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ASCO Presentations Highlight Advances in Antibody Treatments for Molecularly Defined Lung Cancers

NEW YORK – Three antibody drugs have demonstrated promising activity in metastatic non-small cell lung cancer patients with molecularly differentiated tumors in studies presented at the American Society of Clinical Oncology's virtual annual meeting.

In an interim analysis from the Phase II DESTINY-Lung01 study, Daiichi Sankyo and AstraZeneca's antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) shrunk tumors in 26 out of 42 patients with HER2-mutated, metastatic NSCLC. Sanofi's investigational antibody-drug conjugate, SAR408701, showed efficacy in heavily pretreated non-squamous NSCLC patients who had high expression of the tumor antigen CEACAM. Lastly, researchers presented the first randomized clinical data on Roche's tiragolumab, a monoclonal antibody that binds to the immune cell receptor TIGIT, and showed that when it was combined with the anti-PD-L1 drug atezolizumab (Roche's Tecentriq), patients with a PD-L1 tumor proportion score (TPS) of at least 50 percent appeared to benefit most.

Although the data from these studies are early, evolving, and in one case, exploratory, drugmakers are hopeful that the studies reflect the potential of their agents and are quickly moving to study them in larger cohorts of patients or Phase III trials.

Homing in on HER2-mutated NSCLC

In DESTINY-Lung01, researchers led by Egbert Smit from the Netherlands Cancer Institute reported data from a cohort of 42 heavily pretreated patients with HER2-mutated unresectable or metastatic NSCLC who all received fam-trastuzumab deruxtecan-nxki. In this cohort, 62 percent responded to treatment, with 1 patient experiencing a complete regression of the tumor and 25 experiencing partial tumor reductions. A dozen patients had stable disease on therapy and the duration of response was not reached. Two patients had tumor progression and two patients were not evaluable.

Smit noted that at the data cutoff on Nov. 25, 2019, 19 patients still remained on treatment, with around half discontinuing participation due to adverse events or disease progression. Patients were censored from the median progression-free survival analysis if they discontinued therapy, and at a median follow-up of eight months, on average, patients were alive and not progressing for around 14 months. The median overall survival was not reached at data cut off.

"These data demonstrate the potential of [fam-trastuzumab deruxtecan-nxki] as a new treatment option for patients with HER2-mutated non-small cell lung cancer," Smit said.

In reviewing the data from DESTINY-Lung01, Grace Dy from Roswell Park Comprehensive Cancer Center agreed that this drug "showed clinical outcomes that meet the standards of what [oncologists] expect a good targeted therapy should have in terms of response rate and progression-free survival."

Between 2 percent and 3 percent of NSCLC patients harbor HER2 mutations. In this study, patients had to have their HER2 mutation status determined by a local lab.

The US Food and Drug Administration last year approved fam-trastuzumab deruxtecan-nxki for HER2-overexpressing advanced breast cancer patients previously treated by other anti-HER2 agents. However, HER2-targeting drugs don't work well in lung cancers that overexpress HER2. Dy explained that historically HER2 antibodies, such as trastuzumab (Genentech's Herceptin), when combined with chemotherapy have shown lackluster efficacy in the subset of lung cancers over-expressing HER2. 

Over time, it has become clear that HER2 mutation status, instead of HER2 overexpression, is the right target in lung cancer. Dy noted that the field has now recognized HER2-mutated lung tumors as a biologically distinct disease.

Based on the results of this trial, she said that fam-trastuzumab deruxtecan-nxki may be a "frontrunner" in the treatment for HER2-mutated NSCLC. The 62 percent response rate in DESTINY-Lung01 is three times the response rate observed with trastuzumab and pertuzumab (Genentech's Perjeta) in HER2-mutated NSCLC patients in the MyPathway basket trial, she highlighted. 

More than 15 percent of patients experienced adverse events to fam-trastuzumab deruxtecan-nxki, most of which were grade 1-2, including nausea, alopecia, anemia, and decreased appetite and neutrophil count. Decreased neutrophil count and lung infections were the most common toxicities that led to dose interruptions. Five patients died during treatment but Smit said that the toxicities from the drug weren't the cause.

Smit underscored the incidence of grade 2 interstitial lung disease, which occurred in five patients, as a drug-related adverse event of "special interest." Four patients had the drug withdrawn as a result and one had the drug administration interrupted. "More investigations into the mechanisms and risk factors for interstitial lung disease will be crucial," Dy said, especially since this antibody-drug conjugate will be studied in combination with immune checkpoint inhibitors and other tyrosine kinase inhibitors.

Based on the results of this interim analysis, researchers plan to study another 50 patients with HER2-mutated NSCLC in DESTINY-Lung01 in order to better understand the risk-benefit profile of the drug.

Targeting CEACAM5 expression

In the second ASCO study, researchers led by Anas Gazzah from Gustave Roussy in France reported updated results from an ongoing, first-in-human trial of Sanofi's antibody-drug conjugate SAR408701 in 92 non-squamous NSCLC patients who overexpress the tumor antigen CEACAM5. SAR408701 contains an antibody that attaches to CEACAM5 on tumor surfaces and releases maytansinoid DM4, a cytotoxic payload, inside cells. 

"As CEACAM5 shows high expression in non-squamous, non-small cell lung cancer, its investigation as a drug target in this population is rational," Roswell Park's Dy said in reviewing the data.

In the study, researchers evaluated the efficacy of the drug in 64 patients who had CEACAM5 high expression in at least 50 percent of tumor cells, and in 28 patients with moderate CEACAM5 expression in 1 percent to 49 percent of tumor cells (as determined by immunohistochemistry 2/3+ staining). High expresser represented 20 percent of the non-squamous, NSCLC population in the study and moderate expressers represented 24 percent of the population.

In the high-expressing cohort, 20 percent of patients saw their tumors shrink, 44 percent had stable disease, and the median duration of response was 5.6 months. In the moderate-expressing arm, by comparison, 7 percent saw tumor shrinkage, 54 percent had stable disease, and median duration of response was not yet calculated. Dy noted that the responses to SAR408701 seen in this study are comparable to the type of efficacy that the chemotherapy docetaxel may have in previously treated NSCLC patients.

The most common adverse events with SAR408701 involved the eyes, with 38 percent of patients experiencing keratopathy and keratitis. "Ocular toxicity is the typical toxicity of this antibody-drug conjugate and was the most frequent reason for dose delays and dose modifications," Gazzah said. CEACAM5 is expressed in the corneal epithelium and therefore reflects an on-target effect of this drug, Dy further pointed out in her review of the data. But she added that this adverse event was fortunately reversible.

Gazzah noted that based on the results from this study, Sanofi has launched a Phase III trial comparing SAR408701 against docetaxel in non-squamous, NSCLC patients who are CEACAM5 high and who have failed an anti-PD-1/-PD-L1 drug plus chemotherapy in the first line.  

Driven by PD-L1 expression

Lastly, Melissa Johnson from the Sarah Cannon Research Institute presented data from CITYSCAPE, the first randomized comparison of tiragolumab in combination with atezolizumab against just atezolizumab in first-line, PD-L1-positive NSCLC.

Tiragolumab is a TIGIT-blocking antibody. By binding to its ligand PVR on tumor cells and antigen-expressing cell, the immune receptor TIGIT helps cancer cells evade attack from the immune system. Roche's antibody is designed to block TIGIT from binding to its ligand. In the Phase II CITYSCAPE trial, researchers hypothesized that tiragolumab might be particularly effective in lung cancers that express PD-L1 when combined with atezolizumab, since the latter drug similarly enhances immune activity against cancer by binding to PD-L1 on tumor cells.

In Phase I studies of tiragolumab monotherapy and tiragolumab-atezolizumab, these agents were well-tolerated across different solid tumors and there was evidence of preliminary activity with the combination regimen. On that basis, the Phase II CITYSCAPE study was launched, in which 135 patients were randomized to tiragolumab-atezolizumab or atezolizumab. All patients had to have tumor PD-L1 TPS of at least 1 percent as determined by the Roche PD-L1 22C3 IHC assay in a local or central lab.

Johnson reported that as of the December 2019 data cutoff, 37 percent of patients in the combination arm and 21 percent in the atezolizumab arm responded. At a median follow-up of around 11 months, median progression-free survival was 5.55 months with tiragolumab-atezolizumab compared to 3.88 months in the comparator arm.

As part of an exploratory analysis, researchers stratified patients according to PD-L1 expression. In those with PD-L1 TPS of at least 50 percent, the overall response rate was 66 percent on tiragolumab-atezolizumab and 24 percent with atezolizumab. Median progression-free survival was not reached in the combination arm but was 4.11 months for those receiving atezolizumab.

In comparison, among those with PD-L1 TPS of between 1 and 49 percent, the overall response rate was 16 percent and 18 percent in the combination and atezolizumab arms, respectively, and median progression-free survival was 4.04 months and 3.58 months, respectively.

In reviewing the data from CITYSCAPE, Dy reflected that the activity appears to be driven by the PD-L1-high subgroup. The efficacy seen with tiragolumab-atezolizumab in this subset in comparison to atezolizumab is particularly compelling since the latter immune-oncology drug received FDA approval a few weeks ago as a front-line option for metastatic NSCLC patients who express PD-L1 in 50 percent or more tumor cells. 

The rates of adverse events in the two arms in CITYSCAPE were similar across different grades. The combination of tiragolumab-atezolizumab resulted in higher rates of immune-related adverse events, "which makes sense because these patients were receiving two active immunotherapies," Johnson said.

Based on the observed activity of tiragolumab-atezolizumab in CITYSCAPE, the combination will advance to the confirmatory Phase III SKYSCRAPER-01 study involving first-line NSCLC patients with PD-L1 TPS of at least 50 percent.

"While we're all excited by the data and we want to see a winner, we should be careful," Dy cautioned, reflecting on the speed with which the tiragolumab-atezolizumab combination has been moved into the Phase III setting. "We have plenty of examples of promising studies that collapsed in later-phase trials."

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