PD-1/VEGFR-2 Inhibitor Combo Shows Durable Responses in Nasopharyngeal Carcinoma

The combination of camrelizumab and apatinib led to long-term antitumor activity with manageable toxicities in patients with recurrent or metastatic nasopharyngeal carcinoma, according to findings from a single-arm phase 2 trial (NCT04586088).

At a median follow-up of 12.4 months, (range, 2.1-19.9), the confirmed overall response rate (ORR) was 65.5% (n = 38; 95% CI, 51.9%-77.5%), including complete responses in 22.4% of patients (n = 13) and partial responses in 43.1% of patients (n = 25).¹

“To our knowledge, this is the first prospective study to evaluate the antitumor activity and safety of immunotherapy combined with antiangiogenesis therapy for recurrent or metastatic nasopharyngeal carcinoma,” lead study author Xi Ding, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues, wrote.

Previously, the single-arm, phase 2 POLARIS-02 trial (NCT02915432), which evaluated the PD-1 inhibitor toripalimab as monotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma, demonstrated an ORR of 20.5%. Although this response rate was modest, the responses were durable, as patients who responded had a median duration of response (DOR) of 12.8 months.² 

As PD-1 inhibition provides long-term responses with a manageable safety profile in this population, this open-label phase 2 trial evaluated the antitumor activity and safety of the PD-1 inhibitor camrelizumab in combination with the VEGFR-2 inhibitor apatinib in patients with nasopharyngeal carcinoma who were refractory to at least 1 prior line of therapy, for whom limited effective treatment options exist.

Eligible patients included those ages 18 to 70 years with histologically confirmed recurrent or metastatic nasopharyngeal carcinoma who were refractory to at least 1 line of systemic chemotherapy or who progressed within 6 months after induction, concurrent, or adjuvant chemoradiotherapy. Patients needed to have nasopharyngeal carcinoma unsuitable for radiotherapy and surgery, an ECOG performance status of 0 or 1, and at least 1 measurable lesion.

Patients could not have received prior therapy with immune checkpoint inhibitors or VEGF(R) inhibitors. Patients were also excluded if they had any factors affecting oral drug absorption, any hemorrhages of grade 2 or higher within 4 weeks of initiating study treatment, tumor invasion to major vessels, or obvious nasopharyngeal necrosis.

Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, all of whom received at least 1 dose of the study treatment. Responses were evaluable for 52 patients.

Patients received 200 mg of intravenous camrelizumab once every 3 weeks and 250 mg of oral apatinib once daily until disease progression, death, unacceptable toxicities, or patient choice to withdraw.

This trial did not allow dose modifications of camrelizumab. One to 2 dose interruptions or reductions of apatinib were permitted for adverse effects (AEs) that were not relieved with supportive care. The first dose reduction was 250 mg for 5 days on and 2 days off. The second dose reduction was 250 mg every other day. Apatinib was discontinued in patients with investigator-assessed high-risk major bleeding, such as nasopharyngeal necrosis that invaded the internal carotid artery.

The primary end point of this trial was ORR. The key secondary end points were disease-control rate (DCR), DOR, progression-free survival (PFS), overall survival (OS), and safety.

In total, 43.1% of patients (n = 25) had locoregional recurrence only, 31.0% of patients (n = 18) had distant metastases only, and 25.9% of patients (n = 15) had both locoregional recurrence and distant metastases. All patients had received at least 1 line of prior systemic therapy, and 17.2% (n = 10) had received at least 2 prior lines.

As of the data cutoff of June 2, 2022, 48.3% of patients (n = 29) had discontinued the study treatment. Of those patients, 26 had disease progression, 2 of whom rechallenged the study regimen, and 3 had unacceptable AEs.

The DCR was 86.2% (95% CI, 74.6%-93.9%), with 96.2% (n = 50) of the response-evaluable patients experiencing tumor shrinkage in their target lesions. The median time to response was 2.1 months (interquartile range, 1.4-3.1).

The median DOR was not reached (NR). Of the 38 responders, 26 (68.4%; 95% CI, 51.4%-82.5%) had responses lasting at least 6 months, and 9 had responses lasting at least 12 months. At the data cutoff, 65.8% of responses (n = 25; 95% CI, 48.7%-80.4%) were ongoing.

The median PFS was 10.4 months (95% CI, 7.2-13.6), and the 12-month PFS rate was 44.3% (95% CI, 29.5%-58.6%).

The median OS was NR, and the 18-month OS rate was 85.7% (95% CI, 76.2%-95.0%). A total of 8 deaths (13.8%) occurred.

In patients with locoregional recurrence only, the ORR was 80.0% vs 54.5% in those with metastatic lesions (P = .043). The DOR for the patients with metastatic lesions demonstrated a nonsignificantly better trend vs the DOR for those with locoregional recurrence only (HR, 0.54; 95% CI, 0.16-1.78; P = .308). The PFS between these 2 groups was similar (HR, 1.11; 95% CI, 0.53-2.33; P = .784).

In a post hoc analysis, the ORRs were 76.7% for patients who had dose reductions and/or permanent discontinuation (n = 30) and 53.6% for patients who received sustained treatment or dose pauses but did not have dose reduction (n = 28). The difference in ORR between these 2 subgroups was not significant (P = .064). The DOR (HR, 2.02; 95% CI, 0.55-7.46; P = .292) and PFS (HR, 1.03; 95% CI, 0.49-2.16; P = .944) were similar between these 2 subgroups.

The investigators observed no difference in ORR between the patients with PD-L1–positive disease (n = 32) and those with PD-L1–negative disease (n = 15), at 65.6% vs 66.7% (P = .944). The patients with PD-L1–positive disease had a significantly longer DOR compared with those with PD-L1–negative disease (HR, 0.20; 95% CI, 0.05-0.73; P = .015). The median PFS was 16.7 months vs 9.0 months in the PD-L1–positive and PD-L1–negative groups, respectively (HR, 0.50; 95% CI, 0.22-1.13; P = .095).

A total of 39.7% of patients (n = 23) had available tumor mutational burden (TMB) information. The investigators observed no significant differences in ORR, PFS, or DOR between patients with low and high TMB.

All patients experienced at least 1 treatment-related AE (TRAE), and 58.6% (n = 34) experienced TRAEs of grade 3 or higher. The most common grade 3 or higher TRAEs were hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), creatinine phosphokinase elevation (10.3%), and AST elevation (10.3%).

Any-grade immune-related AEs occurred in 72.4% of patients (n = 42), and 69.0% (n = 40) were grade 1 or 2. Two patients had grade 3 fever or rash, and 2 patients had grade 4 hyperglycemia or pneumonia. No treatment-related deaths were observed.

In total, 87.9% of patients (n = 51) required at least 1 apatinib dose interruption, and 44.8% of patients (n = 26) had dose reductions. The most common reasons for apatinib dose reductions were headache (19.0%) and liver dysfunction (12.1%).

A total of 27.6% (n = 16) patients discontinued apatinib before progression because of TRAEs. The most common TRAE leading to apatinib discontinuation was nasopharyngeal necrosis, which occurred in 56.3% (n = 9) of the patients who discontinued apatinib. Additionally, 1 patient each discontinued because of clinical worsening or debridement for necrosis. Two patients paused apatinib because of grade 3 to 4 liver dysfunction and 1 patient paused apatinib because of ketoacidosis and progressed before restarting. Two patients declined further apatinib administration despite manageable AEs (grade 2 epistaxis and grade 3 hand-foot syndrome, fatigue, and dyspepsia).

After treatment, nasopharyngeal necrosis was assessed in 53 patients and found in 18. The median time to necrosis occurrence was 2.3 months (range, 0.7-9.2). A correlation test revealed significant positive correlations between necrosis and recurrent nasopharyngeal lesions (odds ratio, 5.94; 95% CI, 1.45-24.24), especially in recurrent T3 to T4 disease, as well as between necrosis and nasopharyngeal reirradiation (odds ratio, 5.33; 95% CI, 1.15-24.79).

Of the patients with nasopharyngeal necrosis, 1 with grade 4 necrosis received internal carotid artery embolization when the necrotic foci had invaded; 2 had grade 4 necrosis devouring the internal carotid arteries, with spontaneous internal carotid artery occlusion or embolization before enrollment; 6 had grade 1 to 2 epistaxis; and 2 developed grade 3 to 4 epistaxis conjectured to be from necrosis invading the internal jugular veins or the descending palatine artery, which were cured by nasal packing or vascular embolization.

“We are now undertaking a prospective small-sample [phase 2] trial to compare the treatment effects of mono-chemotherapy, chemoimmunotherapy, antiangio-immunotherapy, and antiangiochemoimmunotherapy [NCT05549466]. Further randomized controlled trials are needed to confirm these findings,” the study authors concluded.

References

1. Ding X, Zhang WJ, You R, et al. Camrelizumab plus apatinib in patients with recurrent or metastatic nasopharyngeal carcinoma: an open-label, single-arm, phase II study. J Clin Oncol. Published online February 3, 2023. doi:10.1200/JCO.22.01450
2. Wang FH, Wei XL, Feng J, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02). J Clin Oncol. 2021;39(7):704-712. doi:10.1200/JCO.20.02712