Experts Analyze Striking ASCO 2020 Data in Small Cell Lung Cancer

Joshua M. Bauml, MD

In a special OncLive video program, The Board, Joshua M. Bauml, MD, assistant professor of medicine, Perelman School of Medicine, University of Pennsylvania, led a discussion regarding key abstracts that were presented during the 2020 ASCO Virtual Scientific Program in extensive-stage SCLC (ES-SCLC) and limited-stage SCLC (LS-SCLC).

Bauml was joined by:

• Paul Bunn, MD: Distinguished Professor of Medicine-Medical Oncology, James Dudley Chair in Cancer Research, University of Colorado School of Medicine
• Stephen Liu, MD: associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center
• Gilberto De Lima Lopes, MD: associate professor of clinical oncology and associate director of global oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System
• Sandip P. Patel, MD: associate professor of medicine, Moores Cancer Center, University of California San Diego Health
• Jonathan W. Riess, MD, MS: associate professor of medicine, Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center
• Mark A. Socinski, MD: executive medical director, AdventHealth Cancer Center
• Viola W. Zhu, MD, PhD: medical oncologist/hematologist, Chao Family Comprehensive Cancer Center, University of California, Irvine
• David R. Spigel, MD: chief scientific officer, director, Lung Cancer Research Program, principal investigator, Sarah Cancer Research Institute

During the discussion, these experts discussed pivotal data that have emerged in the ES-SCLC paradigm, the potential utility of lurbinectedin (Zepzelca) in the space, and whether recent data signal a new radiotherapeutic standard in LS-SCLC.

Chemoimmunotherapy Combos Elicit Mixed Results in Frontline ES-SCLC

Zhu kicked off the conversation by highlighting the phase 2 ECOG-ACRIN EA5161 study (NCT03382561), which evaluated cisplatin/carboplatin and etoposide alone or in combination with nivolumab (Opdivo) as frontline therapy for patients with ES-SCLC.

Findings from the trial showed that, in the intent-to-treat population, the median progression-free survival (PFS) was 5.5 months with the addition of nivolumab compared with 4.6 months with chemotherapy alone (HR, 0.65; 95% CI, 0.46-0.91; P = .012).¹ The median overall survival (OS) was also improved, at 11.3 months versus 8.5 months, respectively (HR, 0.67; 95% CI, 0.46-0.98; P = .038).

“We already have 2 immunotherapeutic agents approved as first-line treatment [for patients with] ES-SCLC. I felt [the ECOG-ACRIN EA5161 study] added more evidence to the approach,” said Zhu. “To me, this study is quite significant because adding nivolumab improved PFS and OS.”

Patients were randomized 1:1 (n = 80 in each arm) to receive either regimen every 21 days for 4 cycles. Patients in the chemoimmunotherapy arm received nivolumab maintenance every 2 weeks following treatment until progressive disease or up to 2 years. Patients who received chemotherapy alone underwent a period of observation following therapy.

Eligible patients (n = 145) had to have an ECOG performance score of 0 or 1 and no prior chemotherapy. Notably, patients with treated brain metastases were allowed on study.

Patient characteristics were similar between arms; however, more patients with brain metastases were enrolled on the combination arm (n = 11) compared with the chemotherapy-alone arm (n = 7).

The objective response rate was 52%, with a median duration of response of 5.6 months in the combination arm versus 47% and 3.3 months with chemotherapy alone.

Regarding safety, common grade 3 or higher treatment-related adverse effects (TRAEs) in both arms included anemia, neutropenia, febrile neutropenia, thrombocytopenia, fatigue, and lung infection.

Additionally, 1 patient died in each arm. The death was not attributable to a grade 5 TRAE in the nivolumab arm and sepsis in the chemotherapy arm.

To round out the discussion, Bauml questioned why a survival benefit was observed with nivolumab in this study when, in the past, nivolumab had not demonstrated a survival benefit in the later-line setting.

“It could be that [nivolumab] was given in the first-line setting concurrently with chemotherapy,” said Reiss. “[Perhaps] the interaction of antigen release from chemotherapy further stimulated the immune response and provided some additional activity.”

Similarly designed, the phase 3 KEYNOTE-604 study2 did not show the same positive results, according to Liu, who provided an overview of the trial.

Findings from the study showed that the addition of pembrolizumab (Keytruda) to etoposide plus platinum in the frontline setting for patients with ES-SCLC led to a significant improvement in PFS compared with placebo (HR, 0.75; P = .0023; significance threshold P = .0048).

Despite a trend toward OS benefit with pembrolizumab, the chemoimmunotherapy combination missed the significance threshold versus placebo (HR, 0.80; P = .0164; significance threshold, P = .0128).

“There are reasons to explain [why the study improved PFS but not OS],” said Liu. “[Charles M. Rudin, MD, PhD, lead study author of the trial, and a medical oncologist at Memorial Sloan Kettering Cancer Center] did show that when some patients were removed from the analysis—1 patient who was put in the wrong arm—it did meet statistical significance. However, at the end of the day, this was a negative trial.”

Finally, the group highlighted the updated results from the phase 3 CASPIAN trial³, which showed continued OS benefit with first-line durvalumab (Imfinzi) plus etoposide/platinum.

At 24 months, the updated results showed that 23.4% of patients were alive who received the combination versus 14.4% who received the control.

The addition of tremelimumab to durvalumab and chemotherapy did not lead to a survival advantage.

As such, the findings support durvalumab plus etoposide/platinum as a frontline standard of care for patients with ES-SCLC.

“Even though this is significant, and it does create a new standard, the benefit is still relatively small,” said Lopes. “We haven’t [seen] an effect similar to what we have seen in non–small cell lung cancer. This is an important advancement, and this is something that we are using in clinic, but we have a lot more work to do.”

Second-Line Setting Open for Investigation in ES-SCLC

In discussing current second-line options, The Board came to the consensus that lurbinectedin was not ready for prime time in the second-line setting, despite its approval in June 2020.

Additionally, Bunn added that there was a limited number of patients treated in the phase 2 study and there are differences in dosing in the confirmatory phase 3 trial.

“[In second-line trials,] the control arm could be dealer’s choice with 4 or 5 reasonable regimens,” added Patel. “I don’t think there is a clear superior [choice], especially if we are doing an international study. However, the point is well taken that we still have a lot of work left to do because so many of our patients progress. There are so many second-line options. No 1 agent has emerged as a true winner here.”

Twice-Daily Radiation Makes a Claim in LS-SCLC

Closing out the SCLC discussion, Bunn provided key insight on a randomized phase 2 trial (NCT02041845) evaluating standard-dose versus high-dose twice-daily thoracic radiotherapy (TRT) in patients with LS-SCLC.⁴

In the study, 170 patients were randomized to receive 60 Gy of TRT twice daily (n = 89) or 45 Gy of TRT twice daily (n = 81).

The results indicated that the median OS and 2-year OS rate was improved for patients who received high-dose TRT without eliciting a greater amount of radiotoxicity compared with the standard dose.

The ORR was 84.9% with 45 Gy of TRT versus 88.5% with 60 Gy of TRT. Moreover, the complete response rates were 23.2% versus 20.5%, respectively. Based on these results, the investigators concluded that delivering 60 Gy of TRT twice daily is feasible in a majority of patients.

“[This] means that patients would have to come twice a day for 1 week longer…but we don’t see big survival advantages frequently [in LS-SCLC],” explained Bunn. “The goal is to cure people. While this was not a huge trial, and probably not enough to become a National Comprehensive Cancer Network guideline for everyone, I do think we should follow up with a phase 3 randomized, cooperative group trial.”

Socinski added that there was not a significant difference in esophageal or lung toxicities. “I’ve always been a big fan of early, intense radiotherapy in LS-SCLC,” Socinski said. “It is on my list of potentially curable diseases; we all have a small group full of patients who have been cured of LS-SCLC. This abstract was quite illustrative [of that to me] as well.”

Despite these findings, ironing out how to best administer twice-daily radiotherapy remains an area of need, as it is currently underutilized, the group consented.

References:

1. Leal T, Wang Y, Dowlati A, et al. Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161. J Clin Oncol. 2020;38(suppl 15):9000. doi:10.1200/JCO.2020.38.15_suppl.9000
2. 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). J Clin Oncol. 2020;38(suppl 15):9001. doi:10.1200/JCO.2020.38.15_suppl.9001
3. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/JCO.2020.38.15_suppl.9002
4. Gronberg BH, Killingberg KT, Fløtten Ø, et al. Randomized phase II trial comparing the efficacy of standard-dose with high-dose twice-daily thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC). J Clin Oncol. 2020;38(suppl 15):9007. doi:10.1200/JCO.2020.38.15_suppl.9007