At this year’s American Society of Clinical Oncology Virtual Meeting, the final results of the RAMES study were presented.1 RAMES was a prospective, placebo-controlled, phase II, randomized study in which patients with malignant pleural mesothelioma (MPM) that progressed after platinum-based chemotherapy and pemetrexed were assigned to receive gemcitabine 1,000 mg/m2 on Days 1 and 8 every 3 weeks, plus placebo (arm A) or gemcitabine with the same schedule plus ramucirumab 10 mg/kg on Day 1 every 3 weeks (arm B), until tumor progression, unacceptable toxicities, or patient refusal. The primary endpoint of the trial was OS, and the secondary endpoints were PFS, overall response rate (ORR) per investigator’s assessment, safety, and quality of life; predictive markers were also explored. Performance status ECOG (0–1 vs. 2), age (> 70 or < 70 years), histology (epithelioid vs. non-epithelioid), and time to progression after first-line therapy (TTP-FL; > 6 or < 6 months) were stratification factors.
Overall, 161 patients were enrolled and included in the final analysis: 80 in arm A, and 81 in arm B. The main baseline characteristics were well-balanced between the two arms. The study showed a borderline statistically significant (HR 0.71; p = 0.057) and a clinically meaningful improvement of OS in the ramucirumab arm, with an increase of median value in the intention-to-treat population by more than 6 months (from 7.5 to 13.8 months; Fig 1). OS at 6 and 12 months was 64% versus 75%, and 34% versus 56%, in arm A and arm B, respectively. Patients with non-epithelioid subtype made up only a small proportion of the study population: 11 in arm A and 12 in arm B. Median OS in these two cohorts was 3.4 and 13.0 months, respectively. The benefit of ramucirumab was observed independently of TTP-FL: median OS for patients with TTP-FL of less than or more than 6 months was 7.1 and 11.5 months, respectively, in arm A, and 13.6 and 13.9 months, respectively, in arm B. Median PFS was 3.3 and 6.2 months (p = 0.26) in arm A and arm B, respectively. No complete responses were observed. Partial response was observed in 10% and 6% and stable disease in 42% and 66% in arm A and arm B, respectively, giving rise to a disease control rate of 52% and 73%, respectively. Four patients in arm A and 7 in arm B discontinued the treatment because of adverse events. Overall, no significant difference in the frequency of adverse events was observed, except for specific ramucirumab-related toxicities, including hypertension, hemorrhages, proteinuria, and thromboembolic events. However, these toxicities were uncommon and mainly grade 1–2. Quality of life and predictive markers data were not reported at the American Society of Clinical Oncology presentation.
Potential Treatment Strategies
There is a strong rationale for inhibiting angiogenesis in MPM. Mesothelioma cells produce high amounts of VEGF-A and VEGF-C and express VEGFR-1 and VEGFR-2; therefore, VEGF acts as an autocrine growth factor.2,3 The MAPS trial demonstrated a statistically significant, albeit clinically modest improvement in OS for the addition of bevacizumab to pemetrexed/cisplatin vs chemotherapy alone in the front line setting.15 But this benefit has yet to be shown in the second-line setting; and other trials in the front-line setting testing vascular targeting agents, including bevacizumab, nintedanib and other TKIs, have proven negative.4 .4 Ramucirumab is a monoclonal antibody selectively directed against the extracellular domain of VEGFR-2. VEGFR2 was found to be strongly and consistently expressed in a retrospective study on MPM tissue samples.5 Interestingly, VEGFR-2 is also expressed by macrophages, which are highly represented in the mesothelioma tumor microenvironment and are thought to be responsible for resistance to both chemotherapy and immunotherapy.6
So far there is no approved treatment for patients with MPM whose disease progresses after standard first-line chemotherapy with pemetrexed and platinum-based chemotherapy. Single-agent chemotherapy with vinorelbine or gemcitabine, and re-challenge with pemetrexed, are commonly used in clinical practice, with limited responses and no demonstrable survival advantage.7 Several targeted therapies and immunotherapy with immune checkpoint inhibitors (ICIs) have failed so far to improve patient outcome in this setting. Single-arm studies of anti–PD-1 and anti–PD-L1 and the combination of these agents with anti–CTLA-4 have shown encouraging activity in patients with MPM that had relapsed; however, the phase III PROMISE-Meso trial showed no superiority of pembrolizumab versus single-agent chemotherapy.8-12

Median OS was prolonged by more than 6 months with the addition of ramucirumab (arm B) to commonly used second-line chemotherapy gemcitabine (arm A; 13.8 vs. 7.5 months). Gemcitabine dose is given in mg/m2.
Abbreviations: dos, dose; HR, hazard ratio; mths, months.
Looking to OS for Answers
The primary endpoint of RAMES was OS, and this is one of the strengths of the study. OS should be the standard endpoint for trials in advanced MPM, as stated in a recent consensus report.13 Endpoints based on radiologic assessment, such as ORR and PFS, can prove misleading in this disease, especially if a central radiologic review is not planned. The survival advantage, although of borderline statistical significance, was clinically meaningful, and was observed in the ramucirumab arm regardless of TTP-FL, age, and histologic subtype, even though a central pathologic review was not performed. The higher disease control rate, despite similar ORR, for patients receiving ramucirumab in addition to gemcitabine is consistent with the mechanism of action of antiangiogenic drugs—that is, more cytostatic than cytotoxic, leading to disease stabilization rather than to tumor regression. It is important to note that the randomized nature of the study and the stratification according to TTP-FL allowed the investigators to exclude a selection bias of patients with more indolent disease. Adding ramucirumab to gemcitabine resulted in a reasonable safety profile, with a low rate of severe adverse events, including some specific class-related toxicities. This extra toxicity (if any) is likely justified by the improved efficacy of the combined treatment.
Two other randomized studies in the second-line treatment of MPM have been recently reported: MAPS2 and PROMISE-Meso, both focused on the role of immunotherapy.12,14 The main patient baseline characteristics and results of these studies and of the RAMES study are summarized in Tables 1 and 2. Patient characteristics were consistent through all the studies, except that in the MAPS2 trial almost one third of patients received treatment in a third or additional line. The median OS of the ipilimumab/nivolumab arm of MAPS2 trial (15.9 months) was numerically longer than OS for patients randomized to the ramucirumab arm of RAMES; however, MAPS2 was a non-comparative study assessing single-agent nivolumab versus a combination of ICIs and was not powered to assess OS as the primary endpoint. Median OS in the control arm of RAMES was shorter compared to the control arm of PROMISE-Meso (7.5 vs. 11.8 months, respectively). Notably, in the RAMES population, about 60% of patients had a TTP-FL of less than 6 months, whereas these data have not been reported so far for PROMISE-Meso; it cannot be ruled out that the population of the PROMISE-Meso study included a higher proportion of patients with a longer TTP-FL, which is an established positive prognostic factor.
In conclusion, the RAMES study has shown a clinically meaningful OS improvement with the addition of ramucirumab to gemcitabine for patients whose disease has progressed on first-line standard chemotherapy with pemetrexed and a platinum-based agent, and can represent a new option in this setting. Whether this treatment option should be used in patients who previously received bevacizumab or ICIs remains an unanswered question.13,14
Table 1. Patient Characteristics in Selected Randomized Studies of Second-Line Therapy in Malignant Pleural Mesothelioma
Study |
||||||
MAPS14 Arm A |
MAPS14 Arm B |
PROMISE-Meso12 Arm A |
PROMISE-Meso 12 Arm B |
RAMES1 Arm A |
RAMES1 Arm B |
|
Drugs and Schedule |
Nivo 3 mg/kg q 2w |
Nivo 3 mg/kg q 2w + Ipi 1 mg/kg q 6w |
Pembro 200 mg q 3w |
Gem 1,000 d1/8 q 3w i.v. or Vino 30 mg/m2 d1/8 q 3w i.v. or Vino 60/80 mg/m2 d1/8 q 3w p.o. |
Gem 1,000 d1/8 q 3w i.v.
|
Gem 1,000 d1/8 q 3w i.v. + Ramucirumab 10 mg/kg d1 q 3w i.v. |
N |
63 |
62 |
73 |
71 |
81 |
80 |
Median Age (years) |
72 (IQR: 33–87) |
71 (IQR: 48–88) |
69 (range: 52–83) |
71 (range: 53–83) |
69 (range: 44–79) |
69 (range: 45–81) |
Sex |
M = 47 (75%), F = 16 (25%) |
M = 53 (85%), F = 9 (15%) |
M = 58 (79%), F = 15 (21%) |
M = 60 (84.5%), F = 11 (15.5%) |
M = 60 (74%), F = 21 (26%) |
M = 59 (74%), F = 21 (26%) |
ECOG Performance Status: n |
PS0: 19 (30%), PS1: 42 (67%) |
PS0: 25 (40%), PS1: 36 (58%), PS2: 1 (2%) |
PS0: 21 (29%), PS1: 51 (70%), PS2: 1 (1%) |
PS0: 14 (20%), PS1: 57 (80%)
|
PS0: 46 (57%), PS1: 34 (42%), PS2: 1 (1%) |
PS0: 50 (63%), PS1: 29 (36%), PS2: 1 (1%) |
Epithelioid: Nn |
52 (83%) |
53 (85%) |
66 (90%) |
62 (87%) |
70 (86%) |
68 (85%) |
Non-epithelioid: n |
11 (17%) |
9 (15%) |
7 (10%) |
9 (13%) |
11 (14%) |
12 (15%) |
> 3rd Line: n |
19 (30%) |
20 (33%) |
None |
None |
None |
None |
TTP After First or Previous Line: n) |
> 3 mos: 37 (59%), |
> 3 mos: 41 (66%), |
Not reported |
Not reported |
> 6 mos: 33 (41%), |
> 6 mos: 33 (41%), |
< 3 mos: 26 (41%) |
< 3 mos: 21 (34%) |
Not reported |
Not reported |
< 6 mos: 48 (59%) |
< 6 mos: 47 (59%) |
Abbreviations: F, female; Gem, gemcitabine; IQR, interquartile ratio; i.v., intravenously; M, male; Nivo, nivolumab; Pembro, pembrolizumab; p.o., by mouth; TTP, time to progression; Vino, vinorelbine.
Table 2. Overview of Selected Randomized Studies of Second-Line Therapy in Malignant Pleural Mesothelioma
Study |
||||||
MAPS14 Arm A |
MAPS14 Arm B |
PROMISE-Meso12 Arm A |
PROMISE-Meso12 Arm B |
RAMES1 Arm A |
RAMES1 Arm B |
|
Drugs and Schedule |
Nivo 3 mg/kg q 2w |
Nivo 3 mg/kg q 2w + Ipi 1 mg/kg q 6w |
Pembro 200 mg q 3w |
Gem 1,000 d1/8 q 3w i.v. or Vino 30 mg/m2 d1/8 q 3w i.v. or Vino 60/80 mg/m2 d1/8 q 3w p.o. |
Gem 1,000 d1/8 q 3w i.v.
|
Gem 1,000 d1/8 q 3w i.v. + Ramucirumab 10 mg/kg d1 q 3w i.v. |
N |
63 |
62 |
73 |
71 |
81 |
80 |
Phase |
II |
II |
III |
III |
II |
II |
Line of Treatment |
2nd, 3rd, further |
2nd, 3rd, further |
2nd |
2nd |
2nd |
2nd |
Primary Endpoint |
DCR-12w *BICR |
DCR-12w *BICR |
PFS *BICR |
PFS *BICR |
OS |
OS |
Response Rate (95% CI) |
19% (8-29) |
28% (16-40) |
22% (13-33) |
6% (2-14) |
10% (NR) |
6% (NR) |
Duration of Response (95% CI) |
7.4 m (5.4-12.8) |
7.9 m (2.6-13.3) |
4.6 m (2.2-10.3) |
11.2 m (6.2-15.3) |
5.4 m (2.1-17) |
8.4 m (4.2-11.5) |
PFS (95% CI) |
4.0 m (2.8-5.7) |
5.6 m (3.1-8.3) |
2.5 m (2.1-4.2) |
3.4 m (2.2-4.3) |
3.3 m ( 2.5-3.7)a |
6.2 m (5.5-7.6)a |
OS (95% CI) |
11.9 m (6.7-17.7) |
15.9 m (10.7-22) |
10.7 m (7.6-NE) |
11.7 m (7.4-NE) |
7.5 m (6.8-8.9)a |
13.8 m (12.7-14.4)a |
DCR (95% CI) |
DCR-12w = 44% (31-58)
|
DCR-12w = 50% (37-63) |
PFS-6m = 27.4% (17.1-38.7) |
PFS-6m = 25% (15.5-35.6) |
NR |
NR |
aCI at 70%.
Abbreviations: BICR, blinded independent centralized review; DCR, disease control rate; Gem, gemcitibane; IQR, interquartile ratio; i.v., intravenously; m, months; NE, not evaluable; Nivo, nivolumab; NR, not reported; Pembro, pembrolizumab; p.o., by mouth; TTP, time to progression; Vino, vinorelbine; w, weeks.
References:
1. Pagano M, Ceresoli GL, Zucali PA, et al. Randomized phase II study on gemcitabine with or without ramucirumab as second-line treatment for advanced malignant pleural mesothelioma (MPM): results of Italian Rames study. J Clin Oncol. 2020;38:(15)(suppl):9004.
2. Ohta, Y, Shridhar V, Bright, R, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer. 1999;81:54-61.
3. Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol. 2001;193:468-475.
4. Nowak AK, Brosseau S, Cook A, Zalcman G. Antiangiogeneic strategies in mesothelioma. Front Oncol. 2020;10:126.
5. Miettinen M, Rikala MS, Rys J, et al. Vascular endothelial growth factor receptor 2 as a marker for malignant vascular tumors and mesothelioma: an immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors. Am J Surg Pathol. 2012;36(4):629-639.
6. Dineen SP, Lynn KD, Holloway SE, et al. Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 2008;68(11):4340-4346.
7. Zauderer MG, Kass SL, Woo K, Sima CS, Ginsberg MS, Krug LM. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer. 2014;84(3):271-274.
8. Quispel-Janssen J, van der Noort V, de Vries JF, et al. Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J Thorac Oncol. 2018;13(10):1569-1576.
9. Okada M, Kijima T, Aoe K, et al. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res. 2019;25(18):5485-5492.
10. Disselhorst MJ, Quispel-Janssen J, Lalezari F, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med. 2019;7(3):260-270.
11. Calabrò L, Morra A, Giannarelli D, et al. Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Lancet Respir Med. 2018;6(6):451-460.
12. Popat S, Curioni-Fontecedro A, Polydoropoulou V, et al. A multicenter randomized phase III trial comparing pembrolizumab versus single agent chemotherapy for advanced pretreated malignant pleural mesothelioma: results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-MESO trial. Annals of Oncology. 2019;30(suppl 5):v851-v934.
13. Tsao AS, Lindwasser OV, Adjei AA, et al. Current and future management of malignant mesothelioma: a consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation. J Thorac Oncol. 2018;13:1655-1667.
14. Scherpereel A, Mazieres J, Greillier L, et al. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 2019;20(2):239-253.
15. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405-1414.
16. Baas P, Scherpereel A, Nowak AK. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Paper presented at: World Lung Cancer Conference 2020, Virtual Presidential Symposium; August 8, 2020.
About the Authors: Dr. Grosso is with the Mesothelioma Unit, Azienda ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. Dr. Ceresoli is with the Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy.