Sotorasib provides an overall survival benefit in pretreated KRAS G12C mutated NSCLC in the Phase II CodeBreak 100 trial

 
Representing the most prevalent oncogenic driver in lung adenocarcinoma, KRAS has been extensively investigated as a potential therapeutic target. However, efforts to target KRAS signaling have been unsuccessful, leading to its reputation as an undruggable target. Additionally, the prognostic and predictive implications of distinct KRAS mutation subtypes are not fully understood. Thus, the current standard of care approaches for the treatment of patients with KRAS-mutant non-small cell lung cancer (NSCLC) mirror those for patients without a known driver mutation.

In recent years, the development of new direct KRAS G12C inhibitors have brought KRAS’s undruggable reputation into question. Through covalent bindings to the mutated cysteine residue in the switch-II pocket, small molecules targeting KRAS G12C can prevent nucleotide exchange and keep KRAS in an inactive state.1 Sotorasib (previously AMG 510) was the first KRAS G12C inhibitor in clinical development and demonstrated promising anti-tumor activity in early investigations. The Phase I/II CodeBreaK 100 trial (NCT03600883) was initiated in 2019 to evaluate the safety and efficacy of sotorasib in pretreated patients with locally advanced or metastatic KRAS G12C mutated NSCLC.

Initial findings from 126 patients after a median follow-up of 12.2 months were reported at the IASLC World Conference on Lung Cancer 2020; sotorasib demonstrated deep and durable responses, with an overall response rate of 37.1% and a median progression-free survival of 6.8 months in patients with KRAS G12C mutated NSCLC.2 Vamsidhar Velcheti, MD, MD, NYU Langone, New York, NY, shares the overall survival (OS) findings and exploratory subgroup analyses from the trial, reported for the first time at ASCO 2021.3 With a median follow-up of 15.3 months, the median overall survival was 12.5 months, making sotorasib the first KRAS G12C inhibitor to demonstrate an OS benefit in a Phase II registrational trial.4

To further explore the activity of sotorasib, several subgroups were analyzed using key baseline characteristics and biomarkers. Responses were observed consistently across subgroups, including age, baseline ECOG status, and prior lines of therapy.4

 

KRAS G12C mutant allele frequency (MAF) and tumor mutational burden (TMB) were analyzed by next-generation sequencing, and it was shown that objective response rates (ORR) were independent of both factors. Analyses of co-mutations revealed that patients with STK11 mutant and KEAP1 wildtype NSCLC demonstrated an improved ORR of 50%, compared with 39% in the total population, and 42% in those with tumors wildtype for both STK11 and KEAP1. KEAP1 mutations appeared to limit the efficacy of sotorasib (ORR = 14%), although these findings were limited by the small sample size.4

In May 2021, sotorasib became the first KRAS-targeted treatment approved by the FDA for locally advanced or metastatic NSCLC.5 Investigations are continuing, with the Phase III CodeBreak 200 trial (NCT04303780) evaluating sotorasib versus docetaxel underway.4 This new approval represents a potentially transformative therapeutic option in a space where effective treatments are lacking, highlighting the importance of genomic testing and personalized development approaches in NSCLC.

IMpower010: adjuvant atezolizumab improves DFS in resected stage II-IIIA NSCLC

 

Atezolizumab is a monoclonal antibody against PD-L1 approved for use in several indications across a range of solid tumors. In the US, atezolizumab has already received 4 approvals across NSCLC both as a monotherapy and in combination with several chemotherapy regimens.6 In May 2020, based on the findings of IMpower110 (NCT02409342), atezolizumab was approved as a single agent for the first line treatment of metastatic NSCLC with high PD-L1 expression and no EGFR or ALK genomic tumor aberrations.6 Given its evidenced ability to improve survival in patients with NSCLC as a single agent in the frontline, as well as providing a clinically meaningful benefit when combined with chemotherapy, IMpower010 (NCT02486718) aimed to assess the role of atezolizumab after adjuvant chemotherapy in patients with early stage resected NSCLC.7

Heather Wakelee, MD, Stanford University, Stanford, CA, shares the interim findings of the Phase III IMpower010 trial of atezolizumab versus best supportive care (BSC) after adjuvant chemotherapy in resected stage IB-IIIA NSCLC.7

 
The trial randomized more than 1000 patients to receive either atezolizumab or BSC, following complete tumor resection and treatment with cisplatin-based chemotherapy.At the data cut-off for the planned interim analysis, median follow-up was 32.2 months. The primary endpoint of disease-free survival (DFS) was assessed in a hierarchical manner, initially looking at participants with Stage II-IIIA disease and PD-L1 expression in ≥1% of tumor cells (TC), before assessing all randomized Stage II-IIIA populations, and subsequently the intention to treat (ITT) population.8

Atezolizumab showed a statistically significant DFS benefit compared to BSC in the PD-L1 TC ≥1% Stage II-IIIA group (HR = 0.66, p = 0.004) and all randomized Stage II-IIIA populations (HR = 0.79, p = 0.02). At this interim analysis, the significance boundary was not reached for DFS in the whole ITT population. Subgroup analyses revealed that PD-L1 status had an impact on the response to atezolizumab. Patients with high expression (over 50%) showed the greatest improvement in DFS (HR = 0.43). Those with at least 1% PD-L1 expression had a hazard ratio of 0.66, whereas patients with less than 1% expression derived little benefit (HR = 0.97). Grade 3/4 adverse events were reported in 21.8% of patients in the atezolizumab arm, compared to 11.5% receiving BSC, leading to a discontinuation rate of 18.2%. Immune-mediated adverse events occurred in 7.9% of atezolizumab-treated patients.

Adjuvant platinum-based chemotherapy provides only a modest improvement in 5-year overall survival compared to observation, and thus, agents that can provide a substantial improvement in survival for patients without targetable mutations is a high unmet need. To date, IMpower010 is the first Phase III study to show a survival benefit with adjuvant immunotherapy in NSCLC.8 The trial is ongoing and will assess DFS and OS in the ITT population in the final analysis.

Patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated NSCLC

 

Overexpression of EGFR has been implicated in the pathogenesis of many malignancies, including NSCLC. The discovery of EGFR activating mutations and the clinical introduction of EGFR tyrosine kinase inhibitors (TKIs) over the last decade has had a dramatic impact on the treatment landscape for patients with NSCLC with mutant EGFR. EGFR TKIs, such as osimertinib, are the current standard of care for patients with newly diagnosed EGFR-mutated NSCLC. However, their benefits are often transient with on-target mechanisms and bypass alterations resulting in the development of resistance.9 Patients have limited treatment options after TKI failure, with platinum-based chemotherapy having limited efficacy and salvage therapy following both TKIs and chemotherapy largely ineffective.

To address this paucity of available options, patritumab deruxtecan (HER3-DXd) is under investigation in NSCLC, as well as metastatic breast cancer and colorectal cancer. HER3-DXd is an antibody drug conjugate, made up of a HER3-targeted monoclonal antibody and a topoisomerase I inhibitor payload.10 HER3 is expressed in around 83% of NSCLC and is not implicated in resistance mechanisms to EGFR TKIs. 9 Thus, it represents a promising target to address the unmet medical need in EGFR-TKI resistant EGFR-mutated NSCLC.

Pasi Jänne, MD, PhD, Dana-Farber/Harvard Cancer Center, Boston, MA, shares the findings of a Phase I dose escalation/expansion study (NCT03260491) assessing the efficacy and safety of HER3-DXd in patients with locally advanced or metastatic EGFR-mutant NSCLC with prior EFGR TKI exposure.10 The recommended dose for expansion was established as 5.6mg/kg IV in the escalation portion. A total of 57 patients were treated at this dose level. All patients had received prior EFGR TKI therapy, predominantly osimertinib, and 91% also had prior exposure to platinum-based chemotherapy. After a median follow-up of 10.2 months, the overall response rate was 39%, with a median duration of response of 6.9 months. Disease control rate was 72%. HER3-DXd was shown to have a tolerable and manageable safety profile in this cohort, with the most common grade ≥3 adverse events being thrombocytopenia, neutropenia, and fatigue.

 

Responses were seen across a range of EGFR TKI resistance mechanisms, as well as in individuals where no known resistance mechanisms were identified. Additionally, when baseline HER3 membrane H-scores were assessed, responses were seen across the range of HER3 expression. The study is ongoing, with 32% of participants remaining on treatment at the data cut off. Further cohorts assessing various dosing regimens have also been enrolled. Additional studies of HER3-DXd in NSCLC are also underway, including a Phase I trial of HER3-DXd in combination with osimertinib and Phase II pivotal study (NCT04619004) of HER3-DXd in patients with EGFR mutant NSCLC following treatment failure with EGFR TKI and platinum-based chemotherapy.

5-year survival outcomes from the PACIFIC trial

 

The current standard of care for patients with locally advanced unresectable NSCLC is platinum-based doublet chemotherapy concurrent with radiotherapy. However, the prognosis for these patients remains poor, with a 5-year overall survival rate of around 15%.11 Various strategies have been investigated to improve this, including increased radiation dose, concurrent treatment with novel therapies, and the addition of novel cytotoxic or targeted agents for consolidation.

The Phase III placebo-controlled PACIFIC trial (NCT02125461) investigated the use of durvalumab as consolidation therapy following chemoradiation.12 Durvalumab is a selective, high-affinity, human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1), blocking its interaction with PD-1 and thus, enabling T-cells to recognize and kill tumor cells.

 
The PACIFIC trial investigating durvalumab as consolidation therapy in patients with unresectable stage III NSCLC that had not progressed after platinum-based chemoradiotherapy (CRT). Over 700 patients were randomized 2:1 to receive durvalumab or placebo every 2 weeks for 12 months, up to 42 days after their CRT. Primary results published in the New England Journal of Medicine in 2017 showed that durvalumab improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients whose disease had not progressed after CRT.12 The survival benefit demonstrated remained consistent throughout subsequent updates in the trial. Findings from the PACIFIC trial revolutionized the treatment landscape in this setting, establishing ‘the PACIFIC regimen’ as standard of care.13

At ASCO 2021, David R. Spigel, MD, Sarah Cannon Research Institute, Nashville, TN, presented updated OS and PFS analyses after 5 years of follow-up.13 The 60-month OS rates were 42.9% and 33.4% with durvalumab and placebo, respectively, consistent with the statistically significant benefit demonstrated in the primary analysis. Additionally, 60-month PFS rates were 33.1% and 19%. Durvalumab was found to have a manageable safety profile, and did not negatively influence patient-reported outcomes, compared with the placebo.

In conclusion, the 5-year findings from PACIFIC continue to support the use of durvalumab consolidation therapy, showing robust and durable survival benefits for patients with NSCLC following chemoradiotherapy. These results represent a new benchmark for the standard of care in the unresectable stage III NSCLC setting. Investigations into the PACIFIC regimen are ongoing, with several studies looking at durvalumab-based combinations after CRT, as well as with different CRT regimens.

Surgical outcomes from the Phase III CheckMate 816 trial

 
 Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor, disrupts PD-1 mediated signaling to help restore the anti-tumor immune response. Immunotherapy-based treatments have been revolutionary in oncology over the past decade, and nivolumab is now an important treatment option across numerous cancers.

While many early-stage non-metastatic NSCLC cases can be treated with surgery, recurrence after resection is common and thus, there is a growing interest in neoadjuvant and adjuvant approaches in lung cancer to improve long-term outcomes. Neoadjuvant nivolumab elicited substantial responses in a small study of patients with resectable lung cancer in 2018 (NCT02259621), which set off an explosion of clinical trials in this setting.

CheckMate 816 (NCT02998528) is a randomized Phase III study investigating the efficacy of nivolumab and platinum-doublet chemotherapy, compared to chemotherapy alone, as neoadjuvant treatments for patients with resectable NSCLC.14 The study involved over 350 adults with stage IB disease and no known EGFR/ALK alterations, who were randomized 1:1 to nivolumab 360 mg plus platinum-doublet chemotherapy or chemotherapy alone. Surgery was to be performed within 6 weeks of treatment. Primary endpoints for this study were pathological complete response (pCR) and event-free survival. Primary data reported in April 2021 showed that neoadjuvant nivolumab plus chemotherapy significantly improved pCR compared to chemotherapy alone (24% vs 2.2%, p<0.0001).15 CheckMate 816 is the first trial to show a significant pCR improvement with an immunotherapy combination in this setting.

At ASCO 2021, Jonathan Spicer, MD, PhD, McGill University, Montreal, Canada, shared the first presentation of the surgical outcomes from the CheckMate 816 trial.14 Surgery feasibility and surgery-related adverse events (AEs) were investigated as exploratory endpoints.

 

The study found that minimally invasive surgery rates were 30% and 22% and the conversion rates from minimally invasive to open surgery were 11% and 16% in the nivolumab arm and the chemotherapy only arm, respectively. Pneumonectomy was performed in 17% of patients who received the combination and in 25% of patients who received chemo alone. Furthermore, an R0 resection was achieved in 83% of those receiving nivolumab plus chemo, versus 78% of patients treated with chemotherapy alone and median residual viable tumor cells in the primary tumor bed were 10% vs 74% for nivolumab plus chemo vs chemo.

The findings from this exploratory analysis demonstrate that neoadjuvant nivolumab and chemotherapy did not impede feasibility or timing of surgery, nor the extent of completeness of resection when compared to chemotherapy alone. The surgical outcome data from CheckMate 816 in combination with a significant improvement in pCR, support nivolumab plus chemotherapy as a viable neoadjuvant treatment option for patients with stage IB to IIA resectable NSCLC.

References

  1. Goebel L, Muller M, Goody R, et al. KRasG12C inhibitors in clinical trials: a short historical perspective. RSC Med Chem. Jun 2020; 11(7): 760-770.
  2. International Association for the Study of Lung Cancer. Sotorasib Provides Durable Clinical Benefit for Patients with NSCLC and KRAS Mutations [Press release]. Jan 2021.
  3. Skoulidis F, Li B, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. [Conference presentation abstract]. ASCO 2021, 4-8 Jun 2021.
  4. Skoulidis F. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. [Conference presentation]. ASCO 2021, 4-8 Jun 2021.
  5. US Food & Drug Association. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC [Press release]. May 2021.
  6. US Food & Drug Association. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression [Press release]. May 2020.
  7. Wakelee H, Altorki N, Zhou C, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). [Conference presentation abstract]. ASCO 2021, 4-8 Jun 2021.
  8. Wakelee H. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). [Conference presentation]. ASCO 2021, 4-8 Jun 2021.
  9. Janne P. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). [Conference presentation]. ASCO 2021, 4-8 Jun 2021.
  10. Janne P, Baik C, Su W-C, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). [Conference presentation abstract]. ASCO 2021, 4-8 Jun 2021.
  11. Jain N, Otterson G. Immunotherapy in inoperable stage III non-small cell lung cancer: a review. Drugs Context. Jun 2019; 8:212578.
  12. Antonia S, Villegas A, Daniel D et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. Nov 2017; 377(20):1919-1929.
  13. Spigel D, Faivre-Finn C, Gray J, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial. [Conference presentation abstract]. ASCO 2021, 4-8 Jun 2021.
  14. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 Checkmate 816 trial: Nivolumab (NIVO)+ platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). [Conference presentation abstract]. ASCO 2021, 4-8 Jun 2021.
  15. Bristol Myers Squibb. Neoadjuvant Opdivo (nivolumab) Plus Chemotherapy Significantly Improves Pathologic Complete Response in Patients with Resectable Non-Small Cell Lung Cancer in Phase 3 CheckMate -816 Trial [Press release]. Apr 2021.

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