming Li, Rongchang Pharmaceuticals, Haichuang, Harbour BioMed, Hutchison Whampoa, and Hengrui.; and has received research funding from Innovent Biologics (which funded this study), Qilu, Zai Lab, Beihai Kangcheng, and Jacobio. Dr. Xu has served as an advisor for Innovent Biologics.

REFERENCES

1. Paz-Ares L, Chen Y, Reinmuth N, et al: Durvalumab, tremelimumab + platinum/etoposide in first-line extensive-stage small cell lung cancer: 3-year overall survival update from the phase III CASPIAN study. ESMO Congress 2021. Abstract LBA61. Presented September 18, 2021.

2. Paz-Ares L, 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. Lancet 394:1929-1939, 2019.

3. Garon EB, Johnson ML, Lisberg, AE, et al: Efficacy of datopotamab deruxtecan (Dato-DXd) in patients with advanced/metastatic NSCLC and actionable genomic alterations: Preliminary results from the phase I TROPION-Pan Tumor01 study. ESMO Congress 2021. Abstract LBA49. Presented September 19, 2021.

4. Popat S, Kim HR, Ahn M, et al: Brigatinib vs crizotinib in ALK TKI–naïve ALK+ NSCLC: Final results from ALTA-1L. ESMO Congress 2021. Abstract 1195P. Presented September 16, 2021.

5. Cremolini C, Rossini D, Antoniotti C, et al: FOLFOXIRI plus bevacizumab plus atezolizumab versus FOLFOXIRI plus bevacizumab as first-line treatment of unresectable metastatic colorectal cancer patients: Results of the phase II randomized AtezoTRIBE study by GONO. ESMO Congress 2021. Abstract LBA20. Presented September 18, 2021.

6. Shen L, Lu Z, Wang J, et al: Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First results of the phase III ORIENT-15 study. ESMO Congress 2021. Abstract LBA52. Presented September 17, 2021.

7. Xu J, Jiang H, Pan Y, et al: Sintilimab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric or gastroesophageal junction adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study. ESMO Congress 2021. Abstract LBA53. Presented September 17, 2021.