The Current Role of Combination Maintenance Therapy (Pemetrexed and Bevacizumab) in the Era of Immunotherapy

Immune checkpoint inhibitors (ICIs) and molecular targeting drugs used against oncogenic drivers, such as EGFR or ALK, have dramatically changed the treatment of NSCLC.^1-6 However, treatment options after those drugs are still limited, and cytotoxic anticancer drugs are the mainstay of subsequent treatment. In addition, because platinum-based combination therapy is the most successful combination with an ICI, platinum-based combination induction therapy and subsequent maintenance therapy are still widely used.^7-9

To date, various maintenance therapies have been developed to maximize the benefits of each drug (Table). Among them, standard combination therapy for nonsquamous NSCLC includes combination carboplatin/paclitaxel with bevacizumab and a platinum-based agent/pemetrexed combination, which are followed by maintenance therapy with bevacizumab alone or pemetrexed alone, respectively.^10-12 In 2019, two important clinical trials investigating new maintenance therapies, ECOG-ACRIN 5508¹³ and COMPASS (WJOG5610L),¹⁴ were reported.

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Overall Survival Comparisons for Maintenance Therapies

The ECOG-ACRIN 5508 trial investigated OS after switching maintenance to either pemetrexed alone or pemetrexed plus bevacizumab versus continuous bevacizumab monotherapy after induction therapy with carboplatin and paclitaxel plus bevacizumab.¹³ Of the 1,516 patients enrolled, 874 (57%) were randomly assigned to bevacizumab, pemetrexed, or combination pemetrexed/bevacizumab maintenance therapy groups. The median OS was 14.4, 15.9 (HR 0.86; p = 0.12), and 16.4 (HR 0.9; p = 0.28) months for the three groups, respectively. The superiority of pemetrexed or combination pemetrexed /bevacizumab in OS was not shown.

The COMPASS trial examined OS after treatment with combination pemetrexed/bevacizumab versus bevacizumab alone as maintenance therapy for patients who received induction therapy with combination carboplatin/pemetrexed/bevacizumab.¹⁴ Of the 907 patients who received induction therapy, 599 were randomly assigned 1:1 to the bevacizumab-alone or pemetrexed/bevacizumab group. The median OS was 19.6 and 23.3 months (HR 0.87; p = 0.069), respectively. The superiority of pemetrexed/bevacizumab over bevacizumab monotherapy was not confirmed. However, it was suggested that patients without an EGFR mutation would benefit from maintenance therapy with pemetrexed/bevacizumab (OS HR 0.82; p = 0.020) and that pemetrexed would be essential for maintenance therapy when carboplatin/pemetrexed/bevacizumab is administered as induction therapy.

Maintenance therapy for nonsquamous NSCLC is still an indispensable part of cancer management. On the basis of the above results, we must decide which induction therapy and which maintenance therapy should be administered to maximize patient benefits.

The Era of Immune Checkpoint Inhibitors 

For EGFR- and ALK-positive cases, the therapeutic effect of an ICI alone is limited.^15-17 Regarding the combination of an ICI and chemotherapy, favorable outcomes of the combination of carboplatin/paclitaxel/bevacizumab with atezolizumab have been reported in patients with EGFR- and ALK-positive disease; however, this outcome is only from one report of an unplanned subgroup analysis.^7,18 In addition, other ICI plus chemotherapy combinations either failed to show any additional effects in patients with EGFR and ALK alterations or excluded those with EGFR- and ALK-positive disease from the trials.^8,9,19 Therefore, induction platinum-based combination therapy followed by maintenance chemotherapy is still an important treatment option for patients with driver oncogene–positive disease.

In patients who are positive for PD-L1, ICI alone or a combination of ICI and chemotherapy is the treatment option for initial treatment. If single-agent ICI is selected as the first-line treatment, platinum-based combination chemotherapy is still an important treatment option for the subsequent second-line treatment.

In addition, platinum-based induction chemotherapy and maintenance therapy is important as a first-line treatment for patients with contraindications for ICIs, such as autoimmune disease and interstitial pneumonia.

In this era of immunotherapy, the combination of an ICI with chemotherapy is frequently used as an initial treatment. If the induction therapy is a pemetrexed-based or bevacizumab-based regimen with an ICI, then pemetrexed plus an ICI or bevacizumab plus an ICI is selected as the maintenance therapy, respectively. In that sense, maintenance therapy with pemetrexed or bevacizumab continues to be used as an integral part of combination therapy with an ICI and chemotherapy.

Preclinically, it has been suggested that pemetrexed induces cancer immunity through immunogenic cell death.²⁰ On the other hand, it has been suggested that bevacizumab, an anti-vascular endothelial growth factor antibody, alters the cancer microenvironment and tumor vessels to induce cancer immunity.²¹ Therefore, it is expected that there will be beneficial effects of using an ICI in combination with these drugs in not only the induction phase but also in the maintenance phase.

We are currently conducting the APPLE study based on the experience of treatment development in the COMPASS study (Fig.). The purpose of this study is to evaluate the effects of adding bevacizumab to carboplatin/pemetrexed/atezolizumab combination therapy. We will promote the development of treatments that further enhance the effects of ICIs by combining pemetrexed and bevacizumab with ICIs.

References: 

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