EU Application Withdrawn for Frontline Nivolumab/Ipilimumab in NSCLC

Samit Hirawat

Bristol-Myers Squibb (BMS) has withdrawn its application in the European Union for the frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a treatment for patients with advanced non—small cell lung cancer (NSCLC).¹

The application, which was based on final progression-free survival (PFS) findings from the phase III CheckMate-227 trial, was originally filed in 2018 as a first-line treatment for patients with NSCLC who have tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb). The application was also later amended to include overall survival (OS) results from part 1a of the CheckMate-227 trial comparing nivolumab plus ipilimumab with chemotherapy for patients whose tumors expressed PD-L1 ≥1%.

While the European Medicines Agency’s Committee for Medicinal Products for Human Use recognized the integrity of the patient level data, BMS stated in a press release that the committee determined that a full assessment of the application was not possible, “following multiple protocol changes the company had made in response to rapidly evolving science and data.” The company added that there are no plans to refile the application in the European Union.

“CheckMate-227 is a robust phase III study of more than 1700 patients. Opdivo plus Yervoy demonstrated a statistically and clinically significant overall survival benefit compared to chemotherapy for patients with first-line NSCLC. The durable survival benefit seen in CheckMate-227 is an important result for patients and we are disappointed with the CHMP’s position,” Samit Hirawat, MD, chief medical officer, BMS, stated in a press release.

In January 2020, the FDA granted a priority review designation to a supplemental biologics license application (sBLA) for the combination of nivolumab and ipilimumab for the first-line treatment of patients with metastatic or recurrent NSCLC that does not have EGFR or ALK genomic tumor aberrations.² Under the Prescription Drug User Fee Act, the FDA will make a decision on the sBLA by May 15, 2020.

The sBLA is also based on findings from part 1 of the phase III CheckMate-227 trial, in which nivolumab combined with ipilimumab demonstrated a significant improvement in OS compared with chemotherapy alone in patients with previously untreated NSCLC.^3,4 In a cohort of patients with PD-L1 expression ≥1%, the median OS with nivolumab and ipilimumab compared with chemotherapy was 17.1 months and 14.9 months, respectively (HR, 0.79; 97.72% CI, 0.65-0.96; P = .007). Moreover, the median OS was 17.1 months with the combination and 13.9 months with chemotherapy in all randomized patients, regardless of PD-L1 expression status (HR, 0.73; 95% CI, 0.64-0.84).

In the multipart, open-label, phase III CheckMate-227 study, investigators evaluated frontline nivolumab-based regimens versus platinum-doublet chemotherapy in patients with advanced NSCLC across nonsquamous and squamous histologies. In part 1a of the study, nivolumab plus low-dose ipilimumab or nivolumab alone was compared with chemotherapy in patients with PD-L1—positive NSCLC. In part 1b, nivolumab/low-dose ipilimumab plus chemotherapy versus chemotherapy alone was evaluated in patients whose tumors do not express PD-L1.

In part 2 of CheckMate-227, nivolumab plus chemotherapy was compared with chemotherapy alone in patients with advanced NSCLC, regardless of PD-L1 expression.

In part 1a, 1189 patients were randomized 1:1:1 to receive chemotherapy (n = 397), nivolumab alone (n = 396), and nivolumab plus low-dose ipilimumab (n = 396). In part 1b, 550 patients were randomized to nivolumab/low-dose ipilimumab (n = 187), chemotherapy (n = 186), and nivolumab/chemotherapy (n = 177).

Nivolumab was administered at 3 mg/kg every 2 weeks, and in the combination arm, 1 mg/kg of ipilimumab was given every 6 weeks. Treatment was administered until disease progression, unacceptable toxicity, or for 2 years for immunotherapy.

To be eligible for enrollment, patients must have had stage IV or recurrent NSCLC, had received no prior systemic therapy, no sensitizing EGFR mutations or ALK alterations, no untreated central nervous system metastases, and an ECOG performance status of 0 or 1. Patients were stratified by squamous and nonsquamous histology.

The independent coprimary endpoints of the study focused on a comparison of nivolumab and ipilimumab versus chemotherapy and were PFS in a high TMB population and OS in the PD-L1—positive (≥1%) population. Secondary endpoints included PFS and OS with nivolumab/chemotherapy versus chemotherapy in the PD-L1 <1% subgroup, and OS with nivolumab versus chemotherapy in patients with PD-L1 expression ≥50%. The minimum follow-up for the primary endpoint was 29.3 months.

Additional results showed that, in the cohort of patients with PD-L1 ≥1% expression, the 1- and 2-year OS rates were 63% and 40% with nivolumab/ipilimumab and 56% and 33% with chemotherapy, respectively.

An exploratory analysis was conducted of the nivolumab/ipilimumab combination, single-agent nivolumab, and chemotherapy alone arms in patients whose tumors had PD-L1 expression ≥1%. Here, the median OS was 17.1 months, 15.7 months, and 14.9 months, respectively (HR for nivolumab/ipilimumab vs chemo, 0.79; 97.72% CI, 0.65-0.96; HR for nivolumab vs chemotherapy, 0.88; 97.72% CI, 0.75-1.04). The 1-year OS rates for the combination, nivolumab, and chemotherapy were 63%, 57%, and 56%; the 2-year OS rates were 40%, 36%, and 33%, respectively.

The median duration of response by blinded independent central review was 23.2 months, 15.5 months, and 6.2 months for nivolumab/ipilimumab, nivolumab, and chemotherapy, respectively. The rates of patients in response at 1 year were 64%, 63%, and 28%, respectively; the rates of those in response at 2 years were 49%, 40%, and 11%, respectively.

In part 1b, which comprised patients with PD-L1 expression <1%, the median OS was 17.2 months, 15.2 months, and 12.2 months with nivolumab/ipilimumab, nivolumab/chemotherapy, and chemotherapy, respectively (HR for nivolumab/ipilimumab vs chemotherapy, 0.62; 95% CI, 0.48-0.78; HR for nivolumab/chemotherapy vs chemotherapy, 0.78; 95% CI, 0.60-1.02). The 1-year OS rates with nivolumab/ipilimumab, nivolumab/chemotherapy, and chemotherapy were 60%, 59%, and 51%, respectively; the 2-year OS rates were 40%, 35%, and 23%, respectively.

For all randomized patients, regardless of PD-L1 expression status, the 1-year OS rates with nivolumab/ipilimumab and chemotherapy were 62% and 54%, respectively; the 2-year OS rates were 40% and 30%, respectively.

Moreover, no new safety findings of the combination were reported with longer follow-up in part 1. Grade 3/4 treatment-related adverse events were reported in 32.8%, 19%, and 36.0% of patients in the nivolumab/ipilimumab, single-agent nivolumab, and chemotherapy arms, respectively.

Earlier data of CheckMate-227 have been mixed. In July 2019, BMS announced that part 2 of the trial did not meet its prespecified primary endpoint of OS with the combination of nivolumab and chemotherapy compared with chemotherapy alone in patients with nonsquamous NSCLC, regardless of PD-L1 expression status (HR, 0.86; 95% CI, 0.69-1.08).⁵ The median OS for patients treated with nivolumab/chemotherapy was 18.8 months versus 15.6 months for chemotherapy, and the 1-year OS rate was 67% compared with 59%, respectively.⁶

However, in an exploratory analysis of patients with squamous NSCLC, the median OS was 18.3 months for first-line nivolumab plus chemotherapy compared with 12.0 months for chemotherapy (HR, 0.69; 95% CI, 0.50-0.97).

In January 2019, BMS withdrew its sBLA for the combination of nivolumab and ipilimumab for the first-line treatment of patients with advanced NSCLC with TMB ≥10 mut/Mb following discussions with the FDA.⁷

The agency had initially accepted the sBLA in June 2018 based on additional data from the phase III CheckMate-227 trial, which showed that the 1-year PFS rate was 43% for patients with high TMB assigned to nivolumab/ipilimumab compared with 13% for those assigned to platinum-doublet chemotherapy.⁸

In October 2018, BMS submitted an exploratory OS analysis to the FDA from part 1 of the CheckMate-227 trial, which comprised a TMB <10 mut/Mb subgroup of patients with stage IV or recurrent NSCLC who had not received prior therapy. With those updated findings, the FDA extended the review period by 3 months, which made the new action date May 20, 2019. Yet, the new data showed no difference in survival outcomes between patients whose tumors had high or low levels of TMB.

Nivolumab is currently indicated for the treatment of patients with metastatic NSCLC who have disease progression on or after platinum-based chemotherapy.

BMS also stated that it plans to file applications in the United States, Europe, and other markets for the combination of nivolumab and ipilimumab administered concomitantly with a limited course of chemotherapy for the frontline treatment of patients with NSCLC.

“Patients with lung cancer should have access to innovative new therapies that offer the promise of long-term overall survival. We are continuing to advance our application in the [United States] for CheckMate-227 and plan to file data from CheckMate-9LA in markets globally to help address the serious unmet need in first-line lung cancer,” Hirawat concluded in the press release.

References

1. Bristol-Myers Squibb withdraws European application of Opdivo (nivolumab) plus Yervoy (ipilimumab) for the first-line treatment of advanced non-small cell lung cancer [news release]: Princeton, NJ. Bristol-Myers Squibb. Published January 31, 2020. https://bit.ly/2ugvGu3. Accessed February 2, 2020.
2. U.S. Food and Drug Administration accepts for priority review Bristol-Myers Squibb’s Application for Opdivo (nivolumab) plus Yervoy (ipilimumab) in first-line non-small cell lung cancer [news release]: Princeton, NJ. Bristol-Myers Squibb. Published January 15, 2020. https://bit.ly/2uRAeXY. Accessed January 15, 2020.
3. Peters S, Ramalingam S, Paz-Ares L, et al. Nivolumab + low-dose ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non—small cell lung cancer: CheckMate-227 part 1 final analysis. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA4.
4. Hellmann MD, Paz-Ares L, Carbo RB, et al. Nivolumab plus ipilimumab in advanced non—small-cell lung cancer. N Eng J Med. 2019;381(21):2020-2031. doi: 10.1056/NEJMoa1910231.
5. Bristol-Myers Squibb Provides Update on Part 2 of CheckMate-227. Bristol-Myers Squibb. Published July 24, 2019. https://bit.ly/32PyxXu. Accessed July 24, 2019.
6. Paz-Ares L, Ciuleanu TE, Yu X et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 - part 2 final analysis. Ann Oncol. 2019;30(suppl_11):mdz453.004. doi: 10.1093/annonc/mdz453.004.
7. Bristol-Myers Squibb reports fourth quarter and full year financial results. Bristol-Myers Squibb [news release]: Princeton, NJ. Published January 24, 2019. https://bit.ly/2FMWGpr. Accessed January 24, 2019.
8. 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).