% ==============================================================================
% NSCLC Biomarker-Guided Cohort Efficacy Report
% Study ONCO-NSCLC-2024-0147 | Data Cutoff: 2025-09-15
% CONFIDENTIAL — De-identified per HIPAA Safe Harbor
% ==============================================================================
\documentclass[11pt,letterpaper]{article}

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\usepackage{enumitem}
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\lhead{\small\textcolor{cbGray}{CONFIDENTIAL — De-identified Data}}
\rhead{\small\textcolor{cbGray}{ONCO-NSCLC-2024-0147}}
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\begin{document}

% ==============================================================================
% PAGE 1: EXECUTIVE SUMMARY
% ==============================================================================
\thispagestyle{empty}

\begin{center}
{\LARGE\bfseries\color{cbBlue} Cohort Efficacy Report}\\[4pt]
{\large Biomarker-Guided Treatment Strategies in Advanced NSCLC}\\[2pt]
{\normalsize Study ONCO-NSCLC-2024-0147 \quad|\quad Phase 2, Multi-Arm \quad|\quad Data Cutoff: 2025-09-15}
\end{center}

\vspace{2pt}

% --- Report Info Box ---
\begin{tcolorbox}[colback=lightblue, colframe=cbBlue, title={\textbf{Report Information}}, fonttitle=\small\bfseries, boxrule=0.5pt, left=4pt, right=4pt, top=2pt, bottom=2pt]
\small
\begin{tabularx}{\textwidth}{@{}lXlX@{}}
\textbf{Document Type:} & Patient Cohort Analysis & \textbf{Population:} & Stage IIIB/IV NSCLC, treatment-naive \\
\textbf{Evaluable N:} & 25 (de-identified) & \textbf{Stratification:} & EGFR mutation $\times$ PD-L1 TPS \\
\textbf{Primary Endpoint:} & PFS per RECIST 1.1 & \textbf{Compliance:} & HIPAA Safe Harbor de-identified \\
\end{tabularx}
\end{tcolorbox}

\vspace{4pt}

% --- Key Finding 1: Primary Endpoint (Blue) ---
\begin{tcolorbox}[colback=lightblue, colframe=cbBlue, title={\textbf{Primary Endpoint: Progression-Free Survival}}, fonttitle=\small\bfseries, boxrule=0.5pt, left=4pt, right=4pt, top=2pt, bottom=2pt]
\small
\begin{itemize}[nosep, leftmargin=12pt]
\item \textbf{Osimertinib} (EGFR+, n=11): median PFS \textbf{16.2 months} (range 8.4--22.3); 3/11 PFS events
\item \textbf{Pembrolizumab + Chemo} (EGFR$-$, n=8): median PFS \textbf{10.9 months} (range 4.3--19.2); 4/8 PFS events
\item \textbf{Chemotherapy alone} (EGFR$-$/PD-L1 Low, n=6): median PFS \textbf{3.8 months} (range 2.4--5.2); 6/6 PFS events
\end{itemize}
\end{tcolorbox}

% --- Key Finding 2: Biomarker (Green) ---
\begin{tcolorbox}[colback=lightgreen, colframe=cbGreen, title={\textbf{Biomarker-Stratified Response Rates}}, fonttitle=\small\bfseries, boxrule=0.5pt, left=4pt, right=4pt, top=2pt, bottom=2pt]
\small
\begin{itemize}[nosep, leftmargin=12pt]
\item EGFR+/PD-L1 High (n=7): ORR \textbf{100\%} (1 CR, 6 PR), DCR 100\%, median TLC $-$39.8\%
\item EGFR$-$/PD-L1 High (n=6): ORR \textbf{100\%} (1 CR, 5 PR), DCR 100\%, median TLC $-$40.5\%
\item EGFR+/PD-L1 Low (n=4): ORR \textbf{75\%} (1 CR, 2 PR), DCR 100\%, median TLC $-$41.5\%
\item EGFR$-$/PD-L1 Low (n=8): ORR \textbf{0\%} (0 CR/PR), DCR 50\%, median TLC +6.0\%
\end{itemize}
\end{tcolorbox}

% --- Key Finding 3: Clinical Implication (Orange) ---
\begin{tcolorbox}[colback=lightorange, colframe=cbOrange, title={\textbf{Clinical Implications}}, fonttitle=\small\bfseries, boxrule=0.5pt, left=4pt, right=4pt, top=2pt, bottom=2pt]
\small
\begin{itemize}[nosep, leftmargin=12pt]
\item Biomarker-guided treatment assignment shows strong differentiation: EGFR+ and PD-L1 High subgroups achieve 100\% ORR regardless of overlap, while EGFR$-$/PD-L1 Low patients derive minimal benefit from chemotherapy alone (ORR 0\%, mPFS 4.4 mo).
\item PD-L1 expression $\geq$50\% in EGFR-WT patients predicts robust response to pembrolizumab-based combination therapy (ORR 100\%, mPFS 12.0 mo).
\item The EGFR$-$/PD-L1 Low subgroup represents an unmet need requiring novel therapeutic strategies.
\end{itemize}
\end{tcolorbox}

% --- Key Finding 4: OS Signal (Blue) ---
\begin{tcolorbox}[colback=lightblue, colframe=cbBlue, title={\textbf{Overall Survival Signal}}, fonttitle=\small\bfseries, boxrule=0.5pt, left=4pt, right=4pt, top=2pt, bottom=2pt]
\small
\begin{itemize}[nosep, leftmargin=12pt]
\item Median OS not reached in EGFR+ (1/11 events) or EGFR$-$/PD-L1 High (0/6 events) subgroups.
\item Chemo-only arm: median OS 10.1 months (6/6 events), consistent with historical benchmarks.
\item Overall cohort: median OS 18.9 months (8/25 events), data immature for definitive survival comparison.
\end{itemize}
\end{tcolorbox}

% --- Key Finding 5: Warning (Red) ---
\begin{tcolorbox}[colback=lightred, colframe=cbRed, title={\textbf{Limitations \& Caveats}}, fonttitle=\small\bfseries, boxrule=0.5pt, left=4pt, right=4pt, top=2pt, bottom=2pt]
\small
\begin{itemize}[nosep, leftmargin=12pt]
\item Small sample size (N=25); results are hypothesis-generating and not powered for confirmatory inference.
\item OS data immature with high censoring in targeted/IO arms; continued follow-up is required.
\item Non-randomized treatment assignment by biomarker status precludes direct cross-arm comparisons.
\end{itemize}
\end{tcolorbox}

\newpage

% ==============================================================================
% TABLE OF CONTENTS
% ==============================================================================
\tableofcontents
\newpage

% ==============================================================================
% SECTION 1: STUDY BACKGROUND
% ==============================================================================
\section{Study Background \& Objectives}

\subsection{Study Design}
ONCO-NSCLC-2024-0147 is a multicenter, open-label, Phase 2, multi-arm study evaluating biomarker-guided treatment strategies in patients with advanced (Stage IIIB/IV) non-small cell lung cancer (NSCLC) who are treatment-naive. Patients were stratified by EGFR mutation status and PD-L1 tumor proportion score (TPS) and assigned to one of three treatment arms:

\begin{itemize}[nosep]
\item \textbf{Arm A:} Osimertinib 80\,mg QD (EGFR-mutant patients, n=11)
\item \textbf{Arm B:} Pembrolizumab 200\,mg Q3W + carboplatin/pemetrexed (EGFR-WT, any PD-L1, n=8)
\item \textbf{Arm C:} Carboplatin/pemetrexed (EGFR-WT, PD-L1 $<$ 50\%, n=6)
\end{itemize}

\subsection{Objectives}
The \textbf{primary endpoint} is progression-free survival (PFS) per RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), and disease control rate (DCR).

\subsection{Biomarker Subgroups}
Four pre-specified subgroups based on the intersection of EGFR status and PD-L1 TPS:
\begin{enumerate}[nosep]
\item EGFR+ / PD-L1 High (TPS $\geq$ 50\%)
\item EGFR+ / PD-L1 Low (TPS $<$ 50\%)
\item EGFR$-$ / PD-L1 High (TPS $\geq$ 50\%)
\item EGFR$-$ / PD-L1 Low (TPS $<$ 50\%)
\end{enumerate}

% ==============================================================================
% SECTION 2: PATIENT DEMOGRAPHICS
% ==============================================================================
\section{Patient Demographics \& Biomarker Distribution}

\subsection{Baseline Characteristics}

\begin{table}[h!]
\centering
\caption{Baseline Patient Demographics (N=25)}
\label{tab:demographics}
\small
\begin{tabular}{@{}lcc@{}}
\toprule
\textbf{Characteristic} & \textbf{n (\%)} & \textbf{Detail} \\
\midrule
\textbf{Age, median (range)} & \multicolumn{2}{c}{63 years (46--75)} \\
\midrule
\textbf{Sex} & & \\
\quad Male & 13 (52\%) & \\
\quad Female & 12 (48\%) & \\
\midrule
\textbf{Race} & & \\
\quad White & 13 (52\%) & \\
\quad Asian & 8 (32\%) & \\
\quad Black & 4 (16\%) & \\
\midrule
\textbf{Histology} & & \\
\quad Adenocarcinoma & 21 (84\%) & \\
\quad Squamous & 4 (16\%) & \\
\midrule
\textbf{Smoking Status} & & \\
\quad Never & 12 (48\%) & \\
\quad Former & 9 (36\%) & \\
\quad Current & 4 (16\%) & \\
\midrule
\textbf{ECOG PS} & & \\
\quad 0 & 10 (40\%) & \\
\quad 1 & 13 (52\%) & \\
\quad 2 & 2 (8\%) & \\
\bottomrule
\end{tabular}
\end{table}

\subsection{Biomarker Distribution}

\begin{table}[h!]
\centering
\caption{Biomarker Stratification and Treatment Assignment}
\label{tab:biomarker}
\small
\begin{tabular}{@{}llccc@{}}
\toprule
\textbf{EGFR} & \textbf{PD-L1} & \textbf{n} & \textbf{Treatment Arm} & \textbf{EGFR Mutation Type} \\
\midrule
\multirow{2}{*}{Positive (n=11)} & High ($\geq$50\%) & 7 & Osimertinib & Exon19del (4), L858R (2), T790M (1) \\
 & Low ($<$50\%) & 4 & Osimertinib & Exon19del (2), L858R (2) \\
\midrule
\multirow{2}{*}{Negative (n=14)} & High ($\geq$50\%) & 6 & Pembro+Chemo & WT \\
 & Low ($<$50\%) & 8 & Pembro+Chemo (2), Chemo (6) & WT \\
\bottomrule
\end{tabular}
\end{table}

% ==============================================================================
% SECTION 3: PATIENT FLOW SCHEMATIC
% ==============================================================================
\section{Patient Disposition}

\begin{figure}[h!]
\centering
\begin{tikzpicture}[
    node distance=1.2cm and 1.8cm,
    box/.style={rectangle, rounded corners=3pt, draw=cbBlue, fill=lightblue,
                minimum width=3.2cm, minimum height=0.7cm, align=center, font=\small},
    armbox/.style={rectangle, rounded corners=3pt, draw=#1, fill=#1!10,
                   minimum width=3cm, minimum height=0.7cm, align=center, font=\small},
    decision/.style={diamond, draw=cbGreen, fill=lightgreen,
                     minimum width=2cm, minimum height=0.8cm, align=center, font=\small,
                     inner sep=1pt},
    arrow/.style={thick,->,>=Stealth, cbGray}
]
% Enrollment
\node (enroll) [box] {\textbf{Enrolled Cohort}\\N = 25};

% EGFR decision
\node (egfr) [decision, below=of enroll] {EGFR\\Status?};

% EGFR branches
\node (epos) [box, below left=1.2cm and 2.5cm of egfr] {\textbf{EGFR+}\\n = 11};
\node (eneg) [box, below right=1.2cm and 2.5cm of egfr] {\textbf{EGFR$-$}\\n = 14};

% PD-L1 for EGFR+
\node (pdl1pos) [decision, below=of epos] {PD-L1\\TPS?};
\node (ephigh) [armbox=osimBlue, below left=1cm and 0.8cm of pdl1pos] {\textbf{E+/PD-L1 Hi}\\n=7};
\node (eplow) [armbox=osimBlue, below right=1cm and 0.8cm of pdl1pos] {\textbf{E+/PD-L1 Lo}\\n=4};

% PD-L1 for EGFR-
\node (pdl1neg) [decision, below=of eneg] {PD-L1\\TPS?};
\node (enhigh) [armbox=pembroGreen, below left=1cm and 0.8cm of pdl1neg] {\textbf{E$-$/PD-L1 Hi}\\n=6};
\node (enlow) [armbox=chemoGray, below right=1cm and 0.8cm of pdl1neg] {\textbf{E$-$/PD-L1 Lo}\\n=8};

% Treatment labels
\node [font=\scriptsize\itshape, color=osimBlue, below=0.1cm of ephigh] {Osimertinib};
\node [font=\scriptsize\itshape, color=osimBlue, below=0.1cm of eplow] {Osimertinib};
\node [font=\scriptsize\itshape, color=pembroGreen, below=0.1cm of enhigh] {Pembro+Chemo};
\node [font=\scriptsize\itshape, color=chemoGray, below=0.1cm of enlow] {Pembro+Chemo (2) / Chemo (6)};

% Arrows
\draw [arrow] (enroll) -- (egfr);
\draw [arrow] (egfr) -- node[above left, font=\scriptsize] {Positive} (epos);
\draw [arrow] (egfr) -- node[above right, font=\scriptsize] {Negative} (eneg);
\draw [arrow] (epos) -- (pdl1pos);
\draw [arrow] (eneg) -- (pdl1neg);
\draw [arrow] (pdl1pos) -- node[left, font=\scriptsize] {$\geq$50\%} (ephigh);
\draw [arrow] (pdl1pos) -- node[right, font=\scriptsize] {$<$50\%} (eplow);
\draw [arrow] (pdl1neg) -- node[left, font=\scriptsize] {$\geq$50\%} (enhigh);
\draw [arrow] (pdl1neg) -- node[right, font=\scriptsize] {$<$50\%} (enlow);
\end{tikzpicture}
\caption{Patient disposition by biomarker stratification and treatment assignment.}
\label{fig:patient_flow}
\end{figure}

% ==============================================================================
% SECTION 4: EFFICACY RESULTS
% ==============================================================================
\newpage
\section{Efficacy Results}

\subsection{Objective Response Rate by Biomarker Subgroup}

\begin{table}[h!]
\centering
\caption{Best Overall Response by Biomarker Subgroup}
\label{tab:response}
\small
\begin{tabular}{@{}lccccccc@{}}
\toprule
\textbf{Subgroup} & \textbf{n} & \textbf{CR} & \textbf{PR} & \textbf{SD} & \textbf{PD} & \textbf{ORR (\%)} & \textbf{DCR (\%)} \\
\midrule
\rowcolor{lightblue} \textbf{Overall} & \textbf{25} & \textbf{3} & \textbf{13} & \textbf{5} & \textbf{4} & \textbf{64.0} & \textbf{84.0} \\
\midrule
EGFR+/PD-L1 High & 7 & 1 & 6 & 0 & 0 & 100.0 & 100.0 \\
EGFR+/PD-L1 Low & 4 & 1 & 2 & 1 & 0 & 75.0 & 100.0 \\
EGFR$-$/PD-L1 High & 6 & 1 & 5 & 0 & 0 & 100.0 & 100.0 \\
\rowcolor{lightred} EGFR$-$/PD-L1 Low & 8 & 0 & 0 & 4 & 4 & 0.0 & 50.0 \\
\midrule
\multicolumn{8}{l}{\textit{By EGFR Status}} \\
\quad EGFR+ & 11 & 2 & 8 & 1 & 0 & 90.9 & 100.0 \\
\quad EGFR$-$ & 14 & 1 & 5 & 4 & 4 & 42.9 & 71.4 \\
\midrule
\multicolumn{8}{l}{\textit{By Treatment Arm}} \\
\quad Osimertinib & 11 & 2 & 8 & 1 & 0 & 90.9 & 100.0 \\
\quad Pembro+Chemo & 8 & 1 & 5 & 1 & 1 & 75.0 & 87.5 \\
\quad Chemotherapy & 6 & 0 & 0 & 3 & 3 & 0.0 & 50.0 \\
\bottomrule
\end{tabular}
\end{table}

\subsection{Progression-Free Survival}

\begin{table}[h!]
\centering
\caption{Progression-Free Survival by Subgroup}
\label{tab:pfs}
\small
\begin{tabular}{@{}lcccc@{}}
\toprule
\textbf{Subgroup} & \textbf{n} & \textbf{Events} & \textbf{Median PFS (mo)} & \textbf{PFS Range (mo)} \\
\midrule
\rowcolor{lightblue} \textbf{Overall} & \textbf{25} & \textbf{13} & \textbf{11.9} & \textbf{2.4--22.3} \\
\midrule
EGFR+/PD-L1 High & 7 & 1 & NR$^{\dagger}$ (16.2) & 11.9--22.3 \\
EGFR+/PD-L1 Low & 4 & 2 & 15.2 & 8.4--21.4 \\
EGFR$-$/PD-L1 High & 6 & 2 & NR$^{\dagger}$ (12.0) & 9.8--19.2 \\
\rowcolor{lightred} EGFR$-$/PD-L1 Low & 8 & 8 & 4.4 & 2.4--6.1 \\
\midrule
\multicolumn{5}{l}{\textit{By Treatment Arm}} \\
\quad Osimertinib & 11 & 3 & NR$^{\dagger}$ (16.2) & 8.4--22.3 \\
\quad Pembro+Chemo & 8 & 4 & 10.9 & 4.3--19.2 \\
\quad Chemotherapy & 6 & 6 & 3.8 & 2.4--5.2 \\
\bottomrule
\multicolumn{5}{l}{\footnotesize $^{\dagger}$NR = Not Reached by Kaplan-Meier; descriptive median shown in parentheses.}
\end{tabular}
\end{table}

\subsection{Overall Survival}

\begin{table}[h!]
\centering
\caption{Overall Survival by Subgroup}
\label{tab:os}
\small
\begin{tabular}{@{}lcccc@{}}
\toprule
\textbf{Subgroup} & \textbf{n} & \textbf{Events} & \textbf{Median OS (mo)} & \textbf{OS Range (mo)} \\
\midrule
\rowcolor{lightblue} \textbf{Overall} & \textbf{25} & \textbf{8} & \textbf{18.9} & \textbf{7.3--28.4} \\
\midrule
EGFR+/PD-L1 High & 7 & 0 & NR (21.1) & 17.4--27.8 \\
EGFR+/PD-L1 Low & 4 & 1 & NR (21.9) & 14.6--26.3 \\
EGFR$-$/PD-L1 High & 6 & 0 & NR (20.5) & 16.5--28.4 \\
\rowcolor{lightred} EGFR$-$/PD-L1 Low & 8 & 7 & 11.0 & 7.3--13.9 \\
\midrule
\multicolumn{5}{l}{\textit{By Treatment Arm}} \\
\quad Osimertinib & 11 & 1 & NR (21.1) & 14.6--27.8 \\
\quad Pembro+Chemo & 8 & 1 & NR (19.2) & 11.2--28.4 \\
\quad Chemotherapy & 6 & 6 & 10.1 & 7.3--12.1 \\
\bottomrule
\end{tabular}
\end{table}

% ==============================================================================
% SECTION 5: WATERFALL PLOT
% ==============================================================================
\newpage
\subsection{Best Change in Target Lesion Size}

\begin{figure}[h!]
\centering
\begin{tikzpicture}[x=0.36cm, y=0.055cm]
  % Axes
  \draw[thick, ->] (-0.5,0) -- (26.5,0);
  \draw[thick, ->] (0,-110) -- (0,40);

  % Y-axis labels
  \foreach \y/\lab in {-100/-100, -80/-80, -60/-60, -40/-40, -20/-20, 0/0, 20/+20, 30/+30} {
    \draw (-0.3,\y) -- (0.3,\y);
    \node[left, font=\tiny] at (-0.5,\y) {\lab};
  }
  \node[rotate=90, font=\small] at (-3, -35) {Best \% Change from Baseline};

  % RECIST thresholds
  \draw[dashed, cbRed, thin] (-0.5, 20) -- (26.5, 20);
  \node[right, font=\tiny, cbRed] at (26.5, 20) {+20\% (PD)};
  \draw[dashed, cbGreen, thin] (-0.5, -30) -- (26.5, -30);
  \node[right, font=\tiny, cbGreen] at (26.5, -30) {$-$30\% (PR)};

  % --- Bars (sorted by TLC) ---
  % 1: DEID-003 -100.0 EGFR+/Low Osim
  \fill[osimBlue] (1,-100) rectangle (1.7,0);
  % 2: DEID-010 -100.0 EGFR-/High Pembro
  \fill[pembroGreen] (2,-100) rectangle (2.7,0);
  % 3: DEID-025 -100.0 EGFR+/High Osim
  \fill[osimBlue] (3,-100) rectangle (3.7,0);
  % 4: DEID-012 -55.8 EGFR-/High Pembro
  \fill[pembroGreen] (4,-55.8) rectangle (4.7,0);
  % 5: DEID-005 -51.3 EGFR+/High Osim
  \fill[osimBlue] (5,-51.3) rectangle (5.7,0);
  % 6: DEID-020 -47.2 EGFR+/Low Osim
  \fill[osimBlue] (6,-47.2) rectangle (6.7,0);
  % 7: DEID-008 -44.6 EGFR-/High Pembro
  \fill[pembroGreen] (7,-44.6) rectangle (7.7,0);
  % 8: DEID-002 -42.1 EGFR+/High Osim
  \fill[osimBlue] (8,-42.1) rectangle (8.7,0);
  % 9: DEID-022 -39.8 EGFR+/High Osim
  \fill[osimBlue] (9,-39.8) rectangle (9.7,0);
  % 10: DEID-007 -38.9 EGFR+/High Osim
  \fill[osimBlue] (10,-38.9) rectangle (10.7,0);
  % 11: DEID-021 -36.4 EGFR-/High Pembro
  \fill[pembroGreen] (11,-36.4) rectangle (11.7,0);
  % 12: DEID-004 -35.7 EGFR+/Low Osim
  \fill[osimBlue] (12,-35.7) rectangle (12.7,0);
  % 13: DEID-009 -33.2 EGFR-/High Pembro
  \fill[pembroGreen] (13,-33.2) rectangle (13.7,0);
  % 14: DEID-019 -31.6 EGFR+/High Osim
  \fill[osimBlue] (14,-31.6) rectangle (14.7,0);
  % 15: DEID-011 -29.1 EGFR-/High Pembro
  \fill[pembroGreen] (15,-29.1) rectangle (15.7,0);
  % 16: DEID-001 -28.4 EGFR+/High Osim
  \fill[osimBlue] (16,-28.4) rectangle (16.7,0);
  % 17: DEID-017 -14.5 EGFR-/Low Pembro
  \fill[pembroGreen!50!chemoGray] (17,-14.5) rectangle (17.7,0);
  % 18: DEID-006 -12.8 EGFR+/Low Osim
  \fill[osimBlue] (18,-12.8) rectangle (18.7,0);
  % 19: DEID-013 -8.4 EGFR-/Low Chemo
  \fill[chemoGray] (19,-8.4) rectangle (19.7,0);
  % 20: DEID-015 -5.2 EGFR-/Low Chemo
  \fill[chemoGray] (20,-5.2) rectangle (20.7,0);
  % 21: DEID-023 -3.1 EGFR-/Low Chemo
  \fill[chemoGray] (21,-3.1) rectangle (21.7,0);
  % 22: DEID-018 +15.2 EGFR-/Low Pembro
  \fill[pembroGreen!50!chemoGray] (22,0) rectangle (22.7,15.2);
  % 23: DEID-014 +18.3 EGFR-/Low Chemo
  \fill[chemoGray] (23,0) rectangle (23.7,18.3);
  % 24: DEID-016 +22.7 EGFR-/Low Chemo
  \fill[chemoGray] (24,0) rectangle (24.7,22.7);
  % 25: DEID-024 +28.4 EGFR-/Low Chemo
  \fill[chemoGray] (25,0) rectangle (25.7,28.4);

  % Legend
  \fill[osimBlue] (2,-108) rectangle (3,-104);
  \node[right, font=\tiny] at (3.2,-106) {Osimertinib (EGFR+)};
  \fill[pembroGreen] (10,-108) rectangle (11,-104);
  \node[right, font=\tiny] at (11.2,-106) {Pembro+Chemo};
  \fill[chemoGray] (18,-108) rectangle (19,-104);
  \node[right, font=\tiny] at (19.2,-106) {Chemo alone};
\end{tikzpicture}
\caption{Waterfall plot of best percentage change in target lesion size from baseline (N=25). Each bar represents one patient. Dashed lines indicate RECIST v1.1 thresholds for partial response ($-$30\%) and progressive disease (+20\%).}
\label{fig:waterfall}
\end{figure}

% ==============================================================================
% SECTION 6: BIOMARKER-RESPONSE CORRELATION
% ==============================================================================
\section{Biomarker--Response Correlation Analysis}

\subsection{EGFR Mutation Subtype Analysis}

Among the 11 EGFR-mutant patients treated with osimertinib:

\begin{table}[h!]
\centering
\caption{Efficacy by EGFR Mutation Subtype}
\label{tab:egfr_mutation}
\small
\begin{tabular}{@{}lcccccc@{}}
\toprule
\textbf{EGFR Mutation} & \textbf{n} & \textbf{ORR (\%)} & \textbf{DCR (\%)} & \textbf{Med PFS (mo)} & \textbf{Med OS (mo)} & \textbf{Med TLC (\%)} \\
\midrule
Exon 19 deletion & 6 & 100.0 & 100.0 & 17.9 & 25.2 & $-$49.3 \\
L858R & 4 & 75.0 & 100.0 & 14.8 & 20.5 & $-$38.3 \\
T790M & 1 & 100.0 & 100.0 & 11.9 & 17.4 & $-$31.6 \\
\bottomrule
\end{tabular}
\end{table}

Exon 19 deletion carriers demonstrated numerically superior outcomes across all efficacy endpoints compared to L858R, consistent with published literature (FLAURA trial subgroup analyses).

\subsection{PD-L1 as a Predictive Biomarker in EGFR-WT Patients}

In the EGFR-wild-type population (n=14), PD-L1 TPS $\geq$50\% was strongly predictive of response:

\begin{itemize}[nosep]
\item \textbf{PD-L1 High} (n=6, all pembrolizumab + chemo): ORR 100\%, mPFS 12.0 mo, mOS NR (20.5 mo descriptive)
\item \textbf{PD-L1 Low, Pembro+Chemo} (n=2): ORR 0\% (1 SD, 1 PD), mPFS 5.2 mo
\item \textbf{PD-L1 Low, Chemo alone} (n=6): ORR 0\% (3 SD, 3 PD), mPFS 3.8 mo, mOS 10.1 mo
\end{itemize}

PD-L1 TPS $\geq$50\% identifies a subpopulation of EGFR-WT NSCLC patients who derive pronounced benefit from pembrolizumab-based combination therapy, with a $>$3-fold PFS advantage over PD-L1 Low patients receiving chemotherapy.

\subsection{Cross-Biomarker Interaction}

\begin{table}[h!]
\centering
\caption{2$\times$2 Biomarker Interaction Summary}
\label{tab:interaction}
\small
\begin{tabular}{@{}l|cc@{}}
\toprule
 & \textbf{PD-L1 High ($\geq$50\%)} & \textbf{PD-L1 Low ($<$50\%)} \\
\midrule
\textbf{EGFR+} & ORR 100\%, mPFS 16.2+ mo & ORR 75\%, mPFS 15.2 mo \\
 & n=7, Osimertinib & n=4, Osimertinib \\
\midrule
\textbf{EGFR$-$} & ORR 100\%, mPFS 12.0+ mo & ORR 0\%, mPFS 4.4 mo \\
 & n=6, Pembro+Chemo & n=8, Chemo $\pm$ Pembro \\
\bottomrule
\end{tabular}
\end{table}

The data suggest that:
\begin{enumerate}[nosep]
\item In EGFR+ patients, PD-L1 status has \textbf{limited predictive value} --- osimertinib drives high ORR regardless of PD-L1 (100\% vs.\ 75\%, not statistically significant given small n).
\item In EGFR$-$ patients, PD-L1 $\geq$50\% is a \textbf{strong positive predictive biomarker} for immunotherapy benefit.
\item The EGFR$-$/PD-L1 Low subgroup represents the clearest \textbf{unmet medical need} with universally poor outcomes.
\end{enumerate}

% ==============================================================================
% SECTION 7: CLINICAL IMPLICATIONS
% ==============================================================================
\newpage
\section{Clinical Implications \& Recommendations}

\subsection{Evidence Summary}

\begin{tcolorbox}[colback=lightgreen, colframe=cbGreen, boxrule=0.5pt, left=4pt, right=4pt, top=4pt, bottom=4pt]
\small
\textbf{Recommendation 1 (GRADE 1B --- Strong, Moderate Quality):}\\
EGFR-mutant advanced NSCLC patients should receive osimertinib as first-line therapy irrespective of PD-L1 status. The observed ORR of 90.9\% and median PFS $>$16 months are consistent with Phase 3 data (FLAURA).

\vspace{4pt}
\textbf{Recommendation 2 (GRADE 1B --- Strong, Moderate Quality):}\\
EGFR-WT patients with PD-L1 TPS $\geq$50\% should receive pembrolizumab-based combination therapy. ORR of 100\% and mPFS of 12.0 months in this subgroup support guideline-concordant IO-chemotherapy combinations.

\vspace{4pt}
\textbf{Recommendation 3 (GRADE 2C --- Weak, Low Quality):}\\
EGFR-WT/PD-L1 Low patients represent an unmet need. Chemotherapy alone yields ORR 0\% and mPFS 3.8 months. Novel strategies (e.g., CTLA-4 combinations, ADCs, bispecific antibodies) should be explored in this population. Enrollment in clinical trials is strongly recommended.
\end{tcolorbox}

\subsection{Biomarker-Guided Treatment Algorithm}

\begin{figure}[h!]
\centering
\begin{tikzpicture}[
    node distance=1cm and 1.5cm,
    box/.style={rectangle, rounded corners=3pt, draw=#1, fill=#1!10,
                minimum width=3.5cm, minimum height=0.9cm, align=center,
                font=\small},
    dec/.style={diamond, draw=cbBlue, fill=lightblue,
                minimum width=1.5cm, minimum height=0.8cm, align=center,
                font=\small, inner sep=1pt},
    result/.style={rectangle, rounded corners=3pt, draw=#1, fill=#1!15,
                   minimum width=3cm, minimum height=0.8cm, align=center,
                   font=\small},
    arrow/.style={thick, ->, >=Stealth, cbGray}
]
% Start
\node (dx) [box=cbBlue] {\textbf{Advanced NSCLC}\\Newly Diagnosed};
\node (egfr) [dec, below=1cm of dx] {EGFR\\Mutation?};
\node (osim) [result=osimBlue, below left=1.2cm and 2.5cm of egfr] {\textbf{Osimertinib}\\ORR 90.9\%};
\node (pdl1) [dec, below right=1.2cm and 2.5cm of egfr] {PD-L1\\$\geq$50\%?};
\node (pembro) [result=pembroGreen, below left=1.2cm and 1cm of pdl1] {\textbf{Pembro+Chemo}\\ORR 100\%};
\node (unmet) [result=cbRed, below right=1.2cm and 1cm of pdl1] {\textbf{Clinical Trial}\\ORR 0\% w/ chemo};

\draw [arrow] (dx) -- (egfr);
\draw [arrow] (egfr) -- node[above left, font=\scriptsize] {Yes} (osim);
\draw [arrow] (egfr) -- node[above right, font=\scriptsize] {No} (pdl1);
\draw [arrow] (pdl1) -- node[left, font=\scriptsize] {Yes} (pembro);
\draw [arrow] (pdl1) -- node[right, font=\scriptsize] {No} (unmet);
\end{tikzpicture}
\caption{Proposed biomarker-guided treatment algorithm based on study findings.}
\label{fig:algorithm}
\end{figure}

\subsection{Recommendations for Continued Development}

\begin{enumerate}[nosep]
\item \textbf{Extended follow-up:} OS data remain immature in the osimertinib and pembrolizumab arms. Continued data collection until $\geq$50\% OS maturity is recommended before definitive survival claims.
\item \textbf{Expanded EGFR$-$/PD-L1 Low cohort:} Enrich this subgroup (n=8 currently) with novel combination strategies (e.g., anti-TIGIT, LAG-3, or antibody-drug conjugates) in an expansion cohort.
\item \textbf{Confirmatory study:} Given N=25, a larger randomized Phase 3 trial is warranted to confirm the biomarker-guided strategy, particularly the role of PD-L1 TPS $\geq$50\% as a treatment selection marker in EGFR-WT NSCLC.
\item \textbf{Biomarker refinement:} Evaluate TMB, STK11/KEAP1 co-mutations, and tumor-infiltrating lymphocyte density as supplementary predictive biomarkers in the EGFR$-$/PD-L1 Low subgroup.
\end{enumerate}

% ==============================================================================
% SECTION 8: STATISTICAL METHODS
% ==============================================================================
\section{Statistical Methods}

\begin{itemize}[nosep]
\item \textbf{PFS and OS:} Kaplan-Meier estimation with descriptive medians reported. Formal KM median reported as ``NR'' (not reached) where $<$50\% of patients experienced the event.
\item \textbf{Response rates:} ORR = (CR + PR) / N; DCR = (CR + PR + SD) / N, assessed per RECIST v1.1.
\item \textbf{Between-group comparisons:} Pre-specified for descriptive purposes only given the non-randomized design and small sample size. Fisher's exact test for response rates; log-rank test for time-to-event endpoints.
\item \textbf{Censoring:} OS censored at last known alive date; PFS censored at last adequate tumor assessment for patients without documented progression or death.
\item \textbf{Software:} Analyses performed per statistical analysis plan (SAP). No multiplicity adjustment applied to this exploratory Phase 2 analysis.
\end{itemize}

% ==============================================================================
% APPENDIX
% ==============================================================================
\newpage
\appendix
\section{Appendix: Individual Patient Data}

\begin{table}[h!]
\centering
\caption{Individual Patient Efficacy Data (N=25, sorted by target lesion change)}
\label{tab:ipd}
\tiny
\begin{tabular}{@{}llllccrrrr@{}}
\toprule
\textbf{ID} & \textbf{Subgroup} & \textbf{EGFR Mut} & \textbf{Arm} & \textbf{BOR} & \textbf{PD-L1 (\%)} & \textbf{TLC (\%)} & \textbf{PFS (mo)} & \textbf{OS (mo)} \\
\midrule
DEID-003 & EGFR+/Lo & Exon19del & Osim & CR & 5 & $-$100.0 & 21.4 & 26.3 \\
DEID-010 & EGFR$-$/Hi & WT & Pem+C & CR & 80 & $-$100.0 & 19.2 & 28.4 \\
DEID-025 & EGFR+/Hi & Exon19del & Osim & CR & 72 & $-$100.0 & 22.3 & 27.8 \\
DEID-012 & EGFR$-$/Hi & WT & Pem+C & PR & 92 & $-$55.8 & 14.5 & 23.7 \\
DEID-005 & EGFR+/Hi & Exon19del & Osim & PR & 70 & $-$51.3 & 18.6 & 24.1 \\
DEID-020 & EGFR+/Lo & Exon19del & Osim & PR & 8 & $-$47.2 & 17.1 & 23.9 \\
DEID-008 & EGFR$-$/Hi & WT & Pem+C & PR & 90 & $-$44.6 & 12.7 & 21.3 \\
DEID-002 & EGFR+/Hi & L858R & Osim & PR & 60 & $-$42.1 & 16.8 & 22.5 \\
DEID-022 & EGFR+/Hi & L858R & Osim & PR & 40 & $-$39.8 & 16.2 & 21.1 \\
DEID-007 & EGFR+/Hi & Exon19del & Osim & PR & 45 & $-$38.9 & 15.3 & 20.7 \\
DEID-021 & EGFR$-$/Hi & WT & Pem+C & PR & 88 & $-$36.4 & 11.3 & 19.6 \\
DEID-004 & EGFR+/Lo & L858R & Osim & PR & 2 & $-$35.7 & 13.2$^{*}$ & 19.8 \\
DEID-009 & EGFR$-$/Hi & WT & Pem+C & PR & 75 & $-$33.2 & 10.4$^{*}$ & 18.9 \\
DEID-019 & EGFR+/Hi & T790M & Osim & PR & 55 & $-$31.6 & 11.9$^{*}$ & 17.4 \\
DEID-011 & EGFR$-$/Hi & WT & Pem+C & PR & 65 & $-$29.1 & 9.8$^{*}$ & 16.5 \\
DEID-001 & EGFR+/Hi & Exon19del & Osim & PR & 85 & $-$28.4 & 14.1 & 18.2 \\
DEID-017 & EGFR$-$/Lo & WT & Pem+C & SD & 10 & $-$14.5 & 6.1$^{*}$ & 13.9 \\
DEID-006 & EGFR+/Lo & L858R & Osim & SD & 15 & $-$12.8 & 8.4$^{*}$ & 14.6$^{*}$ \\
DEID-013 & EGFR$-$/Lo & WT & Chemo & SD & 3 & $-$8.4 & 5.2$^{*}$ & 12.1$^{*}$ \\
DEID-015 & EGFR$-$/Lo & WT & Chemo & SD & 1 & $-$5.2 & 4.6$^{*}$ & 10.8$^{*}$ \\
DEID-023 & EGFR$-$/Lo & WT & Chemo & SD & 4 & $-$3.1 & 4.9$^{*}$ & 11.5$^{*}$ \\
DEID-018 & EGFR$-$/Lo & WT & Pem+C & PD & 6 & +15.2 & 4.3$^{*}$ & 11.2$^{*}$ \\
DEID-014 & EGFR$-$/Lo & WT & Chemo & PD & 8 & +18.3 & 3.1$^{*}$ & 9.4$^{*}$ \\
DEID-016 & EGFR$-$/Lo & WT & Chemo & PD & 12 & +22.7 & 2.8$^{*}$ & 8.2$^{*}$ \\
DEID-024 & EGFR$-$/Lo & WT & Chemo & PD & 2 & +28.4 & 2.4$^{*}$ & 7.3$^{*}$ \\
\bottomrule
\multicolumn{9}{l}{\footnotesize $^{*}$Event occurred (progression for PFS, death for OS). Unmarked = censored.} \\
\multicolumn{9}{l}{\footnotesize BOR = Best Overall Response; TLC = Target Lesion Change; Osim = Osimertinib; Pem+C = Pembrolizumab + Chemotherapy.} \\
\end{tabular}
\end{table}

\vfill

\begin{center}
\small\textcolor{cbGray}{\rule{0.6\textwidth}{0.4pt}}\\[4pt]
\textcolor{cbGray}{CONFIDENTIAL --- This document contains de-identified clinical trial data.}\\
\textcolor{cbGray}{All analyses comply with HIPAA Safe Harbor de-identification standards.}\\
\textcolor{cbGray}{Do not attempt to re-identify patients.}\\[4pt]
\textcolor{cbGray}{Study ONCO-NSCLC-2024-0147 \quad|\quad Report generated: \today}
\end{center}

\end{document}
