By Ted Bosworth

Precision medicine in non-small cell lung cancer (NSCLC) is accelerating substantially, according to several key studies presented at the 2020 World Conference on Lung Cancer. The meeting, organized by the International Association for the Study of Lung Cancer (IASLC), was held in January 2021 after being converted to a virtual meeting.

Presented during the Presidential Symposium, the activity of the first-in-class inhibitor of KRAS G12C mutation, sotorasib, is considered a breakthrough. Studies with tepotinib, mobocertinib, and the antibody drug conjugates (ADC) partritumab deruxtecan and trastuzumab deruxtecan offered promise for other novel targets. Conversely, the news with immune checkpoint inhibitors (ICI) was mixed. One of two major trials had negative results.

New Targeted Oral Therapies are Exploding the Possibilities in Advanced NSCLC

The most significant news from the World Congress included the impressive activity achieved with sotorasib in KRASG12C-mutated NSCLC. This mutation was once considered undruggable.

In the multinational CodeBreaK 100 study, involving centers in 11 countries, all 126 heavily pretreated NSCLC patients had a confirmed KRASG12C mutation. About 90% had received either an ICI or a platinum-based chemotherapy; 81% of participants had received both.

“Tumor shrinkage of any magnitude was observed in 81% of patients. The median percentage of best tumor shrinkage among all responders was 60%,” reported Bob T. Li, MD, Co-Director of the Thoracic Liquid Biopsy Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York.

Sotorasib (960 mg, once daily) was administered until disease progression. The primary endpoint was objective response rate (ORR).

The ORR was 37.1%, including a complete response in three patients (2.4%). Stable disease was achieved in an additional 43.5%, producing a disease control rate of 86%. The median duration of response was 10 months. Dr. Li characterized this level of response in a population with diminishing treatment options “deep and durable.”

Diarrhea was the most common adverse event. It occurred in 31%, and reached grade 3 severity in only 4% of patients. Except for a blood alkaline phosphatase increase in one patient, the only other grade 3 events, occurring in less than 10% of patients, were liver enzyme elevations.

Due to the importance of KRAS mutations, which is the driver of progression in an estimated 13% of advanced NSCLC, Dean Fennell, MBBS, PhD, Chair of Thoracic Medical Oncology University of Leicester, UK, said these results mean that characterization of KRAS status will now be an essential step to NSCLC management.

Other Oral Targeted Therapies Active on Unique Targets

Mobocertinib and tepotinib are prominent examples of additional therapies targeting a very specific, often previously undruggable driver of NSCLC. Mobocertinib targets epidermal growth factor receptor (EGFR) exon20 insertions. Tepotinib is among several highly specific MET inhibitors in development to block the mutant variant MET exon14.

In a phase 1/2 trial presented by Caicun Zhou, MD, PhD, Director, Department of Oncology, Shanghai Pulmonary Hospital, China, the ORR with 160 mg of once daily mobocertinib in 96 patients with advanced EGFR exon20+ advanced NSCLC was 28%. All of the patients had been treated previously with platinum-based chemotherapy.

“The median duration of response was 17.5 months,” according to Dr. Zhou. He characterized this as a meaningful benefit in a treatment-experienced group with diminishing treatment options. There are no approved therapies currently for NSCLC with EGFR exon20 insertions.

The degree and duration of response with this agent are “noteworthy,” according to Pasi A. Jänne, MD, PhD, Dana-Farber Cancer Institute, Boston. He said there is a “critical need” for new options for this target.

In the phase 2 VISION study of tepotinib, 152 patients with MET exon14 skipping advanced NSCLC were enrolled. Just over half (55%) had received previous therapy including ICI in a small subset. Results were updated from those published several months ago (Paik PK et al. N Engl J Med 2020;383:931-943).

Similar to sotorasib and mobocertinib, tepotinib at a dose of 500 mg once daily produced a substantial ORR (45.2%) and prolonged duration of response (11.1 months), according to Paul K. Paik, MD Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City. Also similar to the other targeted therapies, the activity of tepotinib was consistent across several stratifications, such as prior exposure to ICI.

Phase 3 trials are underway or planned for sotorasib, mobocertinib, and tepotinib.

ADCs Move Forward in HER-Related NSCLC

Human epidermal growth factor receptor (HER) is expressed commonly in NSCLC, and this is proving to be a promising target for ADCs, according to two studies presented. In one study, partritumab deruxtecan was administered in unresectable metastatic NSCLC patients overexpressing HER3, for which there are no therapies currently approved. In the other study, trastuzumab deruxtecan was administered in unresectable metastatic NSCLC overexpressing HER2.

In the phase 1 study with partritumab deruxtecan, data were presented on 57 patients with previously treated NSCLC who participated in a dose expansion evaluation. At baseline, almost all were positive for HER3, which is expressed in more than 80% of all NSCLC, according to the lead author, Helena A. Yu, MD, an oncologist specializing in lung cancer at MSKCC.

The confirmed ORR was 25% with a complete response in one patient. Forty-five percent achieved a durable response. The disease-control rate was 70%. The median duration of response was 6.9 months.

Despite heavy exposure to prior treatment with a median of four prior lines of therapy, durable responses were observed in several patients who were still on partritumab deruxtecan at the last assessment.

“Activity was observed in patients with and without diverse mechanisms of TKI [tyrosine kinase inhibitor] resistance, including EGFR C797S mutation, MET amplification, HER2 mutation, BRAF fusion, and PIK3CA mutation,” Dr. Yu reported.

The side effect profile was called “manageable.” The most common grade 3 or higher side effects were thrombocytopenia (28%) and neutropenia (19%). There was once case each of grade 3 or higher interstitial lung disease, pneumonitis, and upper respiratory infection. Discontinuation for an adverse event occurred in 9%. A phase 2 study with partritumab deruxtecan is now enrolling patients.

Trastuzumab deruxtecan has already reached phase 2 testing for HER2-overexpressing NSCLC. Data from the phase 2 DESTINY-LungO1 trial included outcomes in the first 42 patients.

The ORR was 61.9%. One patient (2.4%) had a complete response. Only 4.8% patients progressed, producing a disease control rate of >90%, reported Egbert F. Smit, MD, PhD, Netherlands Cancer Institute, Amsterdam.

Median progression-free survival was 14.0 months; median duration of response has not yet been reached.

Side effects were significant but manageable, according to Dr. Smit. This included a drug-related adverse event of grade 3 severity of greater in 52.4%. Nausea was the most common, occurring in more than half of patients. Others included anemia and neutropenia. Ten (23.8%) patients discontinued treatment for an adverse event.

Similar to NSCLC overexpressing HER3, there is “a high unmet need” for therapies that target NSCLC overexpressing HER2, according to Dr. Smit. Based on these data, he is optimistic that trastuzumab deruxtecan represents a potential new treatment for this patient population.

ICI for NSCLC: Neoadjuvant Benefit — No Advantage for Dual Drug Therapy

The studies of ICI in NSCLC provided mixed results. In one trial, neoadjuvant atezolizumab was effective for downstaging disease prior to surgery. In the other, adding ipilimumab to pembrolizumab in previously untreated stage IV NSCLC was not associated with benefit.

The LCMC3 trial enrolled 181 patients with stage IB-IIIB NSCLC and no targetable mutation. All participants were treated with two cycles of 1200 mg atezolizumab prior to planned resection. Of the 159 who went onto surgery, 140 (88%) did so within the predefined protocol window of 30 to 50 days after initiating the first dose of atezolizumab. The median time from the end of cycle 2 of atezolizumab and surgery was 22 days.

“The primary endpoint of a pathologic response was achieved in 21% of patients, including a complete response in 7%,” reported Jay M. Lee, MD, Chief, Division of Thoracic Surgery, University of California, Los Angeles. He characterized this trial as a “landmark.”

Tumor-free (RO) margins were achieved in 92% of those who underwent surgery. After 1.5 years of followup, 79% of those with stage I or II NSCLC and 77% of those with stage III remained in disease-free survival (DFS). The rates of overall survival (OS) at this interval were 91% and 87%, respectively, which compare favorably to historical data.

Of the 14 surgeries (8%) without tumor-free margins at completion, 7 (4%) were R1. The remainder was R2.

Atezolizumab did not appear to complicate surgery, which was minimally invasive in the majority of cases. For example, the length of hospitalization was 7.5 days or about the same as that reported in previous series.

These data confirm that neoadjuvant ICI is feasible, according to Shinichi Toyooka, MD, Director, Department of General Thoracic Surgery, Okayama University Hospital, Japan. Invited as an expert discussant by the IASLC, Dr. Toyooka advised ICI plus chemotherapy might still be preferable in those with stage III disease and good performance status.

Dual ICI Adds Nothing to Pembrolizumab Alone in Stage IV NSCLC

The hypothesis that adding a second ICI could improve outcomes over a single ICI in patients with stage IV NSCLC was not validated by the randomized KEYNOTE-598 trial. In a study that recruited patients with no prior systemic therapy but a high rate of PD-L1 expression, the addition of ipilimumab, an ICI targeting CTLA-4, plus pembrolizumab, which targets PD-1, did not achieve an advantage over pembrolizumab for any of the major study endpoints.

“The addition of ipilimumab did not improve efficacy but it did increase toxicity in first-line treatment for stage IV NSCLC,” reported Michael Boyer, MBBS, PhD, Chair of Thoracic Oncology, Chris O’Brien Lifehouse, Camperdown, Australia. He added, “This means that pembrolizumab remains the standard of care in this population.”

In this phase 3 study, patients were required to have PD-L1 expression of at least 50% tumor proportion score (TPS). The 568 enrolled patients were randomized to pembrolizumab (200 mg) every three weeks plus ipilimumab (1 mg/kg) every six weeks or to the same dose of pembrolizumab plus placebo. The co-primary endpoints were OS and progression-free survival (PFS).

The study was stopped when the lack of difference in the outcomes crossed previously defined boundaries of futility. At 12 months, survival was 63.6% in the patients on two ICIs versus 67.9% for those on pembrolizumab plus placebo. At the interim analysis the hazard ratio (HR) for the combination went the wrong way for OS (HR 1.08; P=0.74) and for PFS (HR 1.06; P=0.72).

“Essentially every adverse event occurred more frequently in the arm that received both ipilimumab and pembrolizumab,” Dr. Boyer reported. Serious treatment-related adverse events (27.7% vs. 13.9%) and discontinuations due to adverse events (19.1% vs. 7.5%) were both higher in the group on the dual ICI.

Dual ICI therapy has shown an advantage over monotherapy in other cancers, such as melanoma, but the IASLC-invited discussant, Yun Fan, MD, PhD, Director of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China, speculated that ipilimumab might be ineffective in tumors with a high rate of PD-L1 tumor expression. Dr. Fan noted that another NSCLC study that enrolled patients with ≥50% TPS also found this dual ICI combination ineffective.

Update: On February 16, 2021 Amgen announced that the FDA had granted Priority Review for sotorasib for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), following at least one prior systemic therapy. The New Drug Application (NDA) is based on phase 2 results from the CodeBreaK 100 clinical trial. The FDA target action date is August 16, 2021. 

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