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New Combos at ASCO 2021
Global Perspectives on the Implications of Key New Data With Targeted Therapy Combinations in Solid Tumors From ASCO 2021

Released: August 05, 2021

Expiration: August 04, 2022

Dirk Arnold
Dirk Arnold, MD, PhD
James Larkin
James Larkin, PhD, FRCP
Prof Isabelle Ray-Coquard
Prof Isabelle Ray-Coquard, MD, PhD
Egbert F. Smit
Egbert F. Smit, MD, PhD
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At the 2021 American Society for Clinical Oncology (ASCO) annual meeting, exciting data from several clinical trials in solid tumors were reported. Below, global oncology experts Isabelle Ray Coquard, MD, PhD; Dirk Arnold, MD, PhD; Egbert F. Smit, MD, PhD; and James Larkin, PhD, FRCP, discuss the clinical relevance of some of the most important findings. The studies were covered online as part of CCO’s Independent Conference Coverage of ASCO 2021: An International Perspective. A downloadable slideset summarizing the data from these studies is available on the CCO website.

Phase II LEAP-004 Trial

James Larkin, PhD, FRCP:
Findings from the open-label, single-arm, international phase II LEAP-004 study were presented at ASCO 2021. LEAP-004 is evaluating lenvatinib plus pembrolizumab in 103 patients with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor. At a median study follow-up of 15.3 months, 17.5% of patients were still receiving lenvatinib and the overall response rate (ORR) remained the same as previous follow-ups at 21.4%; the number of complete responses (CRs) among patients increased by 1. Median duration of response (DoR), compared with the previous analysis, increased from 6.3 months to 8.3 months.

These are encouraging data for a difficult-to-treat population of patients with melanoma who have not had benefit or only temporary benefit from prior immunotherapy with anti–PD-1 or anti–PD-L1. To see a signal in this space is, without question, exciting. Lenvatinib is an interesting drug that has been around for a while, but the question is whether lenvatinib when given with pembrolizumab is really sensitizing patients to having further immunotherapy or not. The caveats of the study are the heterogenous group of patients and the nonrandomized trial design. Ideally, we would want to see some randomized data with more patients in this setting. Designing a phase III trial would have to consider what a randomized trial looks like, what the control arm would be, and what would be acceptable to clinicians and patients.

Phase III CheckMate -9ER Trial

James Larkin, MD, PhD:
In the phase III CheckMate -9ER trial, cabozantinib in combination with nivolumab is compared with sunitinib as a first-line treatment for advanced renal cell carcinoma (RCC). In this new, exploratory analysis presented at ASCO 2021, patient subgroups were prespecified based on the following baseline characteristics: International Metastatic RCC Database Consortium risk status (favorable-, intermediate-, or poor-risk disease), site of metastases (liver, bone, or lung), number of organ sites with tumor lesions (1 or at least 2), and size of tumor lesions (< or ≥ to the median). Across subgroups, median progression-free survival (PFS) was longer and ORR rates were consistently higher for patients treated with cabozantinib in combination with nivolumab compared with sunitinib. CR rates were also higher in most subgroups, ranging up to 16.3% for cabozantinib in combination with nivolumab vs 8.4% for sunitinib in the subgroup with a lower than median tumor lesion size.

It is very encouraging to see further data from this phase III study as it gives us confidence that this is a potentially useful treatment option for patients with metastatic renal cancer. There are a few options in this setting now and choosing between them is something that clinicians need to discuss carefully with their patients. It would be important to see further follow-up in due course as we really want to know what the long-term outcomes look like for efficacy—how many patients are still alive at 5 years. However, what we have seen so far is very encouraging for this combination.

Phase II EFFORT Trial

Isabelle Ray Coquard, MD, PhD:
This randomized, 2-arm, noncomparative phase II EFFORT trial is evaluating the efficacy of the Wee1 inhibitor, adavosertib, with or without olaparib, in overcoming poly-ADP-ribose polymerase (PARP) resistance in women with ovarian cancer. In a patient population with a median of 4 prior lines of therapy, a 23% ORR was seen with adavosertib and a 29% ORR with the combination. Toxicity led to dose interruptions in most patients, but grade 3/4 adverse events were considered to be manageable.

PARP inhibitors have become the backbone treatment in ovarian cancer, and we anticipate that giving chemotherapy after a PARP inhibitor will not be the best option for our patients. Exploring new options is very important, so this trial is interesting and innovative as it is looking at treatments after PARP inhibitors. The EFFORT study answers the question for patients who are progressing on PARP inhibitors, randomizing treatment between 2 options, the Wee1 inhibitor, adavosertib, vs the combination of adavosertib and olaparib. The objective is to see if the combination can reverse the resistance to the PARP inhibitor.

Interesting data were reported in terms of response rate for both the monotherapy and the combination. As it is a randomized phase II trial, there is no statistical comparison between the 2 arms. They reported also on BRCA-mutant and non-BRCA-mutant patient populations where we can see that the Wee1 inhibitor may be effective beyond BRCA, but as it is a small subgroup of patients, it is only a hypothesis at this stage. Regarding the safety profile, only 5% of the monotherapy patients and 10% of the patients in the combination arm discontinued treatment due to toxicity. However, we do see more toxicity with the combination arm, so we must be certain that this approach will improve the efficacy of the monotherapy. The ongoing translational research will really help us define if we move to monotherapy and for which patients. An important question for the future is looking at patients who have already received a PARP inhibitor but did not progress.

In summary, the outcome of this study holds promise for patients who have progressed on PARP inhibitor therapy. However, the trial did not report any median PFS or overall survival (OS), so it is too early to make any strong conclusions.

Phase I CHRYSALIS

Egbert Smit, MD, PhD:
The standard of care for patients with metastatic adenocarcinoma of the lung characterized by activating EGFR mutations is an EGFR receptor, tyrosine kinase inhibitor (TKI). Today, treatment with the third-generation EGFR TKI osimertinib is associated with a median PFS of more than 18 months when administered in first line of treatment. However, resistance to these agents invariably occurs, and treatment options at progression are limited to cytotoxic chemotherapy with or without immune checkpoint inhibitors.

Data presented from the phase I CHRYSALIS study at ASCO 2021 show that treatment with amivantamab, a fully human, bispecific antibody targeting EGFR and MET receptors in combination with lazertinib, a new, third-generation, irreversible EGFR TKI, led to a median DoR of 9.6 months in chemotherapy-naive patients with non-small-cell lung cancer (NSCLC) and EGFR exon 19 deletion or L858R mutations whose disease had progressed after treatment with osimertinib. The mechanisms of resistance of third-generation EGFR TKI, osimertinib, have been studied preclinically and clinically. Several genomic on-target alterations and signaling pathways have been implicated, among other bypass track signaling through another receptor tyrosine kinase, cMET. Cotargeting EGFR and cMET in the clinic upon progression of both first-generation and third-generation EGFR TKIs has been shown to be associated with relevant efficacy and manageable toxicity. Of importance, in these studies, patients were selected for either high cMET protein expression or cMET gene amplification.

The CHRYSALIS study included patients with metastatic adenocarcinoma of the lung with activating EGFR del19 or L858R mutations progressing on single-agent osimertinib. No other therapy was provided after the progressing event. Patients were treated with lazertinib, combined with amivantamab. The combination was found to be safe and associated with an ORR of 36% among the 45 included patients. Biomarker analysis, including next-generation sequencing on either tumor-derived DNA or ctDNA and cMET immunohistochemistry (IHC), produced some counterintuitive results. Consistent with the notion that monoclonal antibodies can only induce response when the target protein is expressed, the ORR in the patients who had tumor tissue available (n = 20) and EGFR/cMET H score >400 (n = 10) was 90% (9/10), in contrast to those IHC negative (n = 10) where the ORR was 10% (1/10). The molecular analyses did not reveal a consistent picture: The ORR in patients with EGFR/cMET-based resistance was not different in patients without such resistance mechanisms (47% vs 29%).

Based on the results presented, the combination of lazertinib and amivantamab requires further clinical evaluation. For instance, narrowing down on the relevant predictive biomarker is of importance as the competition in the post -space is increasing with agents that also have clinically relevant activity regardless of the mechanism of resistance, such as patritumab deruxtecan, an investigational, HER3-targeted antibody–drug conjugate.

Phase III KEYNOTE 811

Dirk Arnold, MD, PhD:
At ASCO 2021, the first data were presented from the KEYNOTE-811 phase III trial, a multicenter, randomized, double‑blind, placebo‑controlled trial in patients with HER2‑positive advanced gastric or gastroesophageal junction adenocarcinoma who had not previously received systemic therapy for advanced disease. On May 5, 2021, based on the prespecified interim analysis of the first 264 patients in this study, the FDA granted accelerated approval to pembrolizumab in combination with trastuzumab plus fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.

Treatment for patients with gastric and gastroesophageal junction cancer is a sensitive issue; the prognosis of patients is still poor, despite improvements with combination chemotherapy, and patients are susceptible to toxicity issues as most already have disease-related symptoms. Very few targeted approaches have succeeded, but the addition of trastuzumab to standard chemotherapy in patients with HER2-positive tumors has resulted in improved OS in patients with metastatic and/or incurable disease stages.

Keynote-811 is a highly pragmatic trial, adding a PD-1 antibody, pembrolizumab (or placebo), to a very practical chemotherapy standard of care, CAPOX, in combination with trastuzumab. First results from an interim analysis have shown that this strategy appears to be successful; 97% of the patients showed tumor shrinkage, and 1 out of 3 patients had a reduction of tumor volume of at least 80%, important for obtaining relief from tumor-related symptoms. The ORR is markedly higher for patients receiving pembrolizumab compared to chemotherapy/trastuzumab alone: 74% vs 52%. For the pembrolizumab arm, there was a very low increase of any toxicity, almost limited to infusion reaction only and no worsening of any other symptoms.

However, there needs to be caution around this promising signal; results are premature, and the current finding reports an interim analysis of a secondary endpoint. Only less than 40% (264 out of a planned total of 692) of patients are evaluated. Time-to-event parameters, like PFS and OS, are still under evaluation, and furthermore, the trial is still actively recruiting. There are some examples in gastrointestinal cancers that gains in response evaluations do not necessarily translate into an OS gain, which still should be the landmark of outcome parameters in advanced gastric or gastroesophageal junction cancers. Therefore, the European view of the FDA’s decision to grant accelerated approval based on these data is to be seen with interest, but also some caution. In summary, it is very likely that an overall benefit will be there, given the excellent toxicity profile and the potential synergy of an anti–HER2-mechanism with anti–PD-1/PD-L1 approaches, as shown preclinically and in other cancers. The key question is whether this interim result deserves such interpretation, which may also harm recruitment into the still open trial. 

Your Thoughts
What results reported at the ASCO 2021 annual meeting did you find most interesting? Join the conversation by leaving a comment below.

Remember to visit the CCO website to download a slideset summarizing the data from these studies and for more coverage of important new findings from recent major conferences.

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