Experts Highlight Developments in Lung, GI Cancers

Roy Herbst, MD, PhD

Lung Cancer

Recent data have moved the needle across the board in oncology, with immunotherapy and targeted agents paving the way for an improvement in survival outcomes. In a panel discussion at the 36th Annual CFS®, key opinion leaders in metastatic non—small cell lung cancer (NSCLC) and gastrointestinal cancer discussed how to distinguish between the available treatments and create a more personalized approach.There have been a number of recent changes in the management of metastatic NSCLC, and the next challenge is determining an established standard for each line of therapy, said Roy S. Herbst, MD, PhD.

Herbst was joined by Joshua Bauml, MD, both of whom highlighted recent positive data in the field and shared their insight on how to manage particular patients.

“This is a very special time in NSCLC,” said Herbst, chief of Medical Oncology and professor of Medicine at Yale Cancer Center, Smilow Cancer Hospital. “We are moving toward immunotherapy and antiangiogenic agents in the frontline setting. We are changing the way we manage this disease.”

Bauml, an assistant professor of Medicine, Hematology/Oncology, at the Perelman School of Medicine and the University of Pennsylvania, echoed this sentiment, sharing insight on the pivotal phase III KEYNOTE-024 trial, which led to the October 2016 FDA approval of pembrolizumab (Keytruda) for the frontline treatment of patients with metastatic NSCLC who have a PD-L1 expression ≥50% and do not have ALK or EGFR aberrations.

“This was the first study that showed immunotherapy can have a meaningful impact in newly diagnosed patients with metastatic NSCLC who do not have an actionable mutation,” Bauml said.

In KEYNOTE-024, pembrolizumab demonstrated a 40% improvement in overall survival (OS) versus standard platinum-based chemotherapy (HR, 0.60; 95% CI, 0.41—0.89; P <.005).¹ There was also a statistically significant advantage in progression-free survival (PFS) at 10.3 months versus 6.0 months in favor of the PD-1 inhibitor.

“Median OS was around 30 months for the patients treated with pembrolizumab, which is pretty remarkable,” said Bauml. “This was significantly higher than what we were used to seeing in this patient population.”

The phase III KEYNOTE-189 trial evaluated the combination of pemetrexed and carboplatin alone or with the addition of pembrolizumab in patients with nonsquamous advanced NSCLC. In the intent-to-treat analysis, the addition of pembrolizumab was associated with an improvement in median OS.²

“When you break this down in terms of PD-L1 staining, the OS benefit was seen across the board,” Bauml noted. “Even in the PD-L1—negative patients, we saw an improvement with the addition of pembrolizumab.”

These data led to the FDA granting a full approval in August 2018 to pembrolizumab in combination with pemetrexed/carboplatin for patients with nonsquamous metastatic NSCLC. The initial accelerated approval, which occurred in May 2017, was based on phase II findings from cohort G from the KEYNOTE-021 trial, which demonstrated a PFS benefit with the addition of pembrolizumab.

KEYNOTE-407 was a clinical trial that impacted the frontline landscape of metastatic squamous NSCLC with pembrolizumab added to carboplatin/paclitaxel or nab-paclitaxel (Abraxane). Results showed there was a 36% reduction in the risk of death with the addition of pembrolizumab to carboplatin plus paclitaxel/nab-paclitaxel.³ Median OS was 15.9 months with the addition of pembrolizumab versus 11.3 months for chemotherapy alone, Bauml said.

“These trials have seemed to create a clear path for patients with squamous or nonsquamous metastatic NSCLC, but we might be in a phase of treatment now where we have too many riches,” Bauml said.

Nivolumab (Opdivo) and ipilimumab (Yervoy) have also shown efficacy. Results of the phase III CheckMate-227 study of frontline nivolumab and ipilimumab in patients with high tumor mutational burden (TMB) showed a 42% reduction in the risk of progression or death with the PD-1 inhibitor and CTLA-4 inhibitor versus chemotherapy in these patients (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).^4,5

In June 2018, the FDA accepted a supplemental biologics license application for the immunotherapy combination based on the CheckMate-227 findings. In October, the FDA added 3 months to the review period for this application, making the new action date May 20, 2019.

GI Cancers

“Overall, these data with immunotherapy have been huge,” said Herbst. “Just last year, we still had pundits debating whether or not these agents would actually take over how we treat NSCLC. Now, there is no debate.”Following the lung cancer portion of the session, Cathy Eng, MD, and David H. Ilson, MD, discussed the management of metastatic colorectal cancer (mCRC) and gastric cancer/gastroesophageal junction (GEJ) adenocarcinoma.

Ilson, an attending physician at Memorial Sloan Kettering Cancer Center, explained that following progression on standard frontline chemotherapy with FOLFIRINOX and oxaliplatin, patients with gastric cancer should receive treatment with ramucirumab (Cyramza) and paclitaxel. This regimen was granted FDA approval in November 2014, specifically for patients with previously treated advanced gastric or GEJ adenocarcinoma, based on findings in the phase III RAINBOW study.

“We have recent phase III data suggesting that the addition of ramucirumab to paclitaxel improves OS, PFS, and responses over paclitaxel alone,” Ilson said. “This would be standard second-line therapy.”

In RAINBOW, the combination of the VEGFR-2 inhibitor ramucirumab and paclitaxel led to a 2.3-month improvement in OS over paclitaxel alone.⁶ Patients with gastric/GEJ adenocarcinoma were randomized 1:1 to receive ramucirumab plus paclitaxel (n = 330) or placebo plus paclitaxel (n = 335). Patients enrolled in the study previously received first-line fluoropyrimidine- or platinum-containing therapy.

Results showed that the median OS was 9.6 months with ramucirumab/paclitaxel versus 7.4 months for paclitaxel alone (HR, 0.81; 95% CI, 0.678-0.962; P = .017). The median PFS was 4.4 versus 2.9 months, for the ramucirumab and placebo arms, respectively (HR, 0.64; 95% CI, 0.536-0.752; P <.0001).

This indication follows the April 2014 approval of single-agent ramucirumab as a treatment for those with unresectable gastric cancer or GEJ adenocarcinoma following fluoropyrimidine- or platinum-containing therapy, based on a significant extension in OS. This decision was based on data in the phase III REGARD trial, in which the median OS was 5.2 months versus 3.8 months with ramucirumab compared with placebo, respectively.7

Additionally, recent data for TAS-102 (trifluridine/tipiracil; Lonsurf) is showing potential, Ilson said. TAGS, a phase II study, was conducted to confirm findings from a phase II Japanese study in patients with metastatic gastric cancer, in which TAS-102 was evaluated after failure of standard chemotherapies (fluoropyrimidines, platinums, and taxanes) or irinotecan. Data showed that the median OS was 8.7 months and the disease control rate was 65.5%.

“However, it is important to remember that chemotherapy is still quite effective in these patients,” Ilson said.

In mCRC, testing for microsatellite instability (MSI) and mismatch repair deficiency (dMMR) is becoming a standard approach.

Checkpoint inhibitors have begun to shape treatment decisions in this subset of patients, said Eng, a professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center.

Ramucirumab is also indicated in the second-line setting in combination with FOLFIRI for patients with mCRC who progress on a frontline bevacizumab (Avastin) regimen. The April 2015 approval was based on results of the phase III RAISE trial, in which the median OS was 13.3 months in those who received ramucirumab/FOLFIRI and 11.7 months for patients treated with placebo/FOLFIRI.⁷

References

1. Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.
2. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
3. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.
4. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT077. 2017;35(suppl 4S; abstr 350).
5. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801946.
6. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus paclitaxel plus placebo in patients with previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (RAINBOW): phase III randomized study. Lancet. 2014 Oct;15(11):1224-35. doi: 10.1016/S1470-2045(14)70420-6.
7. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383)9911):31-39. doi: 10.1016/S0140-6736(13)61719-5.
8. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0.