Liu Lends Insight on Highlights From ASCO 2020 in Lung Cancer

Stephen Liu, MD

A number of influential clinical trials were presented during the 2020 ASCO Virtual Scientific Program, 8 of which Stephen Liu, MD, associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center, discussed in depth in a virtual presentation during the 2020 ASCO Direct Highlights^TM webcast, a program developed by Physicians’ Education Resource^®(PER^®), LLC.

Small Cell Lung Cancer

Since the 1970s, the standard of care in extensive-stage small cell lung cancer (ES-SCLC) has been platinum and etoposide chemotherapy. The combination is characterized by high response rates but short progression-free survival (PFS) and overall survival (OS).

The introduction of immunotherapy, particularly the addition of PD-L1 inhibitors to chemotherapy in the frontline setting, has led to improved outcomes. In the phase 3 IMpower133 trial, the addition of atezolizumab (Tecentriq) to carboplatin and etoposide led to a 30% reduction in the risk of death versus carboplatin and etoposide alone (HR, 0.70; 95% CI, 0.54-0.91; P =.007).¹ Data from the trial served as the basis for the March 2019 FDA approval of the combination as frontline therapy in ES-SCLC.

Just 1 year later, in March 2020, the FDA approved the combination of durvalumab (Imfinzi) and platinum/etoposide, according to results of the phase 3 CASPIAN trial, in which the combination led to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).²

“In ES-SCLC, we now have 2 current standards of care that are superior to chemotherapy alone,” said Liu.

At the 2020 ASCO Virtual Scientific Program, data from a third arm of the CASPIAN trial and preliminary data from the KEYNOTE-604 trial challenged those standards of care.

In KEYNOTE-604, patients with untreated ES-SCLC and an ECOG performance status (PS) of 0 to 1 without unstable brain metastases were randomized to pembrolizumab (n = 228) or placebo (n = 225) with platinum-based chemotherapy (carboplatin or cisplatin) and etoposide, followed by pembrolizumab or placebo maintenance.

The 2 arms were fairly representative of a patient population with SCLC, said Liu. Though, slightly more patients had brain metastases in the pembrolizumab arm (14.5%) than in the placebo arm (9.8%).

At the time of data cutoff in December 2019 in the final PFS analysis, the median PFS was 4.8 months in the pembrolizumab arm and 4.3 months in the placebo arm, meeting the co-primary end point of the study (HR, 0.73; 95% CI, 0.60-0.88).³

Although the addition of pembrolizumab resulted in a numerical improvement in OS, it was not statistically significant, said Liu. The median OS was 10.8 months and 9.7 months in the pembrolizumab and placebo arms, respectively (HR, 0.80; 95% CI, 0.64-0.98; P = .0164).

As expected, response rates were fairly high, said Liu, at 70.6% and 61.8% in pembrolizumab and placebo arms, respectively. Additionally, the duration of response (DOR) favored the pembrolizumab arm by 0.5 months.

The most common adverse effects (AEs) in both arms were hematologic in nature, attributable to the platinum/etoposide backbone, said Liu. In the pembrolizumab arm, the most common AEs included hypothyroidism (10.3%) and hyperthyroidism (6.7%), the majority of which were low grade. Pneumonitis was seen in 4.0% of patients in the pembrolizumab arm, which was approximately double than that seen in the placebo arm.

“While there were durable responses and no surprises from a safety standpoint, in a setting where we have approved regimens that have demonstrated survival benefit, the pembrolizumab regimen does not really change my clinical practice,” said Liu.

In CASPIAN, patients with untreated ES-SCLC with asymptomatic or treated brain metastases were randomized to 1 of 3 arms: durvalumab and tremelimumab plus etoposide and platinum, durvalumab plus etoposide and platinum, or etoposide and platinum alone followed by durvalumab and optional prophylactic cranial irradiation in the investigational and control arms, respectively.

There were some imbalances in the tremelimumab arm, explained Liu, in that there were slightly more men and a higher incidence of brain or liver metastases. Though, patients in this arm had a better PS overall.

The addition of durvalumab and tremelimumab did not lead to improved OS. Rather, the median OS was numerically lower in the tremelimumab arm versus the etoposide/platinum arm, at 10.4 months versus 10.5 months, respectively (HR, 0.82; 95% CI, 0.68-1.00; P =.0451).⁴ 

Similarly, there was no difference between arms in terms of PFS or DOR. However, the 1- and 2-year rates of all 3 end points favored the tremelimumab arm, said Liu.

Also included in the presentation were updated findings from the durvalumab/chemotherapy arm, in which the combination showed sustained OS benefit versus chemotherapy alone (HR, 0.75; 95% CI, 0.62-0.91; P = .0032).

“The addition of a PD-L1 antibody to chemotherapy improves survival. The addition of tremilimumab and durvalumab to chemotherapy increased toxicity and did not offer an OS benefit,” said Liu.

Non–Small Cell Lung Cancer

The standard of care for patients without oncogene-driven disease is immunotherapy, said Liu, citing PD-(L)1 monotherapy, chemoimmunotherapy, and dual checkpoint blockade as the 3 preeminent standard approaches.

At the 2020 ASCO Virtual Scientific Program, Martin Reck, MD, PhD, of the Lung Clinic Grosshansdorf, Germany, presented updated data from the phase 3 CheckMate-9LA trial, in which patients with stage IV or recurrent non–small cell lung cancer (NSCLC) with no known sensitizing EGFR mutations or ALK alterations were randomized to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) plus 2 cycles of chemotherapy (n = 361) versus 4 cycles of chemotherapy alone.

In the investigational arm, chemotherapy was histology specific, and in the control arm, patients with nonsquamous histology could receive pemetrexed maintenance.

On May 26, 2020, the FDA approved the combination and 2 cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations, according to interim findings from the trial, which showed a median OS of 14.1 months and 10.7 months in the nivolumab/ipilimumab and chemotherapy-alone arms, respectively (HR, 0.69; 96.71% CI, 0.55-0.87; P = .0006).⁵ The benefit was seen regardless of PD-L1 expression.

The study continued to show positive results with extended follow-up, said Liu, improving median OS from 10.9 months in the chemotherapy-alone arm to 15.6 months in the nivolumab/ipilimumab arm (HR, 0.66; 95% CI, 0.55-0.80). OS favored the nivolumab/ipilimumab arm, irrespective of nonsquamous (HR, 0.69) or squamous histology (HR, 0.62), as well as across PD-L1 expression levels less than 1% (HR, 0.62), 1% or higher (HR, 0.64), 1% to 49% (HR, 0.62), and 50% or higher (HR, 0.66).⁶

The combination also led to an improvement in PFS (HR, 0.68)––though the curves didn’t separate until after 3 months––objective responses rates (ORRs), and DOR.

“There were no new safety signals, though the toxicity was higher than chemotherapy alone,” said Liu. “We now have many appropriate immunotherapy-based options, all better than chemotherapy alone, which is no longer an acceptable standard of care.”

Targeted Therapy

The list of actionable targets in NSCLC continues to grow, as should the use of multipanel next-generation sequencing, said Liu. At the 2020 ASCO Virtual Scientific Program, Justin Gainor, MD, of Massachusetts General Hospital, presented data from the phase 1/2 ARROW trial with the RET inhibitor pralsetinib (BLU-667) in patients with advanced RET fusion–positive NSCLC.

RET fusions are one of the rarer alterations in lung cancer, occurring in 1% to 2% of patients with NSCLC. However, with an appropriate targeted therapy, patients can experience deep and sustained responses, which is what was seen with pralsetinib, explained Liu. In the response-evaluable population with NSCLC (n = 116), the ORR was 65% and 56% in patients with measurable central nervous system metastases at baseline. The complete response (CR) rates were 12% and 5% in untreated patients and those who had received prior platinum, respectively. The median DOR was not reached, and 75% of responding patients remain on treatment^.7

The response rate was balanced with fairly good safety data, said Liu. Only 4% of patients discontinued due to treatment-related AEs.

“Pralsetinib provided rapid and durable tumor responses and will hopefully become an option for our patients in the relatively near future,” said Liu.

A historically underdeveloped target in lung cancer, HER2 is beginning to show signs of actionability, explained Liu, specifically with the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu).

T-DXd is a novel ADC that consists of a humanized anti-HER2 IgG1 monoclonal antibody whose amino acid sequence mirrors that of trastuzumab (Herceptin). T-DXd has a tetrapeptide-based cleavable linker that is coupled with a topoisomerase I inhibitor payload.

According to interim results from the phase 2 DESTINY-Lung01 trial, T-DXd led to an ORR of 61.9% (n = 26) and a CR rate of 2.4% (n = 1) in patients with relapsed/refractory HER2-mutant NSCLC. The median PFS surpassed 1 year, at 14 months with a median DOR and OS that had not been reached.⁸

However, the drug was not without toxicity, explained Liu. Approximately 75% of patients experienced some degree of nausea. Investigators also reported grade 3 TRAEs in 52.4% of patients, leading to discontinuation in approximately 1 of every 5 patients, said Liu.

Grade 2 interstitial lung disease occurred in 11.9% of patients. All patients were treated with steroids. By the time of data cutoff, 2 patients had recovered, 1 recovered with sequelae, 1 was recovering, and 1 had not recovered.

“Despite the toxicity, T-DXd is very exciting based on its high response rate and durable responses,” said Liu. 

EGFR

The current standard of care for patients with advanced EGFR-mutant NSCLC is EGFR TKI-based therapy. At the 2020 ASCO Virtual Scientific Program, the field saw data from 3 randomized phase 3 trials with the first-generation and third-generation EGFR TKIs, erlotinib (Tarceva), gefitinib (Iressa), and osimertinib (Tagrisso), respectively.

In the NEJ026 trial, investigators evaluated the combination of erlotinib and the VEGF inhibitor bevacizumab (Avastin) in patients harboring activating EGFR mutations. The rationale for the combination is multifold, explained Liu, in that bevacizumab inhibits tumor angiogenesis, in theory improving the delivery of erlotinib through vascular normalization, alleviating immunosuppression and promoting efficient tumor infiltration by effectors immune cells.

However, the results from the trial merely confirmed the findings of the phase 2 JO25567 trial, in which the combination led to an improvement in PFS but not OS in patients with activating EGFR mutations.⁹

“Though the improvement in PFS was substantial, the OS was similar between the 2 arms, with a hazard ratio of 1.007, both surviving approximately 4 years,” said Liu.

EGFR TKIs, having demonstrated a survival benefit in the advanced setting, are now being tested in the adjuvant setting. In the CTONG 1104 trial, investigators evaluated gefitinib versus vinorelbine/cisplatin in patients with resected stage II to IIIA EGFR-mutant NSCLC with involved N1/N2 lymph nodes.

Results showed that gefitinib led to an improvement in disease-free survival (DFS), at 30.8 months versus 19.8 months (HR, 0.56; 95% CI, 0.40-0.79; P =.001).¹⁰ Notably, gefitinib was given for 2 years, after which its benefit started to wane. This was well evidenced by the Kaplan Meier curves, in which the 3- and 5-year DFS rates were 39.6% versus 32.5% and 22.6% vs 23.2% in the gefitinib and chemotherapy arms, respectively.

The 5-year OS was similar in the gefitinib and chemotherapy arms, at 53.2% and 51.2%, respectively.

The results of the NEJ026 and CTONG trials made the results of the phase 3 ADAURA trial all the more exciting, explained Liu. In ADAURA, patients with nonsquamous EGFR-mutant resected stage IB, II, and IIIA NSCLC were randomized to receive 80 mg of adjuvant osimertinib (n = 341) or placebo (n = 341) once daily for up to 3 years.

Unlike the CTONG trial, brain imaging was required prior to study entry, said Liu.

The data that were presented at the 2020 ASCO Virtual Scientific Program came from an unplanned interim analysis after the Independent Data Monitoring Committee unblinded the trial. At the time of unblinding, all patients had been followed for at least 1 year.

Patients’ baseline characteristics were fairly representative of an EGFR-positive patient population, favoring younger, female, nonsmokers, said Liu. Only 55% of patients received adjuvant chemotherapy, said Liu, who added that 30% of patients had stage IB disease where adjuvant chemotherapy is not as frequently given.

The results in the stage II/IIA population were overwhelmingly positive, said Liu, with a median DFS that was not reached with osimertinib versus 20.4 months with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). The 2-year DFS rate was 90% and 44%, respectively.¹¹

Though impressive, Liu highlighted the fact that the phase 2 SELECT trial with adjuvant erlotinib also showed an impressive 2-year DFS benefit of 88% that dropped to 56% at 5 years, suggesting that adjuvant EGFR TKI therapy merely delayed relapse.

“After 3 years, will we see a precipitous drop in DFS? Will this DFS improvement, which is substantial, translate to an OS benefit?” asked Liu.

In the overall population, the median DFS was not reached versus 28.1 months with placebo in the osimertinib and placebo arms, respectively (HR, 0.21; 95% CI, 0.16-0.28; P <.0001). The 2-year DFS rate also favored osimertinib, at 89% versus 53% with placebo.

The benefit was observed across all subgroups, added Liu. Though, the greatest DFS benefit was observed in the IIIA setting (HR, 0.12), followed by II (HR, 0.17), and IB (HR, 0.50), as well as among patients with exon 19 deletions versus L858R mutations.

The safety profile was consistent with the known safety profile of osimertinib. Though, AEs leading to discontinuation occurred in 11% of patients in the osimertinib arm versus 4% in the placebo arm.

“These results certainly have the potential to be practice changing,” concluded Liu. 

References

1. Horn L, Mansfield AS, Szczesna A, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
2. 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. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
3. 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; abstr 9001). doi:10.1200/JCO.2020.38.15_suppl.9001
4. 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; abstr 9002). doi:10.1200/JCO.2020.38.15_suppl.9002
5. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) combined with limited chemotherapy as first-line treatment of metastatic or recurrent non-small cell lung cancer. News release. FDA. May 26, 2020. Accessed June 18, 2020. https://bit.ly/2zMzztG.
6. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (nivo) + ipilimumab (ipi) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1l) treatment (tx) for stage IV/recurrent non-small cell lung cancer (nsclc): CheckMate-9LA. J Clin Oncol. 2020;38(suppl; abstr 9501). doi:10.1200/JCO.2020.38.15_suppl.9501
7. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer. J Clin Oncol. 2020;38(suppl; abstr 9515). doi:10.1200/JCO.2020.38.15_suppl.9515
8. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl; abstr 9504). doi:10.1200/JCO.2020.38.15_suppl.9504
9. Maemondo M, Fukuhara T, Saito H, et al. NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations. J Clin Oncol. 2020;38(suppl; abstr 9506). doi:10.1200/JCO.2020.38.15_suppl.9506
10. Wi YL, Zhong W, Wang Q, et al. CTONG1104: adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation––final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial. J Clin Oncol. 2020;38(suppl; abstr 9005). doi:10.1200/JCO.2020.38.15_suppl.9005
11. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl; LBA5). doi:10.1200/JCO.2020.38.18_suppl.LBA5