Lung cancer Preview Highlights

While ASCO 2022 annual meeting is close, pharma giants, namely Mirati Therapeutics, Hoffmann-La Roche, Bristol-Myers Squibb, and others, are looking at this opportunity to present their data readouts for different cancers, including Lung Cancer. The 2022 ASCO Annual Meeting Program will offer presentations on the latest research in cancer care. This year’s program will feature over 200 sessions complementing the meeting’s theme: Advancing Equitable Cancer Care through Innovation. Delveinsight, maintaining an essence of brevity, has compiled all the Late-breaking abstracts while discussing a few.

Abstract Number - LBA9009

Mirati to present adagrasib’s registration enabling results from the KRYSTAL-1 trial in patients with KRASG12C-mutated NSCLC. Can it have the edge over its rival Lumakras?

KRYSTAL-1, a Phase II trial is evaluating adagrasib, in patients with advanced non-small cell lung cancer (NSCLC) harboring the KRASG12C mutation following prior systemic therapy. Mirati Therapeutics is going to present full results from the registration-enabling Phase II cohort of the KRYSTAL-1 study.

In June 2021, the analysis was completed in the intent-to-treat population, which showed adagrasib 600 mg BID demonstrated an objective response rate (ORR) of 43% and a disease control rate of 80%. The median follow-up was 9 months. Notably, 98.3% of patients received adagrasib following treatment with immunotherapy and chemotherapy. The safety and tolerability profile was consistent with previously reported findings for adagrasib in patients with advanced NSCLC. The company plans to submit detailed results from the ongoing Phase II registration-enabling cohort of the KRYSTAL-1 study in previously-treated patients with KRASG12C-mutated NSCLC for presentation at ASCO 2022.

The adagrasib New Drug Application (NDA) is currently being reviewed by the US Food and Drug Administration (FDA) for Accelerated Approval (Subpart H) as a treatment for patients with NSCLC harboring the KRASG12C mutation who have received at least one prior systemic therapy. The application is being reviewed under the FDA Real-Time Oncology Review (RTOR) pilot program; therefore, we expect the drug to be made available to patients as early as possible. Adagrasib has also achieved Breakthrough Therapy Designation in the US as a potential treatment for patients with NSCLC. Mirati has an Expanded Access Program (EAP) for investigational adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, in the US Excitingly, the US FDA has already accepted the NDA for adagrasib in patients with NSCLC harboring the KRASG12C with a PDUFA date of December 14, 2022.

Conclusion:

Although adagrasib might have a strong efficacy (as per interim data published), it can be weighed down by a major side effect, which is an increased incidence of a serious heart rhythm problem (QT prolongation) that comes as an advantage for Lumakras. In NSCLC, Lumakras and Adagrasib might have comparable data; we believe they can face competition from later market entrants, namely second generation KRAS inhibitors by Eli Lilly and Revolution Medicine. While Lumakras might have an edge in lung cancer, we do not expect Lumakras to beat Mirati’s adagrasib in colorectal and pancreatic cancer. In fact, we look forward to the encouraging data from the combination trial of adagrasib and cetuximab in colorectal cancer.

Excitingly, both Mirati and Amgen have initiated physician marketing campaigns to spread awareness about the importance of genetic testing and the role of KRAS activity in lung cancer among oncologists. We assume this move will be fruitful for both the competitors in the long run, as both have colorectal and pancreatic cancer on their future bucket lists

Abstract Number - LBA8507

The Failure of Skyscraper-02 Calls Into Question the Next Move

SKYSCRAPER-02 is a global Phase III trial evaluating tiragolumab plus Tecentriq (atezolizumab) and chemotherapy as an initial (first-line) treatment versus Tecentriq and chemotherapy alone in 490 people with extensive-stage small-cell lung cancer.

Genentech, a member of the Roche Group, recently announced that the Phase III SKYSCRAPER-02 study did not meet its co-primary endpoint of progression-free survival. The co-primary endpoint of overall survival was not met in its interim analysis and is unlikely to reach statistical significance in the planned final analysis. Data suggest tiragolumab plus Tecentriq and chemotherapy was well-tolerated, and no new safety signals were identified when adding tiragolumab.

SCLC is the most aggressive form of lung cancer and is characterized by rapid progression and poor survival. Tecentriq was the first cancer immunotherapy to show a survival benefit in ES-SCLC (Phase III IMpower133 study) and was the first approved treatment option in 20 years. The tiragolumab program continues to explore advances in multiple clinical trials to build on Tecentriq, expand into earlier stages of the disease, and seek to provide new treatment options in advanced and difficult-to-treat cancers with high unmet medical needs. Tiragolumab was granted Breakthrough Therapy Designation by the US Food and Drug Administration in 2021 for the initial treatment of PD-L1-high metastatic non-small cell lung cancer, based on the results of the Phase II CITYSCAPE study – representing the only investigational anti-TIGIT therapy to be granted this designation. The Phase III SKYSCRAPER-01 trial is currently ongoing to confirm the CITYSCAPE results. Since 2020, Genentech has initiated five Phase III trials, including NSCLC (SKYSCRAPER-01, SKYSCRAPER-03), ES-SCLC (SKYSCRAPER-02), esophageal cancers (SKYSCRAPER-07, SKYSCRAPER-08), and multiple early trials in various tumor types.

Conclusion:

The outcomes of Skyscrapper are disappointing as company was hoping to continue building on the advances of Tecentriq in extensive-stage small-cell lung cancer, which remains difficult to treat. Full Skyscraper-01 data are needed before drawing firm conclusions, especially as no other TIGIT player has been able to rival Roche’s earlier Cityscape dataset or show meaningful single-agent activity. Additional data from the upcoming Phase III trial in PD-L1-high non-small cell lung cancer based on the encouraging results from the CITYSCAPE study is most awaited for this cancer.

Interest in TIGIT has increased over the last 2–3 years, and several key players are now active in this field, including BeiGene’s Ociperlimab, which is in the Phase III stage of development for NSCLC; early and mid-stage active players include Innovent Biologics, BMS/Compugen, Astrazeneca, iTeos Therapeutics/GSK.