A phase II study of the L19IL2 immunocytokine in combination with dacarbazine in advanced metastatic melanoma patients

Abstract

Engineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000 mg/m² of body surface on day 1 of 21-day cycles) as single agent, while in two other arms L19IL2 (22.5 million international units of IL2 equivalents) was added, based on two different schedules of administration. In total, 69 patients with stage IV melanoma were enrolled (24 in the dacarbazine arm, 23 and 22 in the other combination arms, respectively) and 67 received treatment. Analyses of efficacy results show a statistically significant benefit in terms of overall response rate and median progression-free survival for patients receiving L19IL2 in combination with DTIC, compared to DTIC as single agent. In light of these results, further clinical investigations with L19IL2 (alone or in combination with other agents) are warranted.

Keywords: Dacarbazine; Immunocytokine; L19IL2; Phase II study; Stage IV melanoma.

Fig. 1

Administration Schedule of L19IL2 and DTIC in the three arms of the study. Schematic representation of the administration schedule of L19IL2 and DTIC in the three arms of the randomized Phase II study. A detailed view of one single cycle is shown in the callouts on the left hand side and on top. Black triangle L19IL2; grey triangle DTIC. Arm 1 used the previously tested schedule (L19IL2 administrations on days 1, 3 and 5 of each 21-day cycle; light grey squares) during the first four cycles, followed by weekly administrations of L19IL2 (dark grey squares). Patients in Arm 2 received directly weekly administration of the immunocytokine (dark squares). DTIC was administered once on day 1 of each cycle (all Arms). In Arm 3 (empty squares), although the protocol foresaw a maximum of eight cycles of DTIC treatment, responders would be allowed to continue with the same treatment until progression

Fig. 2

Flowchart of trial profile and patient allocation to each treatment arm

Fig. 3

Waterfall plot of best objective response for target lesions. Waterfall plot of the best response recorded for each patient evaluable for efficacy in the randomized phase II study. a Waterfall plot of the best response for patients who received L19IL2/DTIC; light gray bars = Arm 1 patients, dark gray bars = Arm 2 patients. b Waterfall plot of the best response for patients who received DTIC alone (Arm 3)

Fig. 4

Kaplan–Meier curves for the progression-free survival and overall survival. a Kaplan–Meier curves showing progression-free survival (PFS) recorded in all efficacy-evaluable patients treated in the randomized phase II study (Arm 1 = blue line; Arm 2 = green line; Arm 3 = red line). b Kaplan–Meier curves of PFS for the 38 patients treated with L19IL2/DTIC (Arm 1 + Arm 2; blue line) and for patients treated with DTIC alone (Arm 3; red line). c Kaplan–Meier curves showing overall survival (OS) for patients of Arm 1 (blue line), Arm 2 (green line) and Arm 3 (red line), recorded in the randomized phase II study. d Kaplan–Meier curves showing OS recorded in all 38 efficacy-evaluable patients treated with L19IL2/DTIC in the phase II study (Arm 1 + Arm 2; blue line) and in the 22 efficacy-evaluable patients treated with DTIC alone (Arm 3; red line)

Fig. 5

Examples of responses in patients of the controlled phase II. a CT images of four different pulmonary coin lesions (I–IV) of patient No. 43. The patient was randomized to Arm 2 of the study and presented at baseline with four pulmonary coin lesions (RECIST score 35.3). Already at week 6, the patient enjoyed a partial response (decrease of 41% in RECIST score), which improved over time reaching an 82% reduction of RECIST score (5.8) on week 24. This partial response was still continuing when the patient was dismissed at the end of study (week 52; not shown). Lesions are indicated by green arrows. b CT images of a paratracheal lymph node of patient No. 97 (best response 100%). The patient was randomized to Arm 1 of the study and presented at baseline with a paratracheal and a pre-carinal (not shown) lymph node metastasis (RECIST score 35.0). Also in this case, already at week 6 both lymph nodes returned to a size of < 1.0 cm (complete response) and remained of normal size until the patient was withdrawn from the study on investigator’s decision on week 36. The complete response, however, was still ongoing at week 52 from the beginning of treatment (not shown). A green arrow indicates the paratracheal lesion