Increasing cure rates of solid tumors by immune checkpoint inhibitors

NSCLC has witnessed the paradigm shift of ICIs from salvage therapy for metastatic cancers to neoadjuvant/adjuvant therapy for early-stage cancers. For patients with advanced NSCLC, first-line systemic treatment generally consists of targeted therapy, immunotherapy, cytotoxic chemotherapy, or a chemo-immunotherapy combination depending on the tumor's expression of programmed death-ligand 1 (PD-L1), histology type (squamous versus nonsquamous) and the presence of driver mutations, such as epidermal growth factor receptor (EGFR) activation mutation and anaplastic lymphoma kinase (ALK) translocation. In case there is no specific driver mutation, ICIs are commonly used as single agents for those NSCLCs with PD-L1 expression of over 50% and with little cancer-related symptoms. So far, three ICIs have been approved by the United States (U.S.) FDA as single agents for the treatment of advanced NSCLC: two anti-PD1 (Programmed Cell Death Protein 1) antibodies, pembrolizumab based on the KEYNOTE-024 trial [10, 11] and cemiplimab based on the EMPOWER-Lung 1 trial [12], and one anti-PD-L1 antibody atezolimab based on the IMpower 110 trial [13]. In cases when PD-L1 expression is less than 50% or in patients with symptomatic cancer or high disease burden, ICI-based combination is commonly used. Currently, the nivolumab plus ipilimumab combination demonstrated superior survival compared with chemotherapy in the CheckMate-227 trial, leading to its approval for metastatic NSCLC (squamous or non-squamous) without EGFR or ALK genomic alterations with PD-L1 expression  ≥ 1% [14, 15]. The nivolumab and ipilimumab combination is also approved in metastatic NSCLC (squamous or non-squamous) after two cycles of platinum-doublet chemotherapy based on the CheckMate-9LA trial [16]. In addition, for non-squamous NSCLC, platinum/pemetrexed plus pembrolizumab (based on the KEYNOTE-189 trial) [17, 18], carboplatin/nabpaclitaxel plus atezolizumab (based on the IMpower130 trial) [19], and carboplatin/paclitaxel plus atezolizumab and bevacizumab (based on the IMpower150 trial) were also FDA approved as a first-line therapy [20]. For squamous NSCLC, pembrolizumab plus carboplatin with either paclitaxel or nabpaclitaxel has been approved for advanced squamous NSCLC following a phase III KEYNOTE 407 trial with 559 patients [21].

SCLC is a poorly differentiated neuroendocrine tumor, representing approximately 15% of lung cancers. Even though the Tumor, Node, Metastasis (TNM) staging classification is recommended, patients are often divided into limited-stage (LS) versus extensive-stage (ES) disease. LS-SCLC is limited to the ipsilateral hemithorax and regional lymph nodes and can be confined to one safe radiotherapy field. ES-SCLC has spread beyond this and often has distant metastases.

For LS-SCLC, surgery for stage I and radiation for stages II and III, supplemented with systemic chemotherapy, are preferred. Prophylactic cranial irradiation (PCI) following chemotherapy is the standard of care for patients who achieve a complete or good partial response following treatment. It has been shown to increase OS in patients with LS-SCLC. No ICI, however, has been approved for LS-SCLC to date.

For ES-SCLC without symptomatic brain metastasis, the first-line therapy is platinum-etoposide chemotherapy paired with an anti-PD-L1 antibody, followed by maintenance immunotherapy with an ICI until progression. Two humanized monoclonal anti- PD-L1 antibodies, atezolizumab and durvalumab, have been approved for the treatment of ES-SCLC in combination with etoposide-platinum for induction and maintenance therapy based on the Impower133 and CASPIAN trials, respectively [29, 30]. Even though OS was significantly improved with addition of an ICI to the first-line chemotherapy, there was no significant improvement (less than 2.5%) of the CR rate compared to the control. Hence, this addition is less likely to induce “cure”.

Bladder cancer has a high tumor mutation burden and, hence, is considered to be more immunogenic. From 2016 to 2017, five ICIs were approved for the treatment of advanced bladder cancer for carboplatin-ineligible patients or as salvage therapy after disease progression within 12 months of platinum-containing chemotherapy [37‐43], even though some of these accelerated approvals were subsequently withdrawn [44]. The unprecedented benefits of immunotherapy in advanced malignancy have increased interest in exploiting these immune stimulatory agents in earlier stages.

Kidney cancer is another highly immunogenic genitourinary cancer. No other cancer has more first-line immunotherapy combinations approved than kidney tumor. Historically, before ICIs, interleukin-2 (IL-2) and interferon were used to treat renal cancer and melanoma. IL-2 is highly toxic with most patients requiring critical care, and an objective response is observed in approximately 15% of patients, with some achieving long-term remission [55]. The response to interferon is usually not durable. Hence, these two agents are rarely used nowadays. So far, five ICI-based combinations have been approved by the FDA (Table 2): nivolumab and ipilimumab [56‐58], pembrolizumab and axitinib [59, 60], avelumab and axitinib [61, 62], nivolumab and cabozantinib [63], and pembrolizumab plus lenvatinib [64]. All five immunotherapy combinations significantly improved PFS and, in some cases, OS compared with the standard-of-care, sunitinib. A combination of lenvatinib plus pembrolizumab demonstrated the highest objective response rate of 71.0%, although it was also associated with the highest severe adverse event rate and discontinuation of therapy secondary to toxicity [64]. Hence, the treatment decision is mainly based on the physician’s preference, disease status, treatment schedule, underlying medical condition and insurance coverage.

For localized kidney cancer, definitive surgery resection is curative and, therefore, the preferred treatment for patients with stage I and II disease (limited to the kidney), stage III disease (extending into major veins or perinephric tissues and/or regional lymph nodes) and even in patients with limited metastasis. No neoadjuvant therapy is currently indicated.

The U.S. FDA has approved adjuvant therapy with pembrolizumab for patients at intermediate-high to high risk of cancer recurrence following nephrectomy, or after nephrectomy and resection of oligometastatic lesions. This was based on the double-blinded placebo-controlled phase III KEYNOTE-564 trial. Pembrolizumab improved the 24-month DFS compared with placebo in the entire study population (77.3 versus 68.1%, HR 0.68; 95% CI 0.53–0.87; p = 0.002). The estimated 24-month OS of 96.6% versus 93.5% of the placebo (HR: 0.54; 95% CI: 0.30–0.96) also showed statistical significance, but long-term follow-up is in progress [65]. All patients with pT2 tumors with grade 4 or sarcomatoid features, pT3 and high-grade tumors, and metastasectomy with no evidence of disease are candidates to undergo adjuvant therapy post-nephrectomy.

Even though adjuvant pembrolizumab therapy improves clinical outcomes, two other adjuvant trials failed to show clinical benefit. In the IMmotion010 trial with atezolizumab, 778 patients were randomized to one year of adjuvant atezolizumab or placebo treatment after nephrectomy. At a median follow-up of 44.7 months, no significant improvement of investigator-assessed disease-free survival was observed: 57.2 months for atezolizumab versus 49.5 months in the placebo group (HR 0.93, 95% CI 0.75–1.15, p = 0.50) [66]. Similarly, the adjuvant nivolumab and ipilimumab combination did not improve disease-free survival over the placebo control in the CheckMate 914 trial: HR, 0.92; 95% CI, 0.71–1.19; P = 0.5347 [67].

Interferon alfa-2b now mainly remains a historical adjuvant therapy after more effective and less toxic ICIs have been approved. Based on the Eastern Cooperative Oncology Group 1684 and 1694 trials as well as meta-analysis of trials with various doses and schedules, interferon alfa-2b improves OS compared to the control [77‐80]. However, interferon is associated with significant unpleasant side effects, such as flu-like symptoms and depression. As discussed above, the intergroup E1609 trial [81] has shown that ICIs are more effective than interferon. Furthermore, the manufacturer has discontinued the production of interferon alfa-2b. Currently, there is almost no role of interferon alfa-2b as a therapeutic option in any malignancy, including melanoma.

In the CheckMate 238 trial, 906 patients with stage IIIB, IIIC or IV melanoma who had complete resection of melanoma were randomized to receive one year of adjuvant nivolumab or ipilimumab (10 mg/kg every three weeks for four cycles followed by every 12 weeks for one year). At a median follow-up of 51 months, the 4-year recurrence-free survival was 51.7% with nivolumab compared with 41.2% with ipilimumab (HR 0.71; 95% CI 0.60–0.86; p = 0.0003) [82, 83]. Five-year OS was not significantly different: 76% versus 72% (HR 0.86; 95% CI 0.66–1.12). In the BRAF-wild-type group, nivolumab also improved five-year RFS (47% versus 36% with ipilimumab, HR 0.69; 95% CI 0.53–0.9). Among 42% (381) of patients with BRAF-mutant tumors, nivolumab adjuvant therapy trends towards improved five-year RFS: 50% versus 42% with ipilimumab (HR 0.8; 95% CI 0.6–1.05).

In the double-blind, placebo-controlled phase III European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial, 1019 patients with completely resected stage III melanoma were randomized to one year of adjuvant pembrolizumab or placebo [84‐86]. With a median follow-up of 42 months, pembrolizumab significantly increased the 3.5-year relapse-free survival from 49.4% of the placebo group to 65.3% (HR 0.60; 95% CI 0.49–0.73; p < 0.0001). Similar results were observed with the coprimary endpoint of RFS in the 853 patients with PD-L1-positive tumors: 51.6% with the placebo versus 66.7% with pembrolizumab (HR 0.61; 95% CI 0.49–0.76; p < 0.0001).

The phase III EORTC18071 trial that led to the U.S. FDA approval of ipilimumab as an adjuvant therapy at 10 mg/kg every three weeks for four doses followed by every three months for up to three years. In that trial, 951 patients were randomized to ipilimumab or placebo. With a median follow-up of 5.3 years, the 5-year recurrence-free survival was 40.8% with ipilimumab compared with 30.3% with placebo (HR 0.76; 95% CI 0.64–0.89; p < 0.001) [87, 88]. In a subsequent North American Intergroup E1609 trial, ipilimumab at 3 mg/kg, but not at 10 mg/kg, significantly improved OS (HR 0.78; 95.6% CI 0.61–0.99; p = 0.044) compared with interferon alfa-2b [81]. Hence, if ipilimumab is used as adjuvant therapy, a dose of 3 mg/kg is commonly used.

The benefit of ICIs has been further extended to high-risk resected melanoma without lymph node involvement. This group of patients mainly have melanoma with deep local disease (> 4 mm) or with relatively superficial disease (2–4 mm) with ulceration but without lymph node metastasis. In this scenario, adjuvant pembrolizumab is commonly recommended based on the KEYNOTE-716 trial, although surveillance and enrollment in a clinical trial are reasonable alternatives. In this double-blinded, placebo-controlled phase III trial, 976 patients with stage IIB and IIC melanoma were randomized to pembrolizumab every three weeks for 17 cycles or a placebo. PFS was the primary endpoint. At a median follow-up of 21 months, pembrolizumab therapy significantly prolonged PFS, with an 18-month PFS of 86% versus 77% in the placebo group (HR 0.61; 95% CI 0.45–0.82) [89].

Built on the success of adjuvant immunotherapy in melanoma, neoadjuvant ICI-based therapy is actively being explored. In the randomized Phase II SWOG 1801 trial, patients with Stage IIIB-IV cutaneous, acral or mucosal melanoma were randomized to surgery followed by pembrolizumab adjuvant therapy for 18 cycles (54 weeks, adjuvant arm) or neoadjuvant pembrolizumab for three cycles, followed by surgery and 15 cycles of adjuvant pembrolizumab (neoadjuvant arm). Patients in the neoadjuvant arm had significant improvement in event-free survival, the study primary endpoint (one-sided log-rank p = 0.0015, Cox HR 0.59, 95% CI 0.40–0.86) [90]. In addition, the neoadjuvant nivolumab and ipilimumab combination has also been explored as a neoadjuvant therapy for locally advanced melanoma with exciting efficacy in several Phase I and II trials [91‐95].

Gastric cancer, including gastroesophageal junction (GEJ) cancer, is the fourth leading cause of cancer-related deaths worldwide. Outcomes remain poor with standard-of-care fluoropyrimidine and platinum-based chemotherapy in unresectable diseases [96, 97]. Current ICIs approved as first-line agents for advanced or metastatic gastric/GEJ cancers include nivolumab in conjunction with chemotherapy (CheckMate 649) [98] and pembrolizumab in conjunction with chemotherapy and trastuzumab for HER2 + tumors (KEYNOTE811) [99].

Immunotherapy with ICIs has revolutionized the treatment of various cancers, initially for more advanced disease and, more recently, for early-stage tumors. With numerous ongoing clinical trials, we expect to see more immunotherapy approvals for early-stage cancers. Similar to those with advanced cancer, only a minority of patients benefit from ICIs as a monotherapy. One approach to counteract this predicament is the biomarker-based selection of patients who are more likely to respond to ICIs, as seen in lung cancer with high PD-L1 expression, cancers with mismatch repair deficiency or cases with a high tumor mutation burden [10, 119, 120]. However, this population is small among all cancer patients. We believe the future of cancer immunotherapy will be combination therapy that induces multiple hits on cancers and achieves synergistic effects [8, 121]. To date, the combinations of two ICIs, ICIs with chemotherapy and ICIs with targeted therapy, have already obtained U.S. FDA approvals, and more combinations, particularly with chimeric antigen receptor (CAR)-engineered immune cells, are being explored.