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Key Studies in Genitourinary, Gastrointestinal, Breast, and Lung Cancers: CCO Independent Conference Highlights of the 2021 Virtual ESMO Annual Meeting
  • CME

Eva M. Ciruelos, MD, PhD
Karim Fizazi, MD, PhD
Eric Van Cutsem, MD, PhD
person default
Vamsidhar Velcheti, MD
Released: December 15, 2021

DESTINY-Lung01: Background

Vamsidhar Velcheti, MD:
HER2 mutations are seen in approximately 3% of all patients with non-small-cell lung cancer (NSCLC), often in younger patients, females, and patients that have never smoked.42HER2 mutations are associated with poor prognosis and an increased risk for brain metastases. Currently, there are no HER2-targeted therapies approved for NSCLC.

The HER2-targeted ADC T-DXd is approved for use in metastatic HER2-overexpressing BC and HER2-overexpressing metastatic gastric or GEJ adenocarcinoma.17

The phase II DESTINY-Lung01 trial evaluated T-DXd in HER2-mutated and overexpressing NSCLC.43,44

Studies in Lung Cancer from ESMO 2021

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Study Design

Vamsidhar Velcheti, MD:
DESTINY-Lung01 is an international, open-label, multicohort phase II trial enrolling patients (planned N = 170) with unresectable/metastatic nonsquamous NSCLC that expresses HER2 or has a HER2-activating mutation.43,44 Patients enrolled on this trial had no prior treatment with HER2-targeted therapy and relapsed or were refractory to standard therapy. Cohort 1 included patients with HER2-expressing tumors and cohort 2 included patients with a HER2-activating mutation. Cohort 1 is currently ongoing, and those data will be reported later.

At ESMO 2021, trial investigators presented an interim analysis of cohort 2. At the time of the analysis, 15 patients (16.5%) remained on treatment.

The primary endpoint of the trial is ORR by independent central review, and the secondary endpoints were DoR, PFS, OS, and safety. Biomarkers of response was an exploratory endpoint in this trial.

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Efficacy

Vamsidhar Velcheti, MD:
The primary objective of the DESTINY-Lung01 trial was ORR, and 54.9% of the patients enrolled in the study had a confirmed objective response. Most responders (53.8%) had a partial response (PR) and 1 patient had a complete response to the treatment.

In patients who had a response, the median DoR was 9.3 months (95% CI: 5.7-14.7) and the median PFS was 8.2 months (95% CI: 6.0-11.9).

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Best Percentage Change in Tumor Size

Vamsidhar Velcheti, MD:
This figure shows the waterfall plot of responses in the DESTINY-Lung01 trial. Most of the patients had some degree of shrinkage in the tumor, and it should be noted that even patients who had extracellular domain mutations received benefit with a reduction in the tumor size. One of the patients with an extracellular domain mutation had a PR.

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: PFS

Vamsidhar Velcheti, MD:
The median PFS in the trial was 8.2 months (95% CI: 6.0-11.9), which is a very respectable median PFS in patients who have been heavily pretreated with CT and immunotherapy.

The median OS was 17.8 months (95% CI: 13.8-22.1).

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Safety

Vamsidhar Velcheti, MD:
Drug related TEAEs were seen in approximately 96% of all patients; 46% of patients had grade ≥3 TEAEs. Twenty-five percent of patients discontinued treatment due to drug-related TEAEs, and discontinuation was most commonly due to pneumonitis (13.2%) and ILD (5.5%).

Dose reduction occurred with 34.1% of patients in this trial, and the most common drug-related TEAEs associated with dose reduction was nausea (11%) and fatigue (8.8%)

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Key Drug-Related TEAEs

Vamsidhar Velcheti, MD:
Of the AEs in the DESTINY-Lung01 trial were experienced in ≥20% of patients, the most frequent any grade event was nausea (72%) and fatigue (52%). Any grade neutropenia was seen in about 35% of patients, and grade ≥3 or higher neutropenia was seen in about 18% of patients, making it the most common grade ≥3 drug-related TEAE.

ILD/pneumonitis were key drug-related TEAEs in this trial, with the median time to onset being 141 days (range 14-462). Twenty-six percent of patients had adjudicated drug related ILD/pneumonitis and 4.4% had grade 3 events. Two patients in this trial had ILD/pneumonitis that led to death. Most patients with ILD/pneumonitis were treated with glucocorticoids, and 54% of cases were fully resolved at the time of data cutoff.

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Conclusions

Vamsidhar Velcheti, MD:
In the phase II DESTINY-Lung01 trial, the response rate was 55% in patients with HER2-mutated NSCLC treated with T-DXd. The durability of response was respectable, especially in a population of patients that were heavily pretreated and experienced platinum doublet CT and immunotherapy. Currently, there are no approved targeted therapy options for patients who have HER2-muted lung cancer, so this is a significant advancement in the field.

The data from the cohort of patients with HER2 overexpressed NSCLC has not yet been reported, and that is data that we'll be eagerly awaiting.

The safety findings were consistent with previous reports with T-DXd. ILD is a key toxicity with this drug, and effective and early detection of ILD is critical in management of these patients. In future studies, we must also explore a lower dose of T-DXd to see if the safety profile can be improved. Overall, the findings of the study confirmed the therapeutic viability of ADC-based approach to target HER2-mutated lung cancers. Further data and information are required and eagerly awaited from the study.

CASPIAN 3-Year Update: Background

Vamsidhar Velcheti, MD:
At ESMO 2021, we also saw an update to the CASPIAN trial. The phase III CASPIAN trial is evaluating the efficacy and safety of adding durvalumab with or without tremelimumab to first-line EP in patients with extensive-stage SCLC.

The initial report showed that significant OS improvement with durvalumab plus EP compared with EP alone.45 This led to the FDA approval of durvalumab in combination with etoposide and either carboplatin or cisplatin as first-line treatment of adult patients with extensive-stage SCLC.46

At more than 2 years of median follow-up, the analysis showed an OS benefit with durvalumab plus EP vs EP alone and with a nonsignificant numerical OS benefit with the addition of tremelimumab to durvalumab plus EP.47

The analysis presented at ESMO this year reported an updated OS outcome after a median follow-up of more than 3 years.48

CASPIAN 3-Year Update: Study Design

Vamsidhar Velcheti, MD:
Here is a quick recap on the design of the CASPIAN trial. This is a randomized, open-label, multicenter phase III study that enrolled patients (N = 805) with treatment-naive extensive-stage SCLC with asymptomatic or treated and stable brain metastases. There were 3 arms in this trial. In the control arm, patients were treated with EP for up to 6 cycles. In the experimental arms, patients received durvalumab plus EP for 4 cycles followed by maintenance durvalumab every 4 weeks or durvalumab plus tremelimumab plus EP for 4 cycles followed by durvalumab maintenance every 4 weeks.

The primary endpoint for the CASPIAN trial is OS, and the secondary endpoints are PFS, ORR, and safety.

CASPIAN 3-Year Update: OS With Durvalumab Plus EP vs EP Alone

Vamsidhar Velcheti, MD:
With a median follow-up of 39.4 months, the median OS was 12.9 (95% CI: 11.3-14.7) months vs 10.5 months (95% CI: 9.3-11.2) with EP only (HR: 0.71; 95% CI: 0.60-0.86; nominal P = .0003).

The 36-month OS was 17.6% in the durvalumab plus EP arm vs 5.8% in the EP arm.

CASPIAN 3-Year Update: Subgroup Analysis of OS With Durvalumab Plus EP vs EP Alone

Vamsidhar Velcheti, MD:
Here is the subgroup analysis of durvalumab plus EP vs EP alone. There were no significant differences noted based on the use of cisplatin vs carboplatin, and there were no significant differences by age, performance status, smoking status, and other subgroups analyzed. The benefit of adding durvalumab to EP was seen across all analyzed groups.

CASPIAN 3-Year Update: OS With Durvalumab Plus Tremelimumab Plus EP vs EP Alone

Vamsidhar Velcheti, MD:
With the addition of tremelimumab to durvalumab plus EP, the median OS was 10.4 months (95% CI: 9.5-12.0) vs 10.5 months with EP (95% CI: 9.3-11.2) (HR: 0.81; 95% CI: 0.67-0.97; nominal P = .0200) at a median follow-up of 39.4 months.

The 36-month OS was 15.3% with the triple-drug regimen, which was comparable to the durvalumab plus EP, compared with 5.8% in the EP only arm.

CASPIAN 3-Year Update: Subgroup Analysis of OS With Durvalumab Plus Tremelimumab Plus EP vs EP

Vamsidhar Velcheti, MD:
With tremelimumab plus durvalumab plus EP there were no subgroup analyses that stood out. Analyzed subgroups included planned platinum agent, age, sex, smoking status, and CNS metastases. The benefit of tremelimumab plus durvalumab plus EP vs EP was seen across all the different subgroups that were analyzed.

CASPIAN 3-Year Update: Treatment Exposure

Vamsidhar Velcheti, MD:
Patients in the durvalumab plus EP group stayed on durvalumab treatment for a longer time than patients in the tremelimumab plus durvalumab plus EP group. At cutoff, 10% of patients in the durvalumab plus EP and 7% of patients in the tremelimumab plus durvalumab plus EP group remained on durvalumab treatment with a median of 7 doses and 6 doses for these groups, respectively. With durvalumab plus EP treatment, the median time on treatment was 28 weeks and it was 23 weeks for those in the tremelimumab plus durvalumab plus EP treatment group.

Overall, the durvalumab plus tremelimumab group had higher rates of discontinuation of durvalumab maintenance compared with the arm with durvalumab alone.

CASPIAN 3-Year Update: Serious Adverse Events

Vamsidhar Velcheti, MD:
The rates of serious AEs for tremelimumab plus durvalumab plus EP, durvalumab plus EP, and EP, were 47.4%, 32.5%, and 36.5%, respectively.

This table shows the most common serious AEs in each treatment arm. The most prevalent serious AE with tremelimumab plus durvalumab plus EP was pneumonia (6%). In the durvalumab plus EP arm and the EP arm, the rate of pneumonia was 2.3% and 4.1% respectively. Other AEs that were more prevalent in with the tremelimumab plus durvalumab plus EP regimen than the other treatments were hyponatremia, diarrhea, and pulmonary embolism.

With the addition of tremelimumab to durvalumab—although tremelimumab was used for only the 4 cycles of induction with durvalumab plus EP—the rates of fatal TRAEs was double that with durvalumab plus EP (4.5% vs 2.3%). The rates of fatal AEs in the EP only arm was 0.8%.

CASPIAN 3-Year Update: Conclusions

Vamsidhar Velcheti, MD:
In conclusion, the 3-year update of the CASPIAN study demonstrated and confirmed the OS benefit of durvalumab plus EP, and the safety profile with durvalumab plus EP was consistent with previous reports. At the 3-year mark, 17.6% of patients treated with durvalumab were alive compared with 5.8% of patients treated with EP only.

The addition of tremelimumab, however, did not show any demonstrable improvement in OS vs durvalumab plus EP. The addition of tremelimumab also increased the risk for AEs and the rates of discontinuation of durvalumab because of toxicity concerns with the addition of tremelimumab.

The current SoC for management of extensive-stage SCLC is durvalumab plus EP. When we look at the data from the CASPIAN trial, we see that in the first year a significant proportion of patients treated with this combination tend to relapse and progress.47 

There is a need for improved treatments for extensive-stage SCLC. There are several combination-based strategies that are currently being evaluated and considered for clinical development, and we look forward to many such studies being conducted and seeing the data in the future.

TROPION-PanTumor01: Background

Vamsidhar Velcheti, MD:
Current therapies have limited benefit in patients with metastatic NSCLC with actionable genomic alterations after they progress on tyrosine kinase inhibitors and platinum CT. We do not have very effective treatment options for these patients after they progress on targeted therapy.

TROP2 is a cell-surface glycoprotein that is highly expressed in NSCLC, and expression of TROP2 is considered a poor prognostic factor.49 Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed ADC with a topoisomerase 1 inhibitor payload.50

The TROPION-PanTumor01 study is evaluating Dato-DXd in patients with solid tumors including NSCLC. Previous results have shown a manageable safety profile and encouraging antitumor activity in heavily pretreated NSCLC populations.51,52 

TROPION-PanTumor01: Study Design

Vamsidhar Velcheti, MD:
The TROPION-PanTumor01 study is a multicohort, dose-escalation/dose-expansion phase I trial. This trial enrolled adults with relapsed/refractory advanced or metastatic solid tumors unselected for TROP2.51-53 The analysis presented at ESMO 2021 focused on NSCLC with actionable genomic alterations post tyrosine kinase inhibitor, immunotherapy, or platinum-based CT.53

The primary objective of the TROPION-PanTumor01 trial is to establish maximum tolerated dose, safety, and tolerability; the secondary objectives were efficacy, pharmacokinetics, and antidrug antibodies.

TROPION-PanTumor01: NSCLC With Actionable Genomic Mutations—Baseline Characteristics

Vamsidhar Velcheti, MD:
In total, 34 patients with actionable genomic alterations were evaluated in this study. The median age was 62, and a little more than one half of the patients (56%) were female. Eighty-two percent of patients had at least 3 prior therapies and were previously treated with platinum-based CT (91%), tyrosine kinase inhibitors (85%), and immunotherapy (41%). The majority of patients had EGFR mutations (85%), followed by ALK fusions (9%), ROS1 fusion (3%), and RET fusions (3%).

Patients with NSCLC included in this analysis were treated with 4 mg/kg, 6 mg/kg, or 8 mg/kg of Dato-DXd. At the time of analysis, 12% were still on the study treatment; 65% of patients discontinued treatment because of disease progression. Fifteen percent of patients discontinued because of AEs, and 3% percent of patients died while on the study.

TROPION-PanTumor01: NSCLC With Actionable Genomic Mutations—Safety

Vamsidhar Velcheti, MD:
All patients had a TEAE: 53% of the patients had a grade ≥3 TEAE, and 38% of the patients had a grade ≥3 drug-related AE. There was 1 patient who had drug related ILD resulting in death.

The most common TEAEs with the Dato-DXd were nausea, stomatitis, fatigue, and alopecia.

TROPION-PanTumor01: NSCLC With Actionable Genomic Mutations—Responses

Vamsidhar Velcheti, MD:
In this heavily pretreated population, the ORR was 35%, with all responding patients (12 out of 34) having a PR. Fourteen patients had stable disease and 2 had progressive disease. The median DoR was 9.5 months (95% CI: 3.3-not evaluable).

TROPION-PanTumor01: NSCLC With Actionable Genomic Mutations—Antitumor Activity

Vamsidhar Velcheti, MD:
Here's a waterfall plot from the TROPION-PanTumor01 study. Many patients had some degree of tumor shrinkage, and this was seen in all different dose levels that were studied. There were a few patients who had ALK alterations that also had tumor shrinkage while on treatment.

TROPION-PanTumor01: NSCLC With Actionable Genomic Mutations—Conclusions

Vamsidhar Velcheti, MD:
In conclusion, TROPION-PanTumor01 study is a phase I study, showing encouraging antitumor activity with a response rate of 35% in a very heavily pretreated patient population with advanced NSCLC actionable genomic alterations who have progressed on targeted therapy or CT. The DoR in this trial was 9.5 months, which is a very encouraging sign of antitumor activity. There is a larger phase III TROPION-Lung05 trial that is currently evaluating the role of Dato-DXd in advanced NSCLC with actionable genomic alterations, posttargeted therapy and platinum CT.54

This is a population of unmet need, and I think the antitumor activity seen in the TROPION-PanTumor01 trial is very encouraging. We are looking forward to seeing the data from the subsequent phase III trial for confirmation of the clinical benefit of Dato-DXd in this population with difficult-to-treat disease.

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