Successful Treatment of Synchronous Double Lung and Colon Cancers Using Immune Checkpoint Inhibitors

Abstract

We herein report a case of successfully treated synchronous advanced cancers: programmed death-ligand1 (PD-L1)-negative squamous cell carcinoma of the left upper lung lobe and adenocarcinoma of the ascending colon. As lung cancer was prioritized as the primary therapeutic target, the patient received a combination of anti-PD-L1 and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, along with chemotherapy (the POSEIDON regimen). This approach proved effective against both lung and colon cancer. Subsequent testing revealed high-frequency microsatellite instability (MSI-H) in the colon cancer. These findings highlight the therapeutic potential of combined anti-PD-L1 and anti-CTLA-4 antibodies in the treatment of PD-L1-negative lung and MSI-H colorectal cancers.

Introduction

Synchronous or metachronous cancers in the same individual are classified as multiple primary cancers when they arise at different sites and/or exhibit distinct histological and morphological features. Synchronous cancer refers to multiple primary cancers diagnosed within two to six months of the first cancer diagnosis (1).

Programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are immune checkpoint molecules expressed on T-cells. Inhibition of these checkpoints with immune checkpoint inhibitors (ICIs) enhances T cell activation and antitumor activity. Programmed death ligand 1 (PD-L1) expression is considered a useful biomarker for predicting ICI responses in lung cancer. In recent phase 3 clinical trials (2,3), PD-L1 negativity was identified as a biomarker, suggesting the benefit of combining anti-CTLA-4 antibodies with treatment. Furthermore, the effectiveness of ICIs against solid tumors with high-frequency microsatellite instability (MSI-H) has been recognized, leading to expanded indications (4).

We herein report a case of synchronous double cancers [PD-L1-negative pulmonary squamous cell carcinoma (SCC) and MSI-H colon cancer] that was successfully treated with a combination of anti-PD-L1 and anti-CTLA-4 antibodies plus chemotherapy.

Case Report

In November 2023, a 71-year-old woman presented after a fall at home due to dizziness and sustained left anterior chest contusion. She initially visited a local clinic because her left chest pain had persisted for two days. Blood tests revealed anemia, with a hemoglobin (Hb) level of 7.4 g/dL, and chest radiography showed abnormal shadows in the middle and lower lung fields. She was referred to our department in mid-November, 2023.

She had no significant medical history but reported a 43-pack-year smoking history, having quit smoking 8 years earlier. The Eastern Cooperative Oncology Group performance status score was 1. Physical examination findings were as follows: height, 154 cm; weight, 47 kg; body temperature, 36.5°C; pulse rate, 74/min; respiratory rate, 20/min; and blood pressure, 110/59 mmHg. No skin lesions or peripheral lymphadenopathy were observed, and the respiratory and cardiac sounds were clear. Laboratory findings included a white blood cell count of 13,400 /μL (neutrophils 89.0%, lymphocytes 6.0%, eosinophils 1.0%, basophils 0.5%, and monocytes 3.5%), Hb 8.2 g/dL (reference: 11.3-15.0 g/dL), and the following blood values: C-reactive protein 12.06 mg/dL (reference: 0-0.3 mg/dL), carcinoembryonic antigen 6.2 ng/mL (reference: 0-5.0 ng/mL), and cytokeratin 19 fragments 34.7 ng/mL (reference, 0-3.5 ng/mL).

Chest computed tomography (CT) revealed a massive tumor in the left upper lobe with a maximum diameter of approximately 6.5 cm (Fig. 1A, B). Contrast-enhanced CT (CE-CT) revealed multiple enlarged mediastinal lymph nodes and a mass in the ascending colon with surrounding regional lymph nodes measuring approximately 1 cm (Fig. 1C). Fluorodeoxyglucose (FDG) positron emission tomography/CT revealed an intense FDG uptake in the left pulmonary mass, bilateral supraclavicular and mediastinal lymph nodes, and colonic mass (Fig. 2).

Figure 1.

(A) Chest computed tomography (CT) scan showing a large tumor in the left upper lobe. (B) Contrast-enhanced CT (CE-CT) scan showing multiple enlarged mediastinal lymph nodes. (C) CE-CT scan showing a mass in the ascending colon. (D-F) After four cycles of durvalumab, tremelimumab, and chemotherapy, CE-CT showing marked shrinkage of the lung cancer, mediastinal lymph node metastases, and colon cancer. (G-I) Twenty months after the initial diagnosis, CE-CT showed sustained shrinkage of the lung cancer and no abnormal findings following laparoscopic surgery for colon cancer.

Figure 2.

(A) Fluorodeoxyglucose (FDG) positron emission tomography/CT showing an intense FDG uptake in the left pulmonary mass and mediastinal lymph nodes. (B) The FDG uptake in the colonic mass.

Bronchoscopy revealed an irregularly elevated lesion in the left main bronchus near the second carina and a tumor obstructing the left lingular bronchus (Fig. 3A, B). A histological examination of endobronchial biopsy specimens from the lingular segment confirmed the diagnosis of SCC. The patient was thus diagnosed with pulmonary SCC, cT4N3M0, stage IIIC (8th TNM classification of lung cancer).

Figure 3.

(A, B) A bronchoscopic examination showing an irregularly elevated lesion in the left main bronchus near the second carina and a tumor obstructing the left lingular bronchus. (C) A colonoscopic examination showing circumferential irregular ulcerative lesions replacing the entire ascending colon and causing stenosis. (D) After four cycles of durvalumab, tremelimumab, and chemotherapy, follow-up colonoscopy showing a reduction of the colonic mass and resolution of the stenosis.

No driver gene mutations or rearrangements were detected, and the PD-L1 tumor proportion score was negative. Colonoscopy revealed circumferential irregular ulcerative lesions involving the entire ascending colon, causing stenosis (Fig. 3C). A histological examination confirmed advanced colorectal cancer with tubular adenocarcinoma. The patient was consequently further diagnosed with ascending colon cancer, cT3N2M0, stage IIIB (8th TNM classification of colon cancer) harboring a BRAF^V600E mutation.

Regarding local complications, untreated lung cancer with enlarged mediastinal lymph nodes can lead to left lung atelectasis, bilateral recurrent laryngeal nerve paralysis with acute respiratory failure, or superior vena cava syndrome. Untreated colorectal cancer carries the risk of intestinal obstruction, which can be managed surgically. As lung cancer complications were considered more prognostically significant, treatment was prioritized for lung malignancy. The patient was ineligible for chemoradiotherapy because of bilateral supraclavicular lymph node metastasis. Furthermore, because PD-L1 was negative, a combination of cytotoxic agents with anti-PD-(L)1 and anti-CTLA-4 antibodies was selected. Colon cancer carries the BRAF^V600E mutation, which is often associated with MSI-H (5). However, from the pulmonologist's perspective, determining MSI-H status in colon cancer would not alter lung cancer treatment; therefore, MSI testing was not performed initially.

At that time, two regimens combining anti-PD-(L)1 and anti-CTLA-4 antibodies with chemotherapy were available for advanced non-small-cell lung cancer (NSCLC): the CheckMate 9LA regimen (nivolumab, ipilimumab, and chemotherapy) and the POSEIDON regimen (durvalumab, tremelimumab, and chemotherapy). The CheckMate 9LA regimen was not used in this patient because it was associated with a high incidence of treatment-related deaths, as reported in a clinical trial conducted in a Japanese population (6). Therefore, the POSEIDON regimen was used.

In late November 2023, she began four cycles of carboplatin (area under the curve =5, day 1), nab-paclitaxel (100 mg/m², days 1, 8, and 15), durvalumab (1,500 mg/body, day 1), and tremelimumab (75 mg/body, day 1) every 3 weeks. This was followed by durvalumab (1,500 mg every 4 weeks), with an additional tremelimumab dose at week 16 (fifth dose), and continued until disease progression. By February 2024, after four cycles of ICI combination chemotherapy, CE-CT revealed significant shrinkage of lung and colon lesions (Fig. 1D-F). Repeat colonoscopy confirmed regression of the colonic mass and resolution of the stenosis (Fig. 3D). To explore why the POSEIDON regimen was effective against colon cancer, MSI testing was performed and MSI-H status was confirmed in the colonic tumor, while it was negative in the lung tumor.

During ongoing durvalumab maintenance, the lung cancer remained in complete response. In October 2024, the patient underwent laparoscopic surgery with D3 lymphadenectomy for colon cancer. Histopathology showed ypT0N1aM0, corresponding to ypStage III, with one lymph node metastasis and a grade 3 histological response to chemotherapy. Twenty months after the diagnosis, the patient remained in complete response for both her lung and colon cancers under maintenance durvalumab therapy (Fig. 1G-I). No treatment-related adverse events from the POSEIDON regimen were observed throughout the course.

Discussion

The reported incidence of multiple primary cancers in cancer populations ranges from 2.4% to 8% and may reach up to 17% over a 20-year follow-up period (1). Amer analyzed 232 patients with lung cancer between 2005 and 2012 and reported a 5.6% incidence of multiple primary cancers (7). In Japan, Kurishima et al. found that 17 (0.54%) of 3,102 patients with lung cancer were diagnosed with colon cancer within one month between 2009 and 2016 (8). Treating patients with synchronous multiple primaries is challenging because therapeutic strategies are not guided by prospective trial data, relying instead on real-world experience. Most studies have shown that patients with synchronous primaries have poorer prognosis than those with metachronous primaries (7,9). In Amer's analysis, the 5-year survival rate for patients with synchronous cancers was 59%, compared to 95% for those with metachronous cancers.

Approximately 5% of colorectal cancers harbor the BRAF^V600E mutation (10). Unresectable metastatic colorectal cancer with this mutation has a median overall survival (OS) of 20.4 months (11), indicating a poor prognosis. However, the prognosis for stage IIIC NSCLC is poor, with a median OS of 12.6 months and a 5-year survival rate of approximately 13% (12). Most cytotoxic drugs used for NSCLC and colon cancer differ, making it difficult to treat both cancers using a single regimen. Our patient had stage IIIC pulmonary SCC unsuitable for chemoradiotherapy along with synchronous colon cancer harboring a BRAF^V600E mutation. In this context, when considering the progression of untreated unresectable lung cancer versus resectable colon cancer, the lung cancer was judged to pose a greater risk of life-threatening complications than the colon cancer due to its direct effects on vital functions such as respiration and circulation. Thus, pulmonary SCC was prioritized as the primary therapeutic target, while colon cancer surgery was reserved when lung cancer was controlled or if intestinal obstruction developed. Two major challenges were identified in treating lung cancer: first, it was PD-L1-negative, and second, it was relatively large.

PD-1 and CTLA-4 are immune checkpoint molecules expressed on T cells that inhibit activation signals but act at different stages of the immune response. PD-1 primarily suppresses CD8+ T cells during the effector phase, whereas CTLA-4 acts on CD4+ T cells during the priming phase. Because of these distinct mechanisms, anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors can have complementary effects by activating different T cell populations. Immunotherapy using ICIs such as anti-PD-1/PD-L1 and anti-CTLA-4 agents has become the standard treatment for gene-negative advanced NSCLC. PD-L1 expression is typically used to predict the response of lung cancer to anti-PD-1/PD-L1 therapy. However, the lung cancer in the present case was PD-L1-negative. Wang et al. examined 199 patients with PD-L1-negative NSCLC and reported that combination therapy with anti-PD-(L)1 and anti-CTLA-4 achieved a significantly longer progression-free survival (PFS) than anti-PD-(L)1 monotherapy (13). Similarly, in the Phase 3 CheckMate 227 trial, the 5-year OS was higher with anti-PD-1 plus anti-CTLA-4 than with anti-PD-1 plus chemotherapy alone (19% vs. 10%) (2). Therefore, PD-L1-negativity is now considered a biomarker that suggests a potential benefit of anti-CTLA-4 therapy.

Monotherapy with anti-PD-(L)1 is reportedly less effective in patients with large tumors than in those with small tumors (14,15). Li et al. examined tumor-infiltrating lymphocytes in 105 newly diagnosed stage III/IV NSCLC cases and found significantly reduced infiltration of CD8+ and CD4+ T cells in tumors larger than 4.5 cm compared to smaller lesions (16). Furthermore, ex vivo studies have shown that anti-CTLA-4 therapy increases both CD4+ and CD8+ T-cell infiltration into the NSCLC microenvironment (17). Uehara et al. reported that maximum baseline tumor size (BTS) is a predictive factor for treatment efficacy in advanced NSCLC. They found that anti-PD-(L)1 plus chemotherapy provided a significantly better PFS than anti-PD-(L)1 monotherapy in patients with a BTS ≥ 50 mm (18).

In the open-label, phase 3 POSEIDON trial, tremelimumab plus durvalumab and chemotherapy (T+D+C), durvalumab plus chemotherapy (D+C), and chemotherapy alone were compared as first-line treatments for metastatic NSCLC. T+D+C provided a sustained OS benefit over chemotherapy alone (5-year OS: 15.7% vs. 6.8%) after a median follow-up of 63.4 months (19). Garon et al. conducted an exploratory subgroup analysis of the POSEIDON trial to evaluate its efficacy in PD-L1-negative cases. T+D+C improved the OS compared with chemotherapy alone, even in the PD-L1-negative subgroup (median OS: 12.7 vs. 11.0 months), although the difference was not statistically significant (20). Tolerability is an important factor in combination regimens. Notably, T+D+C, which incorporates dual-checkpoint inhibition, was generally well tolerated and did not significantly affect patient-reported outcomes related to global health status, quality of life, functioning, or symptom burden (19). Given our patient's preference for a regimen that is well tolerated and the available evidence supporting its efficacy, we selected the T+D+C regimen. This approach led to a near-complete response in the lung cancer that was maintained for approximately 20 months.

Microsatellites are short repetitive DNA sequences in the genome. MSI-H reflects instability in the number of these repeats (21). Although microsatellites themselves do not cause cancer, MSI-H tissues are particularly prone to malignant transformation. MSI-H tumors account for 2-4% of all diagnosed cancers and approximately 15% of sporadic colorectal cancers (22). The frequency of MSI-H in BRAF^V600E-mutant colorectal cancer has been reported to range from 20.8% to 36.8% (5,23). Although the BRAF^V600E mutation is a poor prognostic factor for colorectal cancer, the prognosis improves when MSI-H is also present (24). MSI-H tumor cells often express PD-L1 on their surface (25), making them responsive to PD-1 inhibitors, such as pembrolizumab and nivolumab (4,26). Therefore, in patients with unresectable colorectal cancer harboring a BRAF^V600E mutation, determining the MSI-H status prior to first-line treatment is essential for selecting the appropriate regimen.

In long-term follow-up (over 5 years), pembrolizumab demonstrated a significantly longer OS than chemotherapy as a first-line therapy for MSI-H colorectal cancer (median OS: 77.5 vs. 36.7 months) (27). More recently, the therapeutic effect of anti-PD-L1 therapy in MSI-H colorectal cancer has also been reported. In a phase 2 trial with a median follow-up of 11.2 months, durvalumab monotherapy in patients with MSI-H metastatic or unresectable colorectal cancer showed promising antitumor activity, with an objective response rate of 43.3% (28).

The additive benefit of anti-CTLA-4 and anti-PD-1 have also been investigated. In the phase 3 CheckMate 8HW trial, which included immunotherapy-naïve patients with unresectable or metastatic MSI-H colorectal cancer, nivolumab plus ipilimumab was compared with nivolumab alone across all treatment lines (29,30). The combination therapy significantly improved the PFS compared with nivolumab monotherapy (PFS at 36 months: 63% vs. 51%). The efficacy of durvalumab plus tremelimumab has not yet been established in MSI-H colorectal cancer; however, this combination has been studied in MSI-H gastric cancer, both in the neoadjuvant setting and as part of a nonoperative management strategy (31).

In the present case, the colon cancer lesions regressed almost completely following treatment with T+D+C. Although the efficacy of durvalumab plus tremelimumab in MSI-H colorectal cancer has not been clearly demonstrated in clinical trials, the observed response suggests that this combination may offer benefits similar to those reported for nivolumab plus ipilimumab. However, if MSI-H status had been identified at the initial diagnosis, the patient could have been more strongly recommended nivolumab plus ipilimumab, which has established evidence of efficacy.

In conclusion, we successfully treated synchronous lung and colon cancers with ICIs in combination with chemotherapy. With advancements in imaging diagnostics, detection of multiple primary cancers has become more frequent in clinical practice. It is essential to pursue cross-organ cancer treatment strategies that leverage broader insights into cancer biology and immunotherapy to improve patient outcomes.

Author’s disclosure of potential Conflicts of Interest (COI).

Akira Yamasaki: Honoraria, AstraZeneca, GlaxoSmithKline, Sanofi.